NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Feasibility study investigating circulating peripheral mitochondrial DNA as a potential non-invasive biomarker for diagnosis and surveillance of high risk cutaneous melanoma
Funder: Cancer Research UK

Abstract: Background
Cutaneous melanoma is the UK’s fifth commonest cancer and is the leading cause of death from skin malignancy. Our recent work highlights the phenomenon of tumour cells obtaining their energy through mitochondrial transfer from its surrounding mesenchymal stem cells, which confers a survival advantage for the emerging cancer. Others have shown that mitochondrial DNA (mtDNA) mutations predominate in the cancer cells. Mitochondrial DNA is an attractive choice for screening and surveillance because it is easily distinguished from nuclear DNA, there is a substantially higher DNA copy number per cell (hundreds versus one) and a significantly lower number of possible mutations in the mtDNA. Such findings suggest the possibility of detecting peripherally circulating mtDNA as a simple and reproducible biomarker for the early detection of recurrence or disease progression.

Aims
A feasibility study in melanoma patients to test the following:
1.To identify patients presenting with high-risk primary melanoma and isolate mtDNA from primary tumour and blood samples pre and post-operatively.
2. To detect novel and existing mutations associated with high-risk primary melanoma
3. Can we detect mtDNA mutation associated with primary tumours in plasma samples taken pre and post-operatively?

Methods
We will undertake an exploratory study in patients presenting with high-risk primary melanoma (AJCC II), prior to staging with sentinel node biopsy and in subsequent follow-up. Historical specimens from melanoma patients held in the Norwich Biorepository will also be studied. Preoperative and sequential postoperative blood samples will be collected from 30 high-risk patients over 12 months. Circulating mtDNA will be compared with mtDNA in the primary melanoma and also from normal white cells from the peripheral blood as internal control. PacBio SMRT Technology analysis will also investigate the frequency of specific mtDNA mutations. The ratio of tumour to normal mtDNA will be assessed using real-time PCR to determine if melanoma derived mtDNA could be further developed to investigate the frequency of specific mtDNA mutations against patient outcome with melanoma. Clinical outcomes data (sentinel node status, recurrence-free survival) will be matched against the circulating mtDNA count and mutational burden.

How the results of this research will be used
Data generated in this exploratory study will be used as a paradigm to undertake larger phase III investigations of the therapeutic utility of mtDNA to determine clinical decision making for melanoma patients in the early detection and early treatment phases and for the surveillance of high-risk patients in follow-up.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Feasibility study of a supported self-management intervention for stroke survivors with aphasia (StarStep study)
Funder: Stroke Association

Abstract: Background: Stroke survivors with aphasia (SSWA) have particularly poor long-term outcomes including reduced psychological and social wellbeing. National clinical guidelines recommend ‘self-management’; however, the evidence base for SSWA is weak. During my PhD project, I explored the suitability of self-management as an approach for SSWA and used Medical Research Council guidance to outline the core components of a supported self-management intervention. Further collaboration with key stakeholders (SSWA, family members and SLTs) is needed to develop this approach before feasibility testing.  

Aim: To refine and feasibility test a supported self-management intervention for SSWA and their family members.

Methods: 
•Stage One: Working together with key stakeholders in a series of workshops, I will refine and optimise the content of the intervention and develop training for SLTs to facilitate the approach. 
•Stage Two: I will undertake a non-randomised feasibility study with 30 SSWA and their family members. I will evaluate recruitment and retention rates and the feasibility of outcome measures. I will undertake a fidelity assessment and explore the acceptability of the intervention through qualitative interviews with participants. 

Expected outcomes: A supported self-management intervention which is feasible to deliver and can be tested in a future, large scale effectiveness randomised controlled trial.

Lay Abstract: Background: Stroke survivors with aphasia (SSWA) have particularly poor long-term outcomes including reduced psychological and social wellbeing. National clinical guidelines recommend ‘self-management’; however, the evidence base for SSWA is weak. During my PhD project, I explored the suitability of self-management as an approach for SSWA and used Medical Research Council guidance to outline the core components of a supported self-management intervention. Further collaboration with key stakeholders (SSWA, family members and SLTs) is needed to develop this approach before feasibility testing.  

Aim: To refine and feasibility test a supported self-management intervention for SSWA and their family members.

Methods: 
•Stage One: Working together with key stakeholders in a series of workshops, I will refine and optimise the content of the intervention and develop training for SLTs to facilitate the approach. 
•Stage Two: I will undertake a non-randomised feasibility study with 30 SSWA and their family members. I will evaluate recruitment and retention rates and the feasibility of outcome measures. I will undertake a fidelity assessment and explore the acceptability of the intervention through qualitative interviews with participants. 

Expected outcomes: A supported self-management intervention which is feasible to deliver and can be tested in a future, large scale effectiveness randomised controlled trial.

Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS
Health Categories: STROKE
Award Title: Fibrin-targeting PLGA microspheres for prevention of post-operative peritoneal adhesions; a pre-clinical proof of concept study
Funder: Medical Research Council

Abstract: Post-operative adhesions are a leading cause of surgery-associated complications. Based on our recent novel finding of the 'anti-adhesion macrophage barrier', we propose fibrin-targeting microspheres (fMS; PLGA microsphere conjugated with anti-fibrin antibody) as an innovative strategy to prevent adhesion formation. fMS is designed to accumulate on the fibrin clots exposed on the damaged tissue surface mimicking resident macrophages and reinforce the macrophage barrier to shield fibrin clots. fMS treatment has potential advantages over current barrier products, including greater specificity to the lesion at risk of adhesions, extensive access to difficult-to-access localizations, and little risk of displacement and misplacement. Our pilot study showed promising results. Thus, this project primarily aims to establish robust pre-clinical proof of concept for fMS treatment. We will first optimise the size and anti-fibrin antibody conjugation of fMS, and then establish a dose-effect relationship and long-term effect and safety of the optimised fMS. The obtained data will be further strengthened by assessing in a different model of post-operative adhesion. Also, we will collect biological information that is related to the safety and efficacy of fMS treatment, including biodistribution of fMS, the cover ratio of fibrin clots by fMS and/or macrophages, impacts of fMS on the mesothelial and peritoneal cells. Reconstitution of peritoneal resident macrophages following the surgery-induced 'macrophage disappearance reaction' and impacts of fMS on this process will be characterised.  fMS treatment has potential to improve surgical outcome and enhance post-operative quality of life of a huge number of patients with reducing the healthcare cost. Obtained results will justify the progression of fMS treatment to the next stage of development toward clinical application. Previously unknown scientific data will also be obtained, paving the way to novel research projects.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Financial lives and wellbeing in low-income groups post Covid-19 (FinWell-Covid)
Funder: Economic and Social Research Council

Abstract: This study builds on two pre-existing samples of low-income individuals in Glasgow (n=69) and Lambeth & Southwark in London (n=29) in whom we explored the relationship between their financial lives and their health and wellbeing. Methods used were: (1) an intensive financial diary, documenting all incomings and outgoings over a six-month period; (2) combined with monthly interviews, to collect quantitative and qualitative data, including health and wellbeing; and (3) two Q methodology studies (n=93) which explored the wider issues of perceptions, not only of the sample but also professional stakeholders, on causes of and solutions to health inequalities in such communities. The similar mixed method study we now propose presents a unique opportunity to identify, in depth, changes in the wider social determinants of health induced by COVID-19 itself as well as its associated interventions (e.g. social distancing and isolating) in some of the most economically-vulnerable members of society. This would be done by continuing to work with our previous samples, some new additions and with the various responsible finance and civil society organisations through which participants were recruited. Data would be collected via a new financial diaries app and continuing with interviews via remote technology. An online Q study would also be conducted, but, this time, with a focus on perceptions of COVID-19 and societal responses to it. These data will be useful in enhancing the acceptability of, adherence to and effective delivery of evidence-based strategies for future prevention and containment.

Lay Abstract: Amongst those hit hardest by COVID-19, and the associated social and economic measures put in place to combat it, will be people in low-income settings, and, within that group, those in hard-to-reach groups continually threatened by financial exclusion. People in such situations already live in precarious financial situations which could be amongst the most vulnerable to measures such as social distancing and self-isolation. Having recently worked with groups in Glasgow and London to explore the relationship between their financial lives and their health and wellbeing, we have an opportunity to follow up with these same groups in order to assess the impact of COVID-19 and measures such as social distancing on their financial portfolios, their short-term health and wellbeing and wider social determinants of health. We propose to do this via a unique combination of financial diary keeping and regular interviews which we have developed for working with such groups, and which can be adapted for remote working. In addition, we will seek the views of such groups as to perceptions of causes and solutions to COVID-19 which can be reconciled with more evidence-based data from other research projects.

Research Activity Codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Frontotemporal dementia-causing mutations in C9orf72: investigation of the toxic mechanism
Funder: Alzheimer's Research UK

Abstract: A mistake in the C9orf72 gene is the most common cause of frontotemporal dementia and of motor neuron disease. Therefore, identifying how this gene causes neuronal death should reveal important new insights into the causes of dementia and other neurodegenerative diseases. We recently used fruit flies to show that two specific proteins called poly-(GR) and poly-(PR) instigate the neuronal death caused by the C9orf72 mistake. We will now build on these exciting findings by combining analysis of fruit flies with investigation of the brains of people with the C9orf72 mistake and by converting patient skin cells into neurons that we can grow and study in the laboratory. Recent evidence suggests that the levels and transport of RNAs and proteins are affected by the C9orf72 mistake. We will use state-of-the–art microscopy techniques in conjunction with innovative methods to measure the levels of all RNAs and the generation of all proteins within neurons. This powerful approach will enable us to pinpoint the specific RNAs and proteins affected by poly-(GR) and poly-(PR). This will identify the most important factors leading to neuronal death and give insight into developing specific therapies.

Lay Abstract: A mistake in the C9orf72 gene is the most common cause of frontotemporal dementia and of motor neuron disease. Therefore, identifying how this gene causes neuronal death should reveal important new insights into the causes of dementia and other neurodegenerative diseases. We recently used fruit flies to show that two specific proteins called poly-(GR) and poly-(PR) instigate the neuronal death caused by the C9orf72 mistake. We will now build on these exciting findings by combining analysis of fruit flies with investigation of the brains of people with the C9orf72 mistake and by converting patient skin cells into neurons that we can grow and study in the laboratory. Recent evidence suggests that the levels and transport of RNAs and proteins are affected by the C9orf72 mistake. We will use state-of-the–art microscopy techniques in conjunction with innovative methods to measure the levels of all RNAs and the generation of all proteins within neurons. This powerful approach will enable us to pinpoint the specific RNAs and proteins affected by poly-(GR) and poly-(PR). This will identify the most important factors leading to neuronal death and give insight into developing specific therapies.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Full Duration Studentship - Accelerator Award A26825 "ACRCelerate: Colorectal Cancer Stratified Medicine Network"
Funder: Cancer Research UK

Abstract: Studentship asssociated with programme: Colorectal cancer (CRC) remains the second most common cause of cancer death, and patients with stage 3/4 cancers at diagnosis only have a 10% survival rate at 5 years. Chemotherapy relies on the use of combination cytotoxics against the proliferating tumour epithelium, with novel targeted therapies having disappointing trial results to date. CRC presents an opportunity for precision medicine as it is common, has known and established driver molecular pathways and pre-treatment molecular stratification is achievable. Recent advances in sequencing technology and biological models have resulted in paradigm shifts in our understanding of CRC biology, but have failed to significantly impact upon patient care. Indeed, stratified medicine clinical trials such as FOCUS4 have been hampered by the lack of robust preclinical prediction, which have left many therapeutic arms of the trial unfilled.


This Accelerator application brings together a European-wide consortium at the forefront of CRC research to align and interrogate a suite of state-of-the art preclinical models (GEMMs, organoids and PDXs). Our platform will accelerate therapeutic target identification and preclinical validation of new and repurposed drugs, to accomplish rapid clinical translation. Our focus will be to generate and share models of CRC that correlate with human CRC molecular subtypes, to enhance testing of CRC therapeutics in functionally relevant microenvironments. By placing molecular phenotyping and stratification at the heart of this programme we will target biologically plausible pathways known to be dysregulated in CRC, and design molecularly stratified clinical trials to test them, to ensure that no therapeutic opportunities are overlooked.

The overarching aim of this proposal is to generate robust and reproducible preclinical data to de-risk future clinical trials based on patient stratification. We will employ and develop preclinical models that recapitulate the molecular subtypes of CRC, characterise their signalling pathways, use DNA and RNA sequencing to subtype the models, identify and test new therapeutics and integrate the data in a bioinformatic analysis pipeline. The data will be shared amongst the consortium for cross-validation, reducing the number of mice used in cancer research and to inform future stratified clinical trials for CRC.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Function of novel epigentic modification pathways and their role in cancer
Funder: Cancer Research UK

Abstract: Function of novel epigenetic modification pathways and their role in cancer

BACKGROUND
Epigenetic modifications on DNA, RNA and histones regulate many important biological processes. Enzymes that mediate these modifications are often found mutated in cancer and consequently such enzymes represent targets for drug discovery. Our lab has a track record in the discovery and mechanistic characterisation of enzymes that modify histones and RNA, and the evaluation of small molecule inhibitors targeting such enzymes. Given these connections to cancer, we expect that the characterisation of novel pathways leading to histone and RNA modifications will lead to the discovery of new validated targets for drug discovery.

AIMS
The aims in this proposal are threefold: Work Package 1 involves the molecular dissection of two new chromatin modification pathways (H4T80 phosphorylation and H3K37 methylation) both of which we identified in the previous quinquennium. Work Package 2 involves the molecular characterisation of three different classes of RNA modification: pseudouridylation, methylation, and uridylation. We will investigate the biological roles of the enzymes that mediate them, giving attention to their chromatin-based functions following recruitment to promoters. Work Package 3 will concentrate on evaluating the importance of RNA modifying enzymes in cancer using small molecule inhibitors and CRISPR knock-out technology.

 METHODS
Work Package 1: We will address the molecular and biological processes regulated by new histone modification pathways in both yeast and mammalian cells using unique antibody reagents we have developed and standard chromatin-appropriate techniques. Work Package 2: We have developed several biological and chemical tools, as well as new mass spectrometry methods of detection, which will be used to characterise the function of RNA modifications. All modifications will be dissected in appropriate cancer cell systems. Work Package 3: We are in close collaboration with STORM Therapeutics, a drug discovery biotech, that is developing small molecule inhibitors against enzymes we have shown to be involved in cancer. These molecules will be provided to us to evaluate them in cell-based viability assays and in synthetic lethality screens.

HOW THE RESULTS OF THIS RESEARCH WILL BE USED
 We expect the results of this proposal will be used to (a) define new targets for drug discovery, (b) provide mechanistic understanding for already established cancer targets and (c) define the selectivity and specificity of small molecule inhibitors against specific epigenetic targets.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: Functional genomics of breast cancer
Funder: Cancer Research UK

Abstract: We have redefined breast cancer as a constellation of 10 genomic driver-based subtypes. This new molecular taxonomy of breast cancer will now be translated into the clinic in stratification, tumour monitoring and therapy studies. In parallel we will continue to develop models to characterize the biology of these subtypes.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health Categories: CANCER AND NEOPLASMS
Award Title: GCRF Action against Stunting Hub
Funder: Medical Research Council

Abstract: Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: ORAL AND GASTROINTESTINAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Gastroenteritis: rehydration for children with severe acute malnutrition (GASTRO-SAM)
Funder: Medical Research Council

Abstract: Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (3 watery stools/day) which is accompanied by poor outcomes (case fatality 21%). Rehydration guidelines for SAM are exceptionally conservative and controversial, as they rely upon expert opinion, recommending restriction of intravenous (iv) to cases with advanced shock and exclusive use of low sodium oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. We aim to evaluate standard (non-SAM) liberal strategies for both iv and oral rehydration in SAM children with diarrhoea.  The Phase II trial will generate feasibility, safety and preliminary data on survival to 7 days and 28 days of rehydration strategies incorporating two strata for management of (A) severe dehydration comparing both rates of rehydration and volume of iv replacement and (B) the composition of ORS for children with some dehydration (and post iv-rehydration) designed as a factorial trial.    The two major questions to be addressed are  (1) In Stratum A involving SAM children with clinical signs of severe dehydration (~10% loss) whether 'liberal' rehydration strategy using 100mls/kg of isotonic Ringers Lactate with either (i) standard WHO Plan C for rapid rehydration over 3-5 hours (incorporating boluses for shock) versus (ii) slower fixed rate of intravenous rehydration over 8 hours (and no boluses) are safer and result in better outcomes versus (iii) current WHO SAM guidelines recommending oral rehydration with low-sodium ReSoMal and restricting iv to those with advanced shock only (15 ml/kg bolus (plus one repeat). (2) In Stratum B in children with diarrhoea with clinical signs of 'some dehydration' and follow on treatment post-intravenous rehydration whether oral rehydration with (i)WHO standard oral rehydration solution (ORS) for non-SAM results in less hyponatraemia and less adverse outcomes than (ii) current recommendation advocating low sodium (ReSoMal) ORS.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL