NIHRDataInsights/HRCSData huggingface dataset:
Award Title: The MyoScreen Study -  Investigating the Utility of Liquid Biopsy as a Method of Early Detection of Idiopathic Inflammatory Myopathy-Associated Cancer
Funder: Cancer Research UK

Abstract: Background
Autoimmune diseases are associated with increased cancer risk and poor outcomes. Early autoimmune-associated cancer diagnosis is vital but under-researched. Blood-based liquid biopsy provides an opportunity for early autoimmune disease-associated cancer diagnosis, potentially improving outcomes. Proof of concept of added benefit of liquid biopsy is vital, however autoimmune disease heterogeneity makes multi-disease research challenging. 
Idiopathic inflammatory myopathy (IIM) represents an ideal condition in which to investigate proof of concept of utility of liquid biopsy as a method of early autoimmune-associated cancer diagnosis.
IIM is a chronic multisystem autoimmune condition predominantly manifesting with muscle inflammation (myositis). One in four adults with IIM are diagnosed with cancer (multiple organs) within three years either side of IIM onset and outcomes are poor (17% remission rate). Research demonstrates significant beneficial survival impact of earlier diagnosis of IIM-associated cancer.

Aim
The MyoScreen study aims to carry out preliminary investigation into the utility of liquid biopsy as a method of early cancer detection in newly diagnosed IIM patients, thus generating pilot data for grant applications to fund a large international longitudinal study. 

Methods
Cohort
Thirty adult participants with new onset (<​6 months) IIM will be recruited from specialist IIM clinics in Salford Royal Hospital, University College London Hospital, and via the National Institute for Health Research Musculoskeletal Translational Research Collaboration (15 UK-wide research active centres). 
Data collection
Participants will undergo blood-based liquid biopsies at the time of recruitment and after six months for circulating tumour DNA detection by the Nucleic Acid Biomarker Team at the CRUK Manchester Institute Cancer Biomarker Centre. Participants will also undergo standard of care "multi-modality" cancer screening at recruitment.
Analysis
Analysis will aim to identify “concordance” of cancer diagnoses between liquid biopsy and conventional "multi-modality" screening. Added benefit of liquid biopsy will be assessed by ability of liquid biopsy to identify early-stage cancer in patients where conventional screening has not.  

How results will be used
- Provide preliminary evidence for future grant applications for a longitudinal study in >100 international adult IIM participants. 
- Stimulate research into liquid biopsy as a method of early autoimmune-associated cancer detection.
- Establish a new onset IIM UK-wide recruitment network, facilitating future research.
- Earlier IIM-associated cancer diagnosis, thus potentially improving survival.
- Establish collaborative partnerships outside non-traditional cancer fields (i.e. IIM, rheumatology, autoimmunity).


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: The New Jerusalems: post-war New Town archives in Britain and Ireland
Funder: Wellcome Trust

Abstract: The project will make accessible for research eleven archives from post-war new towns in England, Wales and Ireland.  Eight of these archives will be catalogued and all will be safeguarded through conservation and preservation work.  The new towns included are: Basildon, Bracknell, Crawley, Cwmbran, Newton Aycliffe, Peterlee, Redditch, Runcorn, Shannon, Stevenage and Warrington.The archives are held by nine partner organisations brought together through the Association of New Towns Archives and Museums.  The Association builds on existing academic partnerships, and this project will develop those further.  Key outcomes include not only itemised catalogues and protected collections, but also a collaborative dissemination programme.This project will provide a substantial increase in the evidence base available for researchers seeking to interrogate the new towns’ legacy. The project is particularly timely in the context of the current public health emergency.  New towns have much to contribute to current policy making in urban planning and public health including: new homes to reduce overcrowding; generous public green space; amenities within 15 minutes of the home; and supporting walking and cycling. There is renewed interest in many aspects of new town design as plans are made for social recovery in the aftermath of Covid-19.


Research Activity Codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: The Nomenclature of Human and Vertebrate Genes
Funder: Wellcome Trust

Abstract: As human genomics is already a crucial aspect of biomedicine, with increasing importance in clinical practice and everyday life, communicating in a common language about genes becomes ever more vital. The HUGO Gene Nomenclature Committee (HGNC) is the sole worldwide authority assigning standardised nomenclature to human genes, and maintains a searchable database of over 40,000 named human genes at www.genenames.org. This funding will enable the continuance of the crucial work of the HGNC, in particular naming newly identified protein-coding and RNA genes and pseudogenes. A further key activity will be the reassignment of genes with uninformative identifiers to function-based names as this information is elucidated. The HGNC will also continue to play a pivotal role in consensus annotation of the remaining unresolved gene structures in the human genome. HGNC recently established the Vertebrate Gene Nomenclature Committee (VGNC, vertebrate.genenames.org), a sister project for naming genes in other vertebrates utilising data from phylogenetic resources and in collaboration with specialist advisors for complex gene families

Lay Abstract: Effective communication between scientists, healthcare professionals and the general public is vital to unlocking the wealth of information encoded in the human genome. Our genome contains thousands of genes, many of which encode proteins, the building blocks of life; each gene needs a unique name and symbol (an abbreviation of the name). The HUGO Gene Nomenclature Committee (HGNC) is the only group worldwide giving names and symbols to human genes. The HGNC's freely available online database (www.genenames.org) lists all human genes with a standardised name; users can find relevant information about these genes and link out to many other online resources, for example to find out the health consequences of alterations in a gene, and identify similar genes in human and other species. As many animal's genomes are being sequenced the HGNC will also name their genes in a similar way (catalogued at vertebrate.genenames.org), to enable comparisons of different genomes.

Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: The Peek Practice-based Evidence Framework
Funder: Wellcome Trust

Abstract: Health system strengthening, as endorsed by the WHO’s global action plan for universal eye health, facilitated a 25% reduction in global visual impairment between 1990 and 2015.  New mobile health technologies have potential to greatly enhance systems strengthening, driving further revolutionary improvements in eye care.
 
Currently, lack of detail in health system data and delayed information flows results in sporadic health systems’ improvement rarely founded on locally derived evidence. Testing single changes typically requires classical research studies, often taking years to produce results, by which time the environment may have changed, causing study data not informing change in practice.
 
In the commercial software sector, a variety of testing methodologies are employed to develop and optimise web-based systems. Learning from these, we propose developing a hypothesis-driven, agile health service improvement approach enabling responsive changes to eye care service systems (our specific field) in low- and middle-income countries. This will use techniques including A/B testing and data-driven perpetual optimisation.
 
These hypothesis-driven methodologies will allow quicker testing, analysis and implementation of service improvements with greater potential for translation to other settings.  Used by local health system leaders, the tools could lead to a paradigm change in health system strengthening, improving health for millions.

Lay Abstract: Worldwide, over 250 million people are blind or have low vision, 90% in low- and middle-income countries.  Yet 75% of cases are avoidable, largely through cost-effective, proven treatments. Why do so many live with poor vision when treatments exist in most cases?
 
One reason is that health services cannot access the information they need to improve.  Understanding the impact of changes requires resource-intensive clinical trials, which can take years.  This leads to entrenched inefficiency and poor outcomes, simply because understanding which improvements work is so challenging.
 
We are developing a new way to test improvements to health services based on strategies from software development.  It will allow services to rapidly test and optimise changes, so their impact can be understood in months, not years.  If successful, this approach will enable eye health services to adapt and improve far quicker than before, ultimately strengthening them and improving outcomes for patients.

Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: EYE
Award Title: The Pluripotent Stem Cells and Engineered Cell (PSEC) Hub
Funder: Medical Research Council

Abstract: We will deliver a platform of technologies and expertise that will enable new human pluripotent stem cell (hPSC) based therapies to more readily enter the clinic. This will be done around 2 major therapeutic areas - hPSC derived dopaminergic neurons and megakaryocytes. These exemplars will contextualise the overarching aim of the hub which is to further understand and develop the next generation of genetic and reprogramming tools needed to allow ANY hPSC-based product to progress to clinic. This will be done through 3 major research programmes: THEME 1 - CELL CHARACTERISATION AND STABILITY: We will assess the phenotypic consequences of specific genetic variants using our clinical exemplars, while also developing sensitive high-throughput detection methods for genetically variant cells. We will the use this information to optimise culture conditions to suppress the appearance of concerning genetic variant, while also producing lists of non-consequential genetic variants that we detect which we will then feed into international guidelines for adoption by relevant regulatory agencies. THEME 2 - IDENTIFYING AND MODELLING KEY DETERMINANTS OF MANUFACTURING OUTCOMES FOR HPSC PRODUCTS AND PROVIDING A REGULATORY ROADMAP: We will address issues to do with manufacturing cells in the quantity and the quality required, for clinical adoption using dynamic process models as well as novel protocols and reagents. This will include a pathway for regulatory integration, to facilitate clinical application and first in human studies. THEME 3 - UNDERSTANDING ROUTES TO DIFFERENTIATION: We will develop a new generation of genetically modified hPSCs with improved differentiation capabilities including purity, cell yield and reduced dependence on expensive media and/or complex cytokine cocktails as well as reducing their immunogenicity such that they can more easily be employed in the clinic without the need for major immunosuppressive anti-rejection therapies and their associated risks.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);5.2 CELLULAR AND GENE THERAPIES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health Categories: NEUROLOGICAL;BLOOD;GENERIC HEALTH RELEVANCE
Award Title: The Role Of Myosin Light Chain Kinase 3 (Mylk3) In Dilated Cardiomyopathy
Funder: Barts Charity

Abstract: The grant will support a Post Doctoral scientist to further investigate a variant in Myosin light chain kinase 3 (Mylk3), a protein involved in the development of dilated cardiomyopathy (DCM), a condition that reduces the capability of the heart to eject blood and can eventually lead to heart failure. The team has collated preliminary data and hypothesises MYLK3 to be a key regulator of post-translational modifications in many proteins which are known to cause DCM in humans, and presents an exciting potential target for patient therapy. The findings will support an application to the British Heart Fundation to further develop the work.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CARDIOVASCULAR
Award Title: The Role of Membrane Attack Complex in Atypical Haemolytic Uraemic Syndrome
Funder: Medical Research Council

Abstract: Atypical haemolytic uraemic syndrome (aHUS) encompasses the triad of; haemolytic anaemia, thrombocytopenia, and renal failure. Tremendous advances led by the Newcastle group has shown aHUS arises due to dysregulation of the alternative pathway of the complement system.  The complement system is a complex series of proteins that results in an enzymatic cascade culminating in activation of the terminal pathway, producing C5a and Membrane attack complex (MAC). These two components whilst protecting self can injure cells and local tissues through their pro-inflammatory and lytic roles; thus are implicated in numerous diseases.  We know that aHUS is driven by complement dysregulation of the terminal pathway evidenced by the successful treatment of aHUS patients with a C5 convertase inhibitor. However, this treatment silences the terminal pathway in its entirety, predisposing vulnerable patients to infections and the cost of therapy prevents access to all.  We do not currently know which protein plays the critical role in the development of aHUS. I have developed a novel murine model of aHUS engineered around a mutation in complement C3 from our aHUS patient cohort. My data clearly shows that my murine model absolutely mirrors aHUS in man, and ongoing experiments confirm the critical nature of C5. I therefore will determine the role of MAC and C5a in aHUS. The increased understanding of MAC and C5a in complement mediated renal disease will enable me to deliver targeted therapies for patients.  I seek to investigate the roles of C5a and MAC in aHUS by rescuing the phenotype of the C3 gain of function D1115N mouse model of aHUS by blocking the terminal pathway: a.) by breeding onto the C5-/- strain  b.) through the use of a murine C5 inhibitor c.) by breeding onto a C6 deficient mouse (no MAC). I will assess the role C5a in the model: a) through breeding the D1115N mouse with the C5AR1-/- & C5ALR-/-  mice  b) therapeutic inhibition using the C5aR1 antagonist.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: RENAL AND UROGENITAL
Award Title: The T6SS as a search engine for naturally validated antibacterial targets
Funder: Medical Research Council

Abstract: The type VI secretion system (T6SS) is an antimicrobial weapon used by Gram-negative bacteria to inject toxins into competitors, restricting their growth to benefit scarce resources. The T6SS toxins, and their cognate immunities, identified so far are phospholipase, DNase or peptidoglycan hydrolase. We consider the T6SS as a gold mine for the search of novel antimicrobial activities since bacteria competed for billions of years and evolved unexpected strategies. Since toxin/immunity (TI) pair genes are only occasionally found genetically linked to T6SS genes, we developed an unbiased approach using transposon mutagenesis and sequencing (TraDIS) to search for T6SS immunity genes in Pseudomonas aeruginosa and characterize the associated T6SS toxins. This was possible using a mutant systematically activating its 3 T6SSs and all associated TI genes as we published recently (Allsopp et al., PNAS, 2017). Our screen is validated by the identification 12 of the known TI pairs, e.g. Tse2/Tsi2; Tle5a/Tli5a. We started to characterize Tse8/Tsi8, which we propose targets the transamidosome and impairs protein synthesis in organisms using this complex to load Asn/Gln on tRNA. We also point at an extra 7 putative novel TI pairs which we believe have original biochemical activity and would direct us toward novel targets. Our proposal shall provide a global vision of the P. aeruginosa's T6SS toxins and antimicrobial strategy which could be mimicked in treatment of resistant bacteria and thus be in the future considered for antimicrobial research. We took the opportunity of having implemented the TraDIS approach to screen for mutants resistant/sensitive to T6SS attack in an immunity-independent manner. The exploitation of these data combined with a "resistance" evolution approach where serial contact of a T6SS-immunity deficient strain with a T6SS attacker result in acquired resistance would take us into an unexplored and ground-breaking area of the T6SS bacterial warfare.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: The clinical impact of inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6): a comprehensive analysis using UK Biobank
Funder: Medical Research Council

Abstract: Human herpesvirus 6A and 6B have the unusual ability to integrate into telomeres of human chromosomes and, in some people, viral genomes are present in the germline, giving rise to inherited chromosomally integrated HHV-6 (iciHHV-6). iciHHV-6 has the potential to cause disease through viral reactivation and by interfering with telomere function. We know that iciHHV-6 can reactivate in vivo, and analysis of two cohort studies has shown an association with an increased risk of angina. However, the overall impact of iciHHV-6 on health is not clear. We estimate that around 1.2% of the UK population is iciHHV-6-positive and it is, therefore, important to understand the health implications. A large study is required to have the power to detect associations with diseases that are not common, and associations with small effect sizes. This study will investigate the clinical impact of iciHHV-6 through analysis of UK Biobank, a cohort with samples and data from 500,000 individuals. iciHHV-6A and 6B status will be determined using a two-stage strategy involving an initial screen of all samples using a triplex TaqMan assay, and secondary analysis of likely positive samples using droplet digital PCR. Most iciHHV-6 in the UK can be traced to a small number of ancestral viral integrations; we will use complementary approaches to identify these ancestral viral lineages as they may influence disease associations. We will test previously reported disease associations and identify new associations by analysing a wide range of physical and mental health phenotypes in an agnostic fashion. We will investigate the link between iciHHV-6 and angina and determine the consequences using the wealth of cardiovascular data in UK Biobank. Analyses will be performed for iciHHV-6 overall, and for iciHHV-6A and 6B. The findings will provide a solid evidence base for counselling individuals found to be iciHHV-6-positive and potentially lead to improved diagnostics and treatment in the future.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: The development of in vitro models of respiratory biofilm assembly to develop novel antimicrobial therapies  (PMF)
Funder: Welsh Government Office for Science

Abstract: This multidisciplinary project aims to tackle one of the largest growing global issues, and a clear unmet clinical need i.e. antimicrobial resistance (AMR). The unrestricted use of antibiotics in medicine and animal husbandry has led to the global epidemic of AMR (1). Most recently, the development of resistance to colistin (our ‘last resort’ antibiotic), which can spread directly between bacteria, may herald the end of the antibiotic era (2).  With no new treatment strategies in the ‘pipeline’, a government-commissioned report predicts, a crisis, with 300 million premature deaths attributable to AMR and a £64 trillion loss to the global economy by 2050 (3). 
 My previous work, across the University and the NHS sector in Wales, has demonstrated the antimicrobial potential of a novel, low molecular weight (Mn ~3.200) oligosaccharide, OligoG CF-5/20 (Fig 1), derived from seaweed (4).  Initial studies showed an ability to increase the effectiveness of antibiotics against highly antibiotic-resistant bacteria (5, 6).  Based on this work, OligoG CF-5/20 entered human trials (Phase IIb was completed in Q4 2016) and was awarded Orphan drug status by the US Food and Drug Administration in 2016.  

It is only by understanding how OligoG CF-5/20 modulates bacterial behaviour, biofilm formation and potentiates antibiotic activity, that we can target therapies to deliver the potential of this exciting technology in the next generation of commercial products.  The research outlined in this Fellowship will address the unmet clinical need for novel anti-infective therapies for patients with multi-drug resistant (MDR) lung infections and cystic fibrosis (CF).  The key objective of my proposal is to develop a reproducible method to screen the effectiveness of new antimicrobial compounds, and to utilise this model to define the optimum oligomer structural compound to improve our understanding of antimicrobial resistance in, and the treatment of, MDR bacterial biofilm infections.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: INFECTION
Award Title: The effect of ageing on inflammation resolution and its causation in age-related immune dysfunction.
Funder: Wellcome Trust

Abstract: The immune system protects us from infection, however as we age it can weaken and even contribute to age-related diseases such as heart disease, cancer and arthritis. The exact reasons for this are not known, and new treatments could help us fight infection, treat age-related disease, and improve lifespan. This laboratory has discovered that one explanation may be that white blood cells cannot neutralise their targets at sites of infection properly, worsening the inflammatory response and causing excessive tissue damage. Another explanation may be that the management or oversight of the immune response seems to change with time. To examine these two ideas we plan to use a safe and effective model of skin infection in adults to look for subtle differences between the immune systems of young and elderly people, before and after local skin infections. If we find a cause for these differences, we will perform experiments in mice to see if they are a cause of age-related immune dysfunction. These results could then be used to design medications and further experiments to help improve the lives of patients with and without age-related disease.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM