Biology subjects

Samson, A.

Publications and source records attributed to Samson, A..

10 recordsLinked to original sources

bioRxiv2025

Oncolytic Reovirus mediates innate-driven SARS-CoV-2 elimination in the absence of cell toxicity

Interplay between type I interferon (IFN) driven innate responses and viral antagonism strongly influences SARS-CoV-2 transmission and the COVID-19 disease course. Hence, variant adaptation includes diminished induction of IFN stimulated genes (ISG) and/or evasion of their effector functions. Exogenous IFN treatment "rewires" innate responses to drive virus elimination, yet therapeutic trials to date have been unremarkable. Resolving this paradox could translate to variant-agnostic innate immunotherapy. By contrast, oncolytic viruses (OV) exhibit profoundly attenuated innate antagonism, resulting in potent IFN responses despite the inherently immunosuppressive nature of tumour microenvironments. Moreover, OV only undergo lytic replication within innate-deficient malignant cells, and not in cells where sufficient innate responses exist. This, combined with previous studies showing that OV suppressed replication of underlying oncogenic viruses in tumours, we explored whether clinical grade oncolytic Orthoreovirus (Reo) superinfection could eliminate SARS-CoV-2 from immune-competent lung epithelial cell lines in the absence of toxicity. Reo exerted profound activation of innate responses, including when SARS-CoV-2 infection was already established, rewiring cells towards an antiviral state emulating that of Reo infection alone. Both intracellular and paracrine mechanisms induced ISG repertoires including multiple known anti-SARS-CoV-2 effectors, as well as others that remain unvalidated. Amongst these, we demonstrate the first direct evidence that MX2 and XAF1 restrict SARS-CoV-2 replication. Thus, with an excellent safety record, self-amplification, and respiratory tract tropism, we propose that Reo superinfection may provide a tractable alternative to recombinant cytokines for innate antiviral immunotherapy.

immunology↗

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↗

bioRxiv2025

DNA methylation and immune infiltration mediate the impact of tobacco exposure on pancreatic adenocarcinoma outcome: a high-dimensional mediation analysis

MotivationHigh-dimensional mediation analysis is critical for dissecting causal pathways in complex diseases. However, existing methods struggle to handle censored survival outcomes and unobserved confounders in epigenetic data. There is a pressing need for scalable, statistically robust frameworks to identify epigenetic mediators of exposure-outcome relationships, especially in cancer research where survival data are central and molecular pathways are highly complex and interconnected. ResultsWe introduce HDMAX2-surv, a two-step framework extending HDMAX2 to survival analysis. HDMAX2-surv integrates (i) latent factor modeling to adjust for unobserved confounders, (ii) flexible survival models (Aalen additive hazards and accelerated failure-time models). Simulations demonstrated superior performance over state-of-the-art methods (e.g., HIMA) in mediator selection and effect estimation. We integrated this approach with causal discovery frameworks and immune deconvolution algorithms to dissect multi-pathway mediation mechanisms. Applied to TCGA pancreatic adenocarcinoma data (n=112), HDMAX2-surv identified 36 aggregated methylated regions (AMRs) mediating tobacco exposure effects on survival, including immune-mediated pathways undetectable via gene expression alone. Availability and implementationHDMAX2-surv is implemented in R and available on GitHub (https://github.com/bcm-uga/tims-pdac), with documentation and example scripts for reproducibility.

bioinformatics↗

bioRxiv2025

Shivering, but not adipose tissue thermogenesis, increases as a function of mean skin temperature in cold-exposed men and women

Skin cooling results in the activation of heat generating mechanisms to counteract heat lost to the environment. Here, we aim to understand the extent that variations in cold-stimulated heat production may be driven by differences in the contribution of shivering and non-shivering thermogenesis (NST) and the interaction with biological sex. Using a novel mean skin temperature clamping technique in healthy men and women, our data shows that cold-stimulated heat production rises with increasing shivering and myocardial oxidative metabolism in a skin temperature-dependent fashion. Shivering and myocardial thermogenesis were also moderately associated. In contrast, adipose tissue NST did not increase in a linear manner to reductions in skin temperature. Men and women displayed similar thermoregulatory responses, although women presented more pronounced shivering through a greater recruitment of lower-body muscles and greater number of motor units recruited. Thus, shivering contributes proportionally to cold-induced thermogenesis whereas adipose tissue thermogenesis displays an all-or-none response.

physiology↗

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↗

bioRxiv2024

E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer

Human papillomaviruses (HPV) are a major cause of malignancy, contributing to [~]5% of all human cancers worldwide, including most cervical cancer cases and a growing number of ano-genital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited proliferation in vitro, whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we show that the LASP1 SH3 domain is essential for LASP1-mediated proliferation in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulated LASP1 mRNA levels by binding to its 3UTR. Finally, we demonstrated that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival role in cervical cancer, thus identifying a potential therapeutic target in these cancers.

cancer biology↗

bioRxiv2022

Biological Sex Influences the Contribution of Sign-Tracking and Anxiety-Like Behaviour toward Remifentanil Self-Administration

Most people sample addictive drugs, but use becomes disordered in only a small minority. Two important factors that influence susceptibility to addiction are individual differences in personality traits and biological sex. The influence of traits on addiction-like behaviour is well characterized in preclinical models of cocaine self-administration, but less is understood in regards to opioids. How biological sex influences trait susceptibility to opioid self-administration is likewise less studied than psychostimulants. Thus, we sought to elucidate how biological sex and several addiction-relevant traits interact with the propensity to self-administer the opioid remifentanil. We first screened female (n=19) and male (n=19) rats for four addiction-relevant traits: impulsivity, novelty place-preference, anxiety-like behaviour, and attribution of incentive value to reward cues. Rats were then trained to self-administer remifentanil in a "conflict model" of drug self-administration. Rats had to endure a mild electric shock to access the response manipulandum that triggered an intravenous infusion of remifentanil. In male rats, high anxiety-like behaviour was positively correlated with the number of drug infusions if the shock level was low or completely absent. In females, sign-tracking was predictive of greater resistance to punishment during drug seeking; an effect that was mediated by anxiety-like behaviour. Females consumed more remifentanil under all conditions, and their drug seeking persisted in the face of significantly greater current than males. These findings demonstrate that the influence of behavioural traits over the propensity to self-administer opioids is dependent upon biological sex.

neuroscience↗

bioRxiv2022

Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling

Persistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (KATP) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or KATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of KATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of KATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer.

microbiology↗

bioRxiv2022

A robust modular automated neuroimaging pipeline for model inputs to TheVirtualBrain

TheVirtualBrain, an open-source platform for large-scale network modelling, can be personalized to an individual using a wide range of neuroimaging modalities. With the growing number and scale of neuroimaging data sharing initiatives of both healthy and clinical populations comes an opportunity to create large and heterogeneous sets of dynamic network models to better understand individual differences in network dynamics and their impact on brain health. Here we present TheVirtualBrain-UK Biobank pipeline, a robust, automated and open-source brain image processing solution to address the expanding scope of TheVirtualBrain project. Our pipeline generates connectome-based modelling inputs compatible for use with TheVirtualBrain. We leverage the existing multimodal MRI processing pipeline from the UK Biobank made for use with a variety of brain imaging modalities. We add various features and changes to the original UK Biobank implementation specifically for informing large-scale network models, including user-defined parcellations for the construction of matching whole-brain functional and structural connectomes. Changes also include detailed reports for quality control of all modalities, a streamlined installation process, modular software packaging, updated software versions, and support for various publicly available datasets. The pipeline has been tested on both healthy and clinical populations and is robust to the morphological changes observed in aging and dementia. In this paper, we describe these and other pipeline additions and modifications in detail, as well as how this pipeline fits into the TheVirtualBrain ecosystem.

neuroscience↗

bioRxiv2018

Targeting hepatitis C virus p7 channel activity reveals prospect for bimodal antiviral prophylaxis

Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or \"viroporins\", contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery.\n\nWe describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.

microbiology↗