NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Recurrent somatic mutations in the cancerisation field effect of chronic liver disease
Funder: Cancer Research UK

Abstract: Background
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. 90% of HCC develops in patients with chronic liver disease (CLD); the causes of CLD are changing, with rapidly rising obesity and type 2 diabetes driving non-alcoholic fatty liver disease (NAFLD). Patients with CLD form a clear at-risk population for HCC development, amenable to early detection. The liver in CLD is marked by a cancerisation field effect; the mechanistic basis of this is unknown.

We hypothesised that it could be encoded at HCC-associated genomic loci. We used whole genome sequencing of non-malignant human CLD tissue, but did not find HCC-associated driver mutations. We identified recurrent somatic mutations in several disease-relevant genes, including FOXO1 (insulin and AMPK signalling) and ACVR2A (activin signalling), with evidence of convergent evolution in the same liver. Mutations in FOXO1 are at a single AMPK phospho-site and we have found that these mutations are functional.

Aims
We aim to understand the role of these recurrent somatic mutations in the cancerisation field effect of CLD, to understand HCC development. We hypothesise they will be:
1) Functional in diseased hepatocytes, leading to mechanistic insights into HCC pathogenesis;
2) Functional in mouse models of CLD, modulating development of HCC;
3) Identifiable in CLD patients, with potential as diagnostic and prognostic biomarkers.

Methods
In Work Package (WP) 1 we will develop novel in vitro models of these recurrent somatic mutations to understand the functional consequences of these mutations and why they provide a positive selective advantage to diseased hepatocytes. We will validate these findings in liver tissues from patients with CLD.

In WP2 we will develop novel mouse models with mosaic hepatocyte-specific Foxo1[mut] knock-ins and Acvr2a-knock-outs to understand their effect upon normal liver biology, their role in the development of CLD and HCC tumorigenesis. We will study the effect of mutant hepatocytes upon surrounding hepatocytes, non-parenchymal cells and systemic metabolism.

In WP3 we will develop novel assays identifying liver-derived recurrent somatic mutations in circulating cell-free DNA. We will use these assays in larger patient cohorts to understand their prognostic implications upon CLD and HCC development.

How the results of this research will be used
If successful, we will deliver:
1) A mechanistic understanding of recurrent somatic mutations in hepatocytes;
2) An understanding of the role of recurrent somatic mutations in mouse models of HCC development;
3) Novel assays to predict risk of HCC development in human CLD.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Refining, reducing and replacing non-model amphibian experiments on amphibian infectious diseases
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: With the urgent conservation issue posed by infectious diseases, licensed experimental


Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Regular as clockwork: the role of circadian rhythms in gut inflammation
Funder: Medical Research Council

Abstract: Inflammatory bowel disease (IBD) carries significant morbidity for 1% of the adult population. There is increasing evidence that circadian rhythms control chronic inflammation, although this has yet to be explicitly elucidated in gut inflammation. Aim 1: Assess the impact of colitis on the circadian clock The circadian clock temporally gates immune responses in the lung and joints. To determine the circadian clock's role in gut inflammation, samples will be collected from our mouse model of colitis at six time points across the circadian (24h) day and compared to healthy controls. I will characterise the extent of circadian dysfunction in colitis through analysis of clock function and gut inflammation at an RNA, protein and cellular level in addition to in vivo bioluminescent clock reporter technology.  Aim 2: Determine the impact of targeted clock disruption on the host with colitis I predict that disruption of core clock genes will worsen the colitis phenotype. Bmal1 is a core clock gene that can be disrupted systemically or locally in cells of interest such as intestinal epithelial cells. The impact of clock gene disruption on the oscillating transcriptome in health and colitis will provide valuable information on the specific pathways and cell types involved in clock-driven inflammation in the gut.  Aim 3: Determine whether time of day influences host response to IBD therapy Circadian expression of multiple drug targets has been shown in non-colon tissue. I will perform transcriptome analysis on healthy and inflamed colonic tissue to identify oscillations in drug targets. The group has previously shown colonic oscillations in gene expression of ppar-gamma, a drug target for the IBD therapy mesalazine. I will use mesalazine to treat the model of colitis at different time points, to coincide with peaks and troughs in PPAR-gamma expression and inflammation.  In gastroenterology, this potential chronotherapeutic approach is entirely novel.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: ORAL AND GASTROINTESTINAL
Award Title: Relative contributions of fructose bisphosphatase-1 (FBP1) and other possible mediators to the antihyperglycaemic action of salicylate
Funder: Diabetes UK

Abstract: Repurposing’ studies utilising salicylate (SA) analogues with improved side effect profiles, such as salsalate, are on the cusp of achieving clinical use in type 2 diabetes (T2D)
SA is one of few drugs believed to ameliorate insulin resistance, consequently SA has the potential by itself, or in support of people making lifestyle changes, to reverse/delay progression of T2D, associated complications, stress and anxiety. 
Clinical adoption of SA and selection of individuals for trial is hampered by incomplete understanding of drug mechanism. 
Recently, another T2D drug metformin, has been found to act through AMP-dependent regulation of fructose bisphosphatase-1 (FBP1) and it is possible that SA, through actions on the mitochondria, shares this action. 
To support properly targeted repurposing of SA, we will study the role of FBP1 in the SA mechanism, following the template established earlier for our award-winning studies on repurposing of metformin.
The outcome will be to define FBP1-dependent and independent actions of SA on glucose uptake, glucose production, anti-inflammatory effects on tissues, including protective effects of SA on kidneys, which could support use of SA in T2D with kidney disease, where metformin is contraindicated.
In future this information will enable selection of the individuals best suited to SA


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Reliable and Efficient Estimation of the Economic Value of medical Research (REEEVR)
Funder: Medical Research Council

Abstract: Value of Information (VoI) analysis is not regularly used by healthcare research funders or the National Institute for Health and Care Excellence (NICE) due to high skill requirements and computational demands. Regression/approximation to estimate Expected Value of Partial Perfect Information (EVPPI) have reduced skill requirements but are only reliable for simple cost-effectiveness models (CEMs). We developed multilevel Monte Carlo (MLMC) to reliably estimate EVPPI, but must be implemented in programming languages such as R or C++, making it inaccessible to Microsoft Excel users. We will develop an online tool for reliable and efficient EVPPI estimation in four workstreams. Workstream 1 will assess the limits of approximation/regression for EVPPI by comparing with gold standard Monte Carlo estimation. We will explore decision tree and Markov CEMs with increasing structural complexity, parameter dimension/correlation, and number of decision options. Workstream 2 will develop software to convert Excel CEMs to R/C++, which works by 'crawling' over the eXtended Markup Language (XML) and Visual Basic scrips underlying Excel CEMs to re-express the net benefit function in R/C++. Example CEMs will come be provided by our partners at NICE and Source Health Economics. We will encourage community extension by making all code publicly available and providing thorough documentation. Workstream 3 will develop R/C++ code for running MLMC on generic R/C++ CEMs. Workstream 4 will package the conversion and MLMC software as an easy-to-use online tool. Based on user-supplied information on the CEM and the findings of workstream 1 our tool will recommend if MLMC is required or if regression/approximation are sufficient.  These workstreams will be supplemented by a workstream collaborating with NICE and Source Health Economics to increase the use of our online EVPPI estimation tool, and a final workstream involving outreach to research funders to use VoI for research prioritisation.


Research Activity Codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Removing the marketing power of cigarettes: A multi-method study aimed at protecting the health of adolescents in Latin America
Funder: Medical Research Council

Abstract: Flavoured cigarettes may encourage young people to try smoking, start to smoke or continue to smoke. Growing market share for flavoured cigarettes in many Latin American countries is due to 'capsule cigarettes', which have frangible capsules in the filter that can be burst to change the flavour. There is limited research on capsule cigarettes, even though they appeal to youth and are a potential route into starting or continuing to smoke. In response to the growing importance of the cigarette stick as a promotional tool for tobacco companies, researchers have begun to explore ways of making the cigarette stick 'dissuasive', for instance by including health messaging and/or making it an unappealing colour. Our objectives are to understand: 1) how tobacco companies' market flavoured cigarettes in Latin America and the impact these have on the adolescent smoking attitudes, intentions, and behaviours, and 2) whether dissuasive cigarettes may deter adolescents from smoking. Three interlinked studies will be conducted in four Latin American countries where flavoured cigarettes have high market share (Argentina, Guatemala, Mexico and Peru). Each study will be conducted in the same four urban and rural locations in each country. In Study 1, we will use a codebook to record how flavoured cigarettes are promoted in retail outlets and via the cigarette pack and stick, and whether single cigarettes are sold. Study 2 will involve focus groups with adolescent smokers and non-smokers to explore their thoughts on flavoured and dissuasive cigarettes. Study 3 will use school surveys with an embedded discrete choice experimental design to assess whether cigarette stick design can influence the desirability of, and interest in, smoking. We will engage with our project partners, which include regional networks and the Ministries of Health in each country, and other key stakeholders, to help us interpret the results, refine a communication plan, and ensure the results are widely shared.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;RESPIRATORY;STROKE
Award Title: Replication-dependent histone pre-mRNA misprocessing and innate immune sensing
Funder: Medical Research Council

Abstract: Most antiviral responses are initiated by innate immune receptors that detect viral nucleic acid. Since the basic molecular structure of DNA and RNA is conserved across species, the existence of such receptors implies the necessity for mechanisms to avoid the sensing of self nucleic acids as non-self. The monogenic type I interferonopathies, disorders  associated with enhanced type I interferon signalling where such signalling is considered central to pathogenesis, emphasize the fundamental importance of nucleic acid signalling in the induction of type I interferon, and highlight the risks to human health of nucleic acid sensing as an antiviral strategy. One way to avoid a situation of type I interferon-mediated autoinflammation is to physically separate self nucleic acids from viral nucleic acid sensors. Thus, it was previously considered that the double stranded (ds) DNA sensor cyclic GMP-AMP synthase, cGAS, was exclusively confined to the cytosol. However, in a surprising recent finding, it has been shown that cGAS can be found within the nucleus, begging the question as to how genomic DNA does not trigger a potent type I interferon response. The present study builds on an observation that we have made, suggesting that chronic type I interferon activation can occur due to a disturbance of histone protein stoichiometry, and consequent abnormalities in chromatin state. As a corollary of this, we suggest that histones play an essential role in rendering nuclear DNA non-immunogenic. The overall goal of our proposal is to understand how a disturbance of chromatin histone composition leads to engagement of the type I interferon signalling machinery. To do this, we will take advantage of a unique patient resource, acquired over almost two decades. Additionally, we will derive a series of cellular tools that we can use to interrogate this question.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Reproductive and cardio-metabolic health
Funder: Medical Research Council

Abstract: Our aim is to provide the evidence base that will improve treatment success with IVF and enable stratified and effective antenatal care in IVF and spontaneous conceptions (SC). This is important because up to 40% or pregnancies are affected by one or more of miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, preterm birth or delivery or a small or large for gestational aged infant, but we do not know the best way of preventing these. IVF is now the commonest treatment for infertility with >250K IVF cycles completed per year in the UK and on average 1 in 30 primary school children were born as a result of in vitro fertilisation (IVF). Success rates vary by couple and treatment characteristics but are between 20-30%. There are suggestions that IVF per se, and pregnancy complications in IVF and SC have important adverse effects on future offspring cardio-metabolic health, but whether these associations are causal and if so their magnitude is unclear. Our objectives are to accurately predict and identify causal paths for: (i) response to IVF; (ii) healthy pregnancy and perinatal outcomes in IVF and SC; and (iii) offspring cardio-metabolic health.  Methods Our focus will primarily be on maternal smoking, physical activity, sleep patterns, adiposity, pregnancy metabolic profiles and fetal (cord-blood) DNA methylation as potential predictors or risk factors.  We will use data from detailed clinical and general pregnancy/birth cohorts. We will work with relevant consortia, including the EuroCHILD pan-European birth cohort that we are involved in establishing from 26 existing cohorts, early growth genetics (EGG) consortia, in which we co-lead maternal-offspring genetic analyses, the Genetics of Diabetes In Pregnancy (GENdip) consortia that we have recently developed, and the pregnancy/birth cohorts working group aligned to the Consortia Of METabolomics Studies (COMETS), which we lead, as well as the Pregnancy And Child Epigenetics (PACE) consortia, which we work closely with alongside Relton’s MRC Integrative Epidemiology Unit programme. We will triangulate results across the following analytical methods applied to these data sources: multivariable regression (MV), Mendelian randomization (MR), non-genetic instrumental variable (IV) analyses, within sibship and negative control studies.  Translation Building on our successful impact on clinical guidelines in the first five-years of this programme, we will continue to work with relevant clinicians, patient groups and NICE guideline developers. For new methodological developments we will provide and share datasets and code and widely disseminate these.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Reproductive function in teenage and young adult cancer patients in the UK
Funder: Medical Research Council

Abstract: The care of cancer patients increasingly recognises the multimorbidity that may result from treatment.  Loss of fertility is a prominent concern among patients, and while most do not lose their fertility, prediction at an individual level is difficult except at extremes of risk, and information on new treatments is very scarce. We will undertake a prospective analysis in teenage and young adult (TYA) male and female patients using the National Cancer Research Institute (NCRI)-linked network of treatment centres to address our hypothesis that cancer treatment and age affect fertility-related biomarkers and long-term reproductive health. This will generate an assessment of post-recovery reproductive function following contemporaneous and emerging treatment regimens, and prediction of that risk in individuals and patient groups. The primary endpoint is the prevalence of gonadal failure or dysfunction by diagnosis and treatment regimen at 2 years after diagnosis, with secondary longer-term outcomes. To determine this, we will recruit patients before starting treatment, and collect blood samples for endocrine analysis of gonadal function at that time, with detailed treatment data. Additional samples will be collected at 1, 2 and 3 years after diagnosis. We will recruit patients at presentation with a new cancer diagnosis, and also recruit patients previously treated who now present with a relapse.  This will increase the proportion of likely high-risk therapies and treatments with novel targeted therapies, on which there are currently minimal data relating to reproductive effects. The prospective design of the study allows for detection and adjustment for previous gonadal toxicity.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Reprogramming resolution in the arthritic joint
Funder: Versus Arthritis

Abstract: ‘…maximise the value of human tissue samples and resources while minimising duplication of effort. This requires better characterisation of tissue samples…and increased linkage to accurate clinical data. Sample collections must then be made more easily discoverable and accessible for use in high quality, ethical research’. To achieve this vision the Funders have highlighted the need for systems to make collections discoverable (Action 9). It also recognised the need for increased harmonisation of collection and storage of samples and the importance of public engagement around tissue donation for research.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Repurposing approved drugs as potent antiviral combinations to treat COVID-19 disease
Funder: Medical Research Council

Abstract: We hypothesise that antiviral drug combinations against SARS-CoV-2, suitable for oral or intranasal administration, will provide therapeutic opportunities for ambulatory COVID-19 patients that are more efficacious and with less propensity for the development of drug-resistant mutants.  We will address this hypothesis by exploiting a comprehensive robust multi-step pre-clinical in vitro and in vivo testing platform for novel drug combinations that ranges from HTS screening of unbiased combinations of drugs with known antiviral activities against SARS-CoV-2 and pharmacometrics to ensure potential for human use, to therapeutic efficacy models in SARS-CoV-2-infected well-differentiated primary human airway epithelial cell cultures (WD-PAECs) and animals (Syrian golden hamsters and hACE2 mice) with the most promising combination drug hits. Promising hits will be subjected to antiviral screening against a panel of variants of concern (VOCs) and endogenously circulating coronaviruses to ensure broad activity against SARS-CoV-2 VOCs and the potential for pan-CoV antiviral activities. We will extend this testing platform to non-biased screening of extensive approved drug libraries that have not previously been mined for drug combinations to treat COVID-19 with a view to ensuring a pipeline of future therapies against SARS-CoV-2. It should also be noted that we will make our pipeline available to the UK-CTAP to make recommendations for candidate evaluation. For this, a candidate/combination could enter evaluation at any WP that is appropriate given data that are available at the time. This project will provide comprehensive data to enable robust decision making regarding the entry of combination antiviral drugs hits into the UK COVID-19 clinical trial platforms or the de-prioritisation of drugs from further development.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health Categories: INFECTION
Award Title: Research and Training to create assets in the form of new companies to develop a new model to generate innovative therapies
Funder: Medical Research Council

Abstract: Cancer is an evolution machine. Decades before diagnosis, a multitude of different clones, carrying differential sets of mutations are setting the scene that makes almost any targeted therapy obsolete. The new era of personalised medicine and of immense knowledge of the genetics, epigenetics, gene expression, metabolomics, and clonal evolution of tumours, converges with the completion of flagship synthetic lethality studies, interrogating pan-cancer functional genomics. However, target discovery still focuses on finding targeted therapies against well-established cancer drivers from which cancer has already evolved out of, even years before diagnosis. This results in limited response rates in the clinic and quick evolution of resistance for targets against such drivers for example BRCA targeted PARP inhibitors. Our Approach: We are stopping the chase for moving targets by building a highly advanced drug discovery machine, that leverages the wealth of data of this new era to identify vulnerable mechanisms that cancer cannot evolve out of and the specific context in which they are effective. To achieve that, we identify cancer systems biology and specific mechanisms of irreversible cancer dependencies through advanced computational methods. Our current approach sets the bar very high, to produce complete and sustained therapeutic responses. We have invented methods that have already produced potential candidates with strong independent validation.My role will be to start as a Founder Analyst within DeepScienceVentures under their unique framework for venture creation. It's a part-time role. As a secondee, my goal is to join the host institution to create a company that will bring novel curative therapies to cancer patients. In order to make this successful, I will apply my skills sets of machine learning/artificial intelligence, understanding heterogeneity, developing patient based biomarkers and hands-on experience in preclinical trials.


Research Activity Codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health Categories: GENERIC HEALTH RELEVANCE