NIHRDataInsights/HRCSData huggingface dataset:
Award Title: TransRAMPART: Renal Adjuvant MultiPle Arm Randomised Trial - Translational Research
Funder: Cancer Research UK

Abstract: Background
Renal cell cancer (RCC) is the most lethal urological malignancy with 50% of patients dying from their disease. Overall, 30% of patients with initially localised RCC, having seemingly curative surgery, will develop incurable metastatic RCC (mRCC); this proportion increases to 75% in patients with high risk disease. As such, there is considerable interest in adjuvant therapies for post-nephrectomy RCC patients to prevent the development of mRCC.
 
RAMPART is a UK academic-led, international Multi-Arm Multi-Stage (MAMS) platform trial in intermediate and high risk localised RCC patients. Patients are randomised between active monitoring (observation by clinical and radiological means), 1 year of the PD-L1 inhibitor durvalumab or a combination of 1 year of durvalumab and 2 cycles of the CTLA-4 inhibitor tremelimumab.  TransRAMPART is the translational study linked to RAMPART.
 
Aims
The aim of TransRAMPART is to collect tissue, blood and urine samples from patients randomised to the RAMPART trial for the development of novel molecular markers of prognosis, minimal residual disease, treatment response, resistance and toxicity. 
 
Methods
A comprehensive, longitudinal sample collection including peripheral blood mononuclear cells (PBMCs), double spun plasma, urine, FFPE tissue blocks and fresh frozen tissue. Samples will be collected at the time of nephrectomy, before first treatment administration and throughout patient follow-up. Additional samples will be collected upon recurrence and development of Grade 3 infusion-related toxicities. Sample sizes have been based on a pre-planned, powered analysis of predictive ability of PD-L1 status for response to adjuvant immune checkpoint inhibitors.
 
How results from this research will be used
TransRAMPART will provide a unique opportunity to address which of our RCC patients are most in need of adjuvant checkpoint inhibitors; predict the patients who will respond to these agents, identify when and how resistance may develop and pre-empt patients who will experience significant toxicity.  To date a number of biomarkers, including PD-L1 expression and tumour mutational burden, have emerged as predictors of benefit from immune checkpoint blockade in other solid tumour types. Given the size of the TransRAMPART cohort and the comprehensive sampling of tumours we would like to carry out we are in a unique position to identify biomarkers of response in this patient group which could ultimately serve both adjuvant and metastatic RCC populations, as well as to identify recurrent mechanisms of resistance and immune-related adverse events. We have a series of planned scientific approaches for the TransRAMPART biorepository incorporating genomic, transcriptomics, proteomics, metabolomics and immunology.


Research Activity Codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Transcriptomic, Proteomic and Bioinformatics Analyses of Cell-Based Therapies for Cartilage Injuries in Humans
Funder: Versus Arthritis

Abstract: ASCOT is a prospective randomised trial nearing completion, it is designed to determine if the modification of standard autologous chondrocyte implantation (ACI) using other cell types will improve clinical outcome. The trial compares autologous chondrocytes with either autologous bone marrow-derived stromal cells (BM-MSCs) or a combination of the two when implanted beneath either a periosteal or a collagen membrane for the treatment of articular cartilage defects in the knee (Richardson et al., 2017).

 

The key goals for the proposed PhD project will be to:
Map the mRNA, miRNA and protein profiles of the ASCOT trial transplanted cell population. Transcriptomic and proteomic data is to be made publicly available on an online repository to enable additive benefit to the broader scientific community.
Identify transcriptomic and proteomic signatures and altered biological pathways that relate to functional and structural outcomes in the ASCOT trial cohort.
Use a systems biology approach to identify molecular differences (a) between BM-MSCs and chondrocytes and (b) across donors with demographic features known to influence the outcome of these cell-based therapies e.g. between cells from different genders.
Training and development of an early career researcher with a desirable, multimodal skillset, which includes innovative scientific approaches to improve cell-based therapies for musculoskeletal injuries and diseases.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES;6.2 CELLULAR AND GENE THERAPIES
Health Categories: MUSCULOSKELETAL
Award Title: Transgenic Modelling of Human Prion Susceptibility and Diseases
Funder: Medical Research Council

Abstract: In studies now spanning well over a decade we have developed highly specialised transgenic transmission facilities for comprehensive studies of human prion disease under appropriate biocontainment. Species-barrier-free transmission of many forms of human prion disease is available. While excellent, well characterised models are now in routine use, further improvement to these models, and the development of improved models for the assay of vCJD prions are underway. In addition to ongoing basic research into intermammalian and strain-specific transmission barriers and characterisation of the prion strains causing human disease, this facility is being applied to address key public health issues which require human prion bioassay (tissue distribution of infectivity and human prion decontamination for example) and to study putative prion therapeutics. Animal models of a range of inherited human prion diseases are being studied, in particular to determine if prions are produced spontaneously in such animals. The specific aims of this programme are as follows:- To establish the full range of prion strains causing human disease and to attempt to biologically clone these for biochemical study (with programme 6) - To complete our long-term characterisation of intermammalian prion transmission barriers of relevance to public health and to understand the interaction between prion strain diversity and these barriers - To model the human inherited prion diseases and determine whether prions can be generated spontaneously in these models - To generate new transgenic lines as required to model novel human PrP polymorphisms and candidate prion modifier genes (in conjunction with programmes 1 and 2) - To generate transgenic models of frontotemporal dementia (in conjunction with programme 10) - Development and use of standardised models for evaluation of candidate therapeutics  - To continue to provide and update the Units Transgenic Core facility and support animal research throughout the Unit


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Translating the potential of the urine steroid metabolome to stage NAFLD (TrUSt - NAFLD)
Funder: Wellcome Trust

Abstract: Fat deposition in the liver is now the commonest chronic liver condition, affecting one-in-three individuals. It can lead to liver problems including cirrhosis and liver cancer as well as increasing your risk of heart attacks and strokes. Simple blood tests are often normal, and the current gold-standard test for assessing NAFLD severity is a liver biopsy. This is an invasive procedure that is associated with significant complications, including pain and bleeding. We have developed a urine test that measures natural steroid hormones and provides an accurate reflection of how the liver is functioning in patients with NAFLD. We wish to extend our findings to a large cohort of patients with NAFLD to ensure that our test is accurate and reliable. If successful, our urine test could be used by GPs and hospitals reducing liver biopsies and making a significant advance to patient care.

Lay Abstract: Fat deposition in the liver is now the commonest chronic liver condition, affecting one-in-three individuals. It can lead to liver problems including cirrhosis and liver cancer as well as increasing your risk of heart attacks and strokes.  Simple blood tests are often normal, and the current gold-standard test for assessing NAFLD severity is a liver biopsy. This is an invasive procedure that is associated with significant complications, including pain and bleeding. We have developed a urine test that measures natural steroid hormones and provides an accurate reflection of how the liver is functioning in patients with NAFLD. We wish to extend our findings to a large cohort of patients with NAFLD to ensure that our test is accurate and reliable.  If successful, our urine test could be used by GPs and hospitals reducing liver biopsies and making a significant advance to patient care.

Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: ORAL AND GASTROINTESTINAL;METABOLIC AND ENDOCRINE
Award Title: Translational Applications of New Insights into Immunoreceptor Signalling
Funder: Medical Research Council

Abstract: Goals To understand the cell biology of the leukocyte surface and to use the insights to alter the behaviour of leukocytes in autoimmune settings. The T-cell biology group is working towards an understanding of the biology of the leukocyte surface and the mechanism of receptor triggering, both for its intrinsic cell biological interest and as the basis for developing new types of immunotherapy. For the last several years we have focused on understanding the composition of the T-cell surface and how receptors expressed there are organized and then ‘triggered’ by ligand binding (1-3). The expression of transcripts encoding known cell surface molecules by a human CD8+ T-cell clone was characterized by a transcriptomic approach (SAGE) and the results suggested that existing models of receptor triggering are unlikely to be wrong because key components remain to be discovered (1). Determination of an anti-CD28 superagonistic antibody Fab fragment bound to CD28 (2) provided insights as to how antibody superagonists work and incorporated CD28 into the family of receptors triggered via kinase/phosphatase segregation – a family that includes the T cell receptor (for a review see reference 3). Assembly of proteins expressed at the cell surface has been studied by bioluminescence resonance energy transfer (BRET), which has been used to characterize the quaternary structures of cell surface molecules. Our new experimental framework for detecting transfected receptor dimers revealed that most proteins expressed at the cell surface are likely to be monomers, undermining the notion that important groups of receptors inexorably form dimers (4). Together with our collaborators we have established a new method for studying the organization of native receptor complexes (two-colour coincidence detection). Analysis of the composition of protein complexes on the surface of live T cells has shown that the TCR is monovalent (5). Recent work has focused on determination of the stoichiometries of each key component of the T cell triggering apparatus – MHC class II, CD4, CD45 – and these too have been shown to be monovalent (6). Future research plans Future work will concentrate on understanding receptor triggering by native ligands and by antibodies and to use this knowledge in the development of new receptor agonist-based therapeutic antibodies – for example against inhibitory receptors such as PD-1 that suppress immune responses both in vivo and in vitro. A key objective is to target molecules that may offer new opportunities to intervene in autoimmunity. References: (1) Evans et al 2003 Immunity 19: 213 (2) Evans 2005 Nature Immmunol 6: 271 (3) Davis and van der Merwe 2006. Nature Immunol 7: 803 (4) James et al. 2006 Nature Methods 3: 1001 (5) James et al 2007 Proc Natl Acad Sci USA 104: 17662 (6) James et al. 2011 J Biol Chem. 2011 16:31993


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Transmissible cancer evolution and host interaction
Funder: Wellcome Trust

Abstract: Transmissible cancers are malignant somatic cell lineages that spread between individuals by the allogeneic transfer of living cancer cells. These cancers, whose three known instances in mammals affect dogs and Tasmanian devils, provide a unique perspective on cancer evolution and host interaction. I will investigate this by deeply sequencing whole genomes from 1100 tumours selected from across each cancer’s range, together with matched bulk RNA sequencing and targeted single-cell RNA sequencing. Time-resolved phylogenetic trees for each clone will be annotated with mutation and gene expression data, and the source and consequence of mutation explored. Host cell contribution to the tumour microenvironment, and its variation across hundreds of tumours, will be assessed using allelic and cell-type deconvolution. Combining genetic, microenvironment composition and clinical data, I will explain how the immunological interface between allogeneic cancer and host varies between individuals, and how this interaction controls the outcome of disease. The inherent heterogeneity and short lifespans of most cancers may obscure their underlying biological patterns. By capturing variation in hundreds of clonally derived tumours inhabiting different hosts, I seek to deeply probe the mutational, evolutionary and immunological principles of cancer.

Lay Abstract: Cancers are outgrowths of abnormal cells driven by a malignant evolutionary programme and supported by a permissive tumour microenvironment. Most cancers arise from and remain within the bodies of their hosts. Rarely, however, cancers may escape their hosts, defy immunological barriers, and spread through populations. Only three such transmissible cancers are known amongst mammals, affecting dogs and Tasmanian devils, and these provide a unique perspective on cancer evolution and host interaction. Here, I outline a plan to sequence the entirety of DNA and RNA from hundreds of tumours, together with targeted single-cell RNA sequencing, in order to understand these cancers’ evolution and mechanisms of immune evasion. I will investigate the source and consequence of mutation and characterise variation in composition and function of the tumour microenvironment. This work will reveal how cancers exploit a transmissible niche, and how the interaction between cancer and immune system controls disease outcome.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Treatment of osteoarthritis by inhibition of aggrecanases using targeted delivery of engineered TIMP-3
Funder: Medical Research Council

Abstract: Joints affected by osteoarthritis (OA) have increased levels of matrix-degrading enzymes such as matrix metalloproteinases (MMP) and aggrecanases that can degrade the articular cartilage and result in joint damage and pain. TIMP-3 is a potent endogenous inhibitor of MMPs and aggrecanases. However, attempts to harness the therapeutic potential of TIMP-3 have been prevented by technical challenges associated with protein production and by observations that synthetic broad-spectrum inhibitors of MMPs caused unwanted side-effects. In this project, TIMP-3 molecules that have been engineered to narrow their inhibitory activity to aggrecanases but not MMPs, will be produced and delivered to sites of arthritic disease. Targeting of these proteins to arthritic joints will be achieved by producing TIMP-3 in fusion with the latency-associated peptide (LAP) of TGF-beta1. This renders the protein biologically inactive until it reaches the site of disease where TIMP-3 is released from the LAP by MMPs present in arthritic joints. The effect of delivery of engineered TIMP-3 on the course of disease in vivo will be assessed by measuring cartilage degradation and subchondral bone thickening by a combination of histology, immunohistochemistry and micro computed tomography. The inhibitory effects of engineered TIMP-3 on various members of the ADAM and ADAMTS families of matrix-degrading enzymes will also be assessed in vitro to provide insight into the potential benefits of this therapeutic strategy. Knowledge of the targeting potential of this approach in OA and of the effects of inhibition of aggrecanases in joints affected by OA could pave the way for a novel treatment for OA that could be used alone or in combination with existing therapies.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MUSCULOSKELETAL
Award Title: Triboelectrically Powered Super-Smart Textiles for Remote Health Monitoring
Funder: Royal Academy of Engineering

Abstract: In the future, wearable healthcare technologies will require efficient, autonomous and sustainable energy sources. Dr Dharmasena investigates nanogenerator technology to develop super-smart textiles that use electro-static interactions of textile yarns to generate electricity from human body movements. These smart textiles function as energy generators and self-powered sensors for remote rehabilitation monitoring.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Tumour Cell Death
Funder: Cancer Research UK

Abstract: Macroautophagy (autophagy) is a catabolic membrane-trafficking process that delivers cytoplasmic constituents to lysosomes.  The process is active in multiple tissues and contributes to cellular fidelity and viability.  As a result, autophagy is implicated in a variety of diseases including cancer and there is clear evidence that it plays important roles in both the prevention of tumour development and in the establishment and maintenance of malignant disease.  Moreover, as certain tumours are autophagy-dependent, autophagy has become an attractive target for cancer therapy.  

My laboratory has made a number of significant discoveries regarding autophagy in cancer and we are one of the leading teams in this area.  In our proposed plan of investigation we aim to build on our previous discoveries and to advance the state of the art in three main areas:

1) We are widely recognized for our work on DRAM family proteins and autophagy in cancer.  We have discovered a molecular function of DRAM-1 that is highly relevant to tumour development and we will explore this mechanism in greater detail.  In addition, using DRAM1-deficient mice we will explore a role we have found for the protein in tumour progression.  These studies will be undertaken alongside further studies into the role of autophagy during tumour development in vivo.

2) Through RNAi screens we have discovered that a transcriptional regulator important for cancer is a novel autophagy regulator.  We plan to explore how this regulator affects autophagy genes and in what contexts.  To this end, we have established collaborations to look at autophagy regulation by this factor in vivo and we aim to examine how this factor selectively regulates different forms of autophagy.

3) Changes in glysosylation are an extremely frequent event in cancer and yet their contribution to the aetiology of the disease is poorly understood.  We have found that a key enzyme involved in glycosylation is required for successful autophagy.  Moreover, we have also discovered that perturbation of this enzyme enhances pancreatic tumour development in a mouse model.  We aim to define the role played by this enzyme in the regulation of autophagy and delineate its contribution to tumour development in pancreas and other tumour types.

These studies will lead to a greater understanding of the role of autophagy and its regulators in cancer and we hope they will lead to the improved application of existing cancer therapies and to the identification of potential new targets for therapeutic intervention.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive Tuberculosis: the "TRUNCATE-TB" trial
Funder: Medical Research Council

Abstract: TRUNCATE-TB is a randomized, open-label, parallel group, non-inferiority trial testing a new strategic approach to the treatment of drug-sensitive pulmonary TB. Patients will be randomized to receive 6 months' initial standard-of-care treatment, or to one of several strategy arms comprising 2 months' treatment with a novel combination followed by 6 months' re-treatment with the standard-of-care combination for those who relapse.  A multi-arm multi-stage (MAMS) design will be used that allows multiple regimens to be tested against a single control group and which allows for treatment arms to be dropped or added during the trial. This represents an efficient and cost-effective approach to evaluating several candidate regimens that may provide high rates of sterilization after 2 months' treatment.  The trial will have a pilot phase in which 300 patients will be enrolled to gather detailed initial safety data, as well as test feasibility of recruitment and follow-up and allow an initial intermediate assessment for efficacy and possible arm drop. The definitive phase of the trial will complete the recruitment of a total of 1300 patients.  Eligible patients must have a pulmonary TB confirmed by molecular test, without rifampicin resistance. HIV infected participants will be eligible (recruited only in the definitive phase), but must have a CD4 above 200 cells/mm3 and be off anti-retroviral therapy at study entry. Patients will be followed for 96 weeks (prolonged if late-re-treatment). The primary endpoint is TB sputum culture status at 96 weeks after randomization. Secondary endpoints include drug resistance, treatment failure or relapse, programme resource use and cost and the safety of the treatment regimens.  The trial will be conducted at approximately 12 sites in Asia, forming a sustainable Asian TB clinical trials network that will make a significant future contribution to the urgent need for increased TB clinical trials capacity.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: INFECTION
Award Title: UK Prevention Research Partnership (UKPRP) - call 2 consortium and network grants
Funder: Wellcome Trust

Abstract: The UKPRP is an inter-disciplinary national initiative supported by an alliance of UK charities, Research Councils and the UK Health Departments, and established in recognition of the need for research into population-level strategies that will prevent non-communicable diseases (NCDs) and reduce inequalities in health.


Research Activity Codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: UK Research in Musculoskeletal Epidemiology - UK-RIME
Funder: Versus Arthritis

Abstract: The 1st term of the Epidemiology Centre Award (UK Research in Musculoskeletal Epidemiology (UK-RiME) partnership) was established with funds within the 1st term of funding for the Centre for Epidemiology. It is a partnership bringing national collaboration between msk epidemiology centres:

For the 2nd term an Annual Research Showcase is supported. The annual showcase provides an opportunity for face-to face meetings between members of the UK-RIME centres and others interested in MSK epidemiology. The showcase is planned and organised by a junior organising committee from all eight UK-RIME centres and typically includes brief presentations from each Centre, ‘elevator pitch' presentations by ECRs and break-out sessions to discuss methodological and clinical topics related to MSK epidemiology. This organising committee also acts as a successful communications network, distributing information and opportunities to all sites.


Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL