NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Liver Fluke (Opisthorchis viverrini) in Southeast Asia: Can Transmission be Halted Through Mass Drug Administration?
Funder: Wellcome Trust

Abstract: Transmission of the human-infective and carcinogenic trematode Opisthorchis viverrini is ongoing in Southeast Asia. Despite decades of control, an estimated 10 million people are currently infected in Thailand and Laos. Determining which interventions will be most effective requires an understanding of fundamental epidemiological processes, many of which are poorly understood. Using longitudinal egg-count data and parasite population genomics, I propose to estimate anthelmintic efficacy, rates of reinfection, parasite migration within and between countries, and the role of zoonotic hosts (cats and dogs) on O. viverrini transmission. I will incorporate these processes into a predictive agent-based model which will allow the impact of interventions to be simulated. The model output will be informative to policy makers, and the results communicated to at-risk communities. In particular, I will investigate the impact of repeated mass treatment with praziquantel on parasite transmission, an approach that is currently being used on a large scale globally to control macroparasites. Whole-genome sequencing will be key to investigating O. viverrini population structure, migration rates and parasite relatedness between humans and other zoonotic hosts. Therefore, an improved O. viverrini reference genome will be produced with long-read sequencing, and methods to sequence parasites from non-invasive samples will be developed.

Lay Abstract: The parasitic worm Opisthorchi viverrini is largely unknown outside of endemic communities, however it causes a liver cancer which is among the leading causes of death in Northeastern Thailand and Laos. Ongoing efforts to control O. viverrini, which is contracted from eating raw fish, have involved health education and case treatment, though it is uncertain if these efforts are sufficient to eliminate the parasite. I propose to improve our understanding by applying modern statistical methods to diagnostic data collected on the parasite in Thailand and Laos. In addition, I will sequence DNA from worms in different locations to learn about how O. viverrini migrates between regions, and whether cats and dogs harbour the same parasites as humans. I will incorporate the findings into a model which can be used by policy makers to test the impact of different disease control measures, including large scale treatment with a deworming drug.

Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Living through the pandemic in post-Brexit Britain: emotional damage and forms of resilience among middle-aged European citizens
Funder: The British Academy

Abstract: This study examines the effects of  the Coronavirus epidemic and Brexit on the emotional wellbeing of middle aged European citizens who have transnational caring responsibilities in the UK and in Europe. This  qualitative research aims to produce an in-depth understanding of the participants’ emotional landscape and to explore how their sense of belonging in the UK has been eroded by this combination of factors. The disconnect engendered by Brexit and the forced estrangement from family in Europe have prompted many EU nationals  to return home causing a  loss of workforce for the UK economy at this crucial time of recovery.  This research will explore their experience to identify their needs and to highlight the resources they are using to adapt to the changes. The results will inform government at national and devolved levels to devise a strategy to retain their contribution by rebuilding a sense of home in Britain.


Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS
Health Categories: INFECTION;MENTAL HEALTH
Award Title: MICA: Childhood arthritis and its associated uveitis: stratification through endotypes and mechanism to deliver benefit; the CLUSTER Consortium.
Funder: Medical Research Council

Abstract: Juvenile idiopathic arthritis (JIA) and its associated eye inflammation, JIA-uveitis, can cause long-term disability and poor quality of life for children and well into adult life. Currently there are no validated tools with which to predict disease course or outcome, select treatment or predict response. Our proposal brings together internationally recognised leaders in childhood arthritis, JIA-uveitis, and bioinformatics, with industry, patient and clinical partners, as the CLUSTER consortium. Our goal is to define distinct 'endotypes' or 'strata' of childhood arthritis and JIA-uveitis, reflecting treatment response and disease course; integrate these with prognostic biomarkers; generate stratification algorithms, facilitate targeted treatment choices and propose new therapies. The specific scientific aims of CLUSTER are to:  1. Discover, replicate and validate biomarkers for prediction of treatment response to drive stratified medicine approaches in JIA and JIA-uveitis; 2. Identify mechanisms and pathways in JIA and JIA-uveitis to define novel therapeutic targets and facilitate stratification;  3. Identify disease and treatment-response strata with markers for stratification; 4. Work with industry partners to deliver new stratified clinical trials in JIA and/or JIA- uveitis.  CLUSTER will build on success of the MRC-funded consortium CHART comprising 5000 JIA cases with biosamples and data (clinical, genetic, omics), and include new cases and cohorts. Initial analyses will inform power calculations for proteome, transcriptome and immunome data generation. Integrated iterative analysis will define strata, biomarkers of response, and enable design of new clinical trials partnering with patients, clinicians and industry. Validated strata with robust predictive biomarkers for JIA and JIA-uveitis will lead to earlier control of inflammation, improved outcomes, reduced disability and exposure to side effects and generate long-term health care savings.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: EYE;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: MICA: Control of tumour cell apoptosis by nuclear F-actin bundling
Funder: Medical Research Council

Abstract: Fascin is an actin binding and bundling protein that is significantly up upregulated in most human cancers and contributes to metastasis. As fascin is not expressed in normal epithelial cells, it is a very attractive target for therapeutic intervention to halt tumour cell invasion. However, despite being discovered nearly 20 years ago and levels analysed in hundreds of cancers, we still know relatively little about the factors that control fascin function and this is a significant barrier to strategic development of therapies. Our recent published and unpublished data has revealed that fascin can associate with a number of previously undescribed binding partners and localizes to the cell periphery, nuclear envelope and inside the nucleus. Our exciting preliminary data has shown that nuclear localised fascin can regulate F-actin bundling within the nucleus, and when this phenotype is artificially enhanced, this results in commitment of tumour cells to apoptosis. The goal of the current study is to use a range of biochemical methods coupled with advanced cell-based imaging approaches to determine the molecular mechanisms that regulate nuclear fascin localisation under homeostatic conditions. In partnership with the major pharmaceutical company AstraZeneca, we will then employ a series of high-content, high resolution imaging screens to identify potential upstream regulators that can promote nuclear fascin and F-actin bundling leading to tumour cell death. These approaches combined will provide significant insight into novel mediators of fascin function and localisation, as well providing new tools and targets for modulators of nuclear F-actin. In the longer-term our goal is to use this information to develop new therapeutic strategies to target tumour cells and initiate cancer-specific cell death.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: MICA: Early Phase Dose-finding Trials: Development of reporting guidance to improve knowledge transfer
Funder: Medical Research Council

Abstract: Results from early phase dose-finding trials (Phase I or Phase I/II) directly influence decisions on further drug development and ultimately whether the selected dose(s) can be confirmed as safe and efficacious. Poorly reported dose-finding trials with inadequate rigour may lead to bias in reporting and lack of reproducibility. This wastes time and resources, but more importantly, may unethically expose participants to ineffective or even harmful interventions.  The main CONSORT Statement provides recommendations for reporting parallel group randomised trials, where participants are randomly assigned to different interventions. They do not address many methodological features such as interim dose-decisions (escalate, de-escalate, stay or stop) that arise in the design, conduct, analysis and interpretation of early phase dose-finding trials. The quality of reporting of such published trials is often inadequate. To address this unmet need and reduce research waste, we will  1. Extend the CONSORT reporting guidance for dose-finding trials to improve reporting, using gold-standard methods for developing consensus-based guidelines recommended by the CONSORT Group (Moher et al 2010) 2. Actively involve, engage and disseminate outputs to stakeholders, including trialists (clinicians, statisticians, trial managers), funders, regulators, patients and public, journal editors and peer reviewers. Besides scientific publications, we will also produce lay summary papers for the public and patient community.  Motivated by the desire to capture diverse views of experts across sectors with multidisciplinary roles, we have strategically brought together a team of national and international statistical methodologists and trialists (clinicians with drug discovery expertise and statisticians) in early phase trials in both academia and pharmaceutical industry, a CONSORT Group representative, a patient and public representative (PPI), with oversight from an Independent Expert Panel.


Research Activity Codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: MICA: Exploiting in silico modelling to address the translational bottleneck in regenerative medicine safety
Funder: Medical Research Council

Abstract: Successful clinical translation of regenerative medicine therapies requires robust preclinical tools for safety, immunogenicity and efficacy purposes.  We will develop a translational preclinical toolkit for the clinical translation of regenerative medicine therapies by combining in silico, in vitro and in vivo approaches. The current clinical translational bottleneck in liver cell therapy development concerns safe delivery of the cell therapy to the site of liver disease; protection of the delivered cells from the host immune systems; as well as ensuring successful cell engraftment and subsequent function at the injury site.  We will address this translational bottleneck by encapsulating cells in a biocompatible and biodegradable micromatrix.   Mathematical modelling in combination with state-of-the art experimental approaches will provide mechanistic understanding into the role of cell encapsulation in ensuring the safety, immune system evasion and efficacy of these next-generation liver cell therapies. We will develop predictive mathematical models that integrate data obtained from complementary in vitro and in vivo approaches thus providing a bridge from understanding gained through reductionist in vitro assays to in vivo animal models.   The quantitative and predictive approach will enable identification and optimisation of cell therapeutic approaches in terms of encapsulation protocols ensuring desired mechanical, anti-inflammatory, engraftment and functional properties and dosing regimens, thereby providing quantitative preclinical evidence for or against the use of encapsulation technologies.  This preclinical toolkit will therefore facilitate successful clinical translation of next-generation cell therapies for liver disease. The  in silico approach will have wider impact across the UKRMP Hub disease exemplars, such as lung and joint, and beyond into wider disease conditions, e.g. cardiovascular, by enabling translational bottlenecks to be overcome.


Research Activity Codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: MICA: Exploiting specialised pro-resolution molecule mediated analgesia to identify novel targets for the treatment of chronic pain
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is the leading cause of chronic pain. Specialised resolution molecules (SPMs) have robust analgesic effects in models of chronic pain, acting via microRNAs (miRNAs) to shut-down multiple pro-inflammatory signalling pathways to restore tissue homeostasis. Levels of the SPM precursor 17-HDHA are significantly associated with pain thresholds in healthy volunteers and levels of OA pain. Aim: to identify the miRNAs critical to the analgesic effects of the SPMs to provide new strategies for OA pain treatment. A clinical study will identify miRNAs associated with 17-HDHA levels and OA pain, with validation in people with diabetic neuropathy +/- pain. Bioinformatic analysis will categorise dataset commonality for the two conditions. Using a publicly available synovial fluid dataset we will focus on miRNAs both implicated in the effects of 17-HDHA and locally at the painful joint. The top 30 clinically relevant miRNAs will be mechanistically probed. Levels of 17- HDHA will be augmented in mice in the presence (and absence) of a clinically relevant model of OA pain behaviour, and blood levels of the top 30 clinically relevant miRNAs will be quantified to confirm which miRNAs are modified by 17-HDHA. Using microfluidic chambers for the culture of mouse sensory nerve axons we will quantify the effects of 17-HDHA on calcium (Ca2+) transients in cell bodies after axon terminals are stimulated with PGE2 plus capsaicin (to mimic hyperalgesia). The effects of manipulating (with inhibitors or mimics) 10-15 of the 17-HDHA modifiable miRNAs on evoked Ca2+responses (in the presence and absence of 17-HDHA) will confirm which miRNAs are essential for the inhibitory effects of 17- HDHA on sensory excitability. The identification of the clinically and functionally relevant miRNAs that underpin SPM_x0002_mediated natural analgesia will provide crucial mechanistic understanding which will underpin the development of novel approaches for treating chronic OA pain.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MUSCULOSKELETAL
Award Title: MICA: Investigating the role of the adenosinergic pathway in anti-tumour immune dysfunction in cutaneous squamous cell carcinoma (cSCC)
Funder: Medical Research Council

Abstract: Background Cutaneous squamous cell carcinoma (cSCC) is one of the commonest cancers worldwide, yet treatments for advanced cSCC are limited, with anti-PD-1 therapy giving complete responses in only 15% of patients. Recent evidence indicates the adenosine pathway contributes to immune dysfunction and poor clinical outcome in cSCC. Investigation of adenosine pathway inhibition in cSCC may lead to improved treatment for aggressive cSCC.  Aims To delineate the role of the adenosine pathway in dysfunctional cSCC immunity using adenosine pathway blockade, alone and with anti-PD-1, to enhance anti-tumour immunity. Objectives 1. Establish whether the effects of adenosinergic pathway inhibition in cSCC differ according to the target of blockade (i.e. CD39, CD73, A2AR). 2. Determine whether a combination of adenosinergic pathway antagonists is more effective than single agents at promoting anti-tumour immunity in this cancer.   3. Examine whether boosting anti-tumour immunity via the adenosinergic pathway is augmented by anti-PD1. Methods 1. Tissue slice culture (TSC) of ex vivo human cSCC will be performed separately with a CD39 inhibitor, anti-CD73 antibody, and an A2AR inhibitor. 10x single-cell RNA sequencing of lymphocytes and macrophages will delineate changes in individual cell types; immune cell functional state will be quantified using flow cytometry (FC), immunofluorescence (IF), supernatant cytokine analysis (SCA), and tumour cell killing (TCK) assays. 2. Tissue slice of cSCC cultured with simultaneous blockade of CD39, CD73 and A2AR, will be compared with single agent blockade and immune responses analysed with qPCR, FC, IF, SCA, and TCK assays.  3. Combined adenosine and PD-1 blockade of cultured cSCC slices will be analysed with qPCR, FC, IF, SCA, and TCK assays. Implications The results from this cSCC TSC project to investigate the adenosine pathway in cSCC immune dysfunction will help inform future clinical trials on cSCC immunotherapy.


Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health Categories: CANCER AND NEOPLASMS
Award Title: MICA: Large-Scale Vaccine Fill and Phase I Clinical Trial of the RH5.1/Matrix-M Vaccine against Blood-Stage Plasmodium falciparum Malaria
Funder: Medical Research Council

Abstract: The Need: Delivery approaches and platforms that can impart sustained and durable immunity are essential to the success of vaccines against a wide variety of difficult human diseases. Examples include seasonal respiratory viruses (such as influenza, RSV), emerging/pandemic pathogens (such as SARS-CoV-2) as well as parasites (such as Plasmodium - the causative agent of malaria). Rationale: We previously developed the first vaccine to show in vivo impact in humans against the disease-causing blood-stage form of the P. falciparum human malaria parasite. The vaccine (called RH5.1) targets the conserved and essential RH5 antigen used by the parasite to invade erythrocytes. With previous MRC DPFS funding support we successfully produced this novel recombinant protein to high yield using new platform biomanufacturing technologies, and with USAID funding, we tested RH5.1 formulated in AS01 adjuvant from GSK in a large Phase I/IIa trial in healthy UK adults. We identified a "delayed-fractional booster" immunisation regimen that dramatically improved the maintenance of the human antibody response over 2.5 years' follow-up, as compared to routine vaccine boosting at monthly intervals. Solution & Development Plan: We now propose to fill our remaining RH5.1 vaccine material (~250mg) to give a second vaccine batch. We will test this vaccine batch in a Phase Ia clinical trial in healthy UK adults in order to i) refine the vaccine delivery regimen, testing a delayed versus delayed-fractional booster regimen; and ii) to bridge to the new Matrix-M adjuvant, with our partner Novavax. RH5.1/Matrix-M offers the possibility of an efficacious blood-stage malaria vaccine that can proceed to future field efficacy testing, as well as a route to identification of a delayed-booster immunisation regimen that affords long-lasting human immunity. Importantly, this work will also exemplify robust vaccine platform delivery technologies that have broad applicability to a range of human diseases.


Research Activity Codes: 3.4 VACCINES
Health Categories: INFECTION
Award Title: MICA: Point-of-care assessment of drug-induced liver injury (POC-DILI)
Funder: Medical Research Council

Abstract: There is a significant unmet need for a rapid, quantitative, point-of-care (POC) biomarker assay to diagnose drug-induced liver injury (DILI) early after paracetamol overdose (POD) (primary context-of-use). Antidote treatment for POD is time-critical, being optimally effective if started within 8h of overdose and near ineffective if delayed >20h. Cytokeratin-18 (K18) is an accurate, early DILI biomarker. In contrast to the current standard, alanine aminotransferase (ALT), K18 can sensitively discriminate between patients with and without DILI within 8h of overdose. This enables prompt, targeted, treatment of patients in need.   To detect K18, and therefore DILI, a POC lateral flow assay (LFA), which detects biomolecules in a sandwich immunoassay format in <20mins, will be used. LFA uses a line of immobilised capture antibodies (CAb) and gold nanoparticles (AuNP) coated with a detection antibody (DAb). Capillary blood will be applied to the device and a sandwich complex formed between the two Ab and K18. This immobilises the AuNP on the LFA strip resulting in a red line.  The assay must be quantitative to allow patients with DILI to be identified with fit-for-purpose sensitivity and specificity. This will be achieved by using optically bright AuNPs coated with a Raman reporter and analysed using Surface Enhanced Raman Scattering (SERS). By illuminating the AuNP line with a handheld Raman reader, a SERS spectrum of the Raman reporter can be obtained. An algorithm developed by our industrial partner will produce a read-out that is easy to interpret at the time of measurement. In its primary context-of-use (supported by the National Poisons Information Service) this innovation will be used by a nurse or other healthcare professional to risk assess a POD patient at first presentation. Those with an increased risk of DILI could then receive immediate treatment. We envisage our assay being further refined for use in drug development and resource-limited settings.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INJURIES AND ACCIDENTS
Award Title: MICA: Targeting the RA synovial fibroblast via cyclin dependent kinase inhibition - a phase IIa study
Funder: Medical Research Council

Abstract: This project aims to repurpose a small molecule anti-cancer drug as an anti-fibroblast drug for RA. The past 20 years have seen major advances in RA therapy; more aggressive use of conventional drugs, and biological targeted therapies have each made a significant impact. However, disease remission remains uncommon and around 20% of patients remain refractory to all therapies. This represents a significant unmet need and suggests key aspects of RA pathogenesis remain untargetted. In health, a delicate nutritive synovial membrane (SM) lines joint cavities. This comprises a few macrophages and fibroblasts in a loose connective tissue stroma. In RA the SM is the focus of autoimmune attack but, in addition to inflammatory cell infiltration, resident synovial fibroblasts (SF) become hyperplastic, forming a vascularised, inflammatory, quasi-malignant pannus which invades articular cartilage and bone. The resultant joint damage underlies the disability and reduced quality of life that characterise RA. Cell proliferation relies on the coordinated activation of specific regulatory proteins: orderly progression through the cell cycle is tightly controlled by the formation and activation of complexes comprising cyclin proteins and cyclin-dependent kinases (CDK). These complexes are in turn regulated by endogenous CDK inhibitors (CDKI). The concept of inhibiting CDKs to correct uncontrolled cell proliferation has led to the evaluation of small molecule CDKI in cancer. RA SF have reduced endogenous CDKI levels, and correction of the deficit normalises their dysregulated phenotype. Indeed, small molecule CDKI ameliorate synovitis in pre-clinical arthritis models. In partnership with the SME Cyclacel, we propose a phase IIa repurposing study of a CDKI in patients with refractory RA. Stage 1 will focus on safety and tolerability, to determine an appropriate dose to progress to stage 2, where we will seek evidence of potential therapeutic activity alongside PK and PD biomarkers.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM