NIHRDataInsights/HRCSData huggingface dataset:
Title: Developing an e-cigarette ontology (E-CigO) for use in e-cigarette research
Funder: Cancer Research UK

Abstract: Background: E-cigarette research is an important example of a contested area in public health in which studies are being reported in ways that permit multiple conflicting interpretations, and evidence synthesis is being carried out using inconsistent and ambiguous terminology. Studies and data analysis are being undertaken that fail to address stated research questions and the most important research gaps are difficult to identify. The problem is compounded by the fact that many disciplines are involved and some of the research is conducted by scientists with limited understanding of the specifics of the topic of study. Formal ontologies have gone a long way to addressing problems of this kind in other areas such as biology, permitting the accumulation of an integrated knowledge base. Aims: The aim of this project to develop an ontology (E-CigO) for those working within the field of e-cigarette research. E-CigO will provide a consistent, integrated and systematic way of defining terms, representing research methods and findings in the field. It will enable much more accurate, complete and detailed searching of relevant literature than is currently possible, providing a basis for evidence integration and interpretation. This in turn will help 1) identify sources of disagreement, 2) prioritise topics for research funding, 3) provide guidance to researchers to improve the reporting and interpretation of findings, and 4) help users of research findings obtain an accurate impression of research findings taking account of possible sources of bias. Methods: As part of a wider Addiction Ontology (AddictO) project, the ontology will be developed using accepted practice involving: 1) identification of relevant entities, their labels and definitions; 2) establishing the properties of entities in terms of their relations with other entities; 3) creation of an online searchable and continually updatable database of entities and their properties; 4) creation of interfaces to sustain development of the ontology and its use in research and practice. All this will be undertaken using extensive stakeholder engagement and comprehensive literature searching to build the system both from the top down and the bottom up. How the results will be used: The ontology will be hosted online and subject to iteration and updating as new evidence emerges or as definitions change and develop in response to new evidence. The ontology will be disseminated to academics, practitioners and policy makers interested in e-cigarette research. Everything will be ‘open source’ and will contribute to a community of practice.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS
Title: Vasilis Stavrinides to visit Cambridge
Funder: Cancer Research UK

Abstract: By somewhat conservative yearly estimates, 12,600 to 17,300 UK men with a prostate MRI lesion will have a cancer-negative MRI-targeted biopsy (MRI-TB).(1) Although misclassification accounts for a minority of these instances, biopsy-negative MRI lesions in the prostate could, in theory, represent pre-malignant states that precede the manifestation of clinically significant cancer. The existence of such states has been proven in other tissues; for example, next-generation sequencing in healthy blood, skin, oesophagus, and endometrium has revealed that non-synonymous mutations of cancer-associated genes are positively selected, increasing the risk of further pathogenic events and, ultimately, malignancy. (2–5) In the prostate, it is already known that differentially methylated CpG biomarkers stratify patients with metastatic-lethal versus non-recurrent prostate cancer (PCa) in men who had radical surgery, indicating a role of epigenetics in disease progression.(6) Epigenetic changes have also been found in negative MRI-TB, which often precede a subsequent cancer diagnosis.(7) Given that MRI-TB is currently the most efficient method to detect csPCa in men with initially negative biopsies and the current diagnostic standard in the UK, EU and the US, there is a clinical need and an unharnessed opportunity to investigate whether phenotypically benign MRI-visible prostate tissue harbours early molecular changes that could be useful for early detection of impending cancer initiation. (8,9) Understanding lesion dynamics requires a fresh approach towards the systematic molecular characterization of MRI-TB prostate tissue, particularly when serially derived from the same man. The analysis and interpretation of composite genomic and epigenetic data that are both highly dimensional and longitudinal requires advanced computational approaches and sophisticated statistical modelling. The proposed Skills Exchange is a unique opportunity for a young ACED investigator from UCL (VS) to learn from world-class cancer evolution experts at Cambridge (JB) and apply the acquired knowledge in the prostate cancer domain, with a view to a new UCL-Cambridge ACED collaboration.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Utilization of salivary extracellular vesicles as non-invasive biomarkers for oral epithelial dysplasia.
Funder: Cancer Research UK

Abstract: Background Oral epithelial dysplasias (OED) are lesions which can become oral squamous cell carcinoma (OSCC). Reported malignant transformation rates (MTR) vary and correlate with histological dysplasia grade and lesion clinical features. However, these features are subjective and their association with MTR is inconsistent. Early detection of OSCC, especially on dedicated OED monitoring clinics, improved patient outcomes highlighting the need for objective, non-invasive tools to identify OED and which lesions are high risk. Extracellular vesicles (EV) are lipid bound nano-scale vesicles which contain nucleic acid cargo. They facilitate cell signalling and removal of cell contents. EV are secreted by all cells and into biological fluids including saliva. The salivary EV in patients with OSCC are more numerous and have different contents than those in healthy mouths. However, OED EV have not yet been characterised, creating a novel target for biomarker discovery. Aims: 1. Determine the physical (size and concentration) characteristics and RNA cargo of EV in the saliva of patients with OED, healthy mouths and OSCC 2. Determine if EV isolated from representative cell lines are comparable to those in patient saliva 3. Determine if EV are retrievable from formalin fixed paraffin embedded (FFPE) tissue Methods Saliva will be collected from patients with OED, OSCC and healthy mouths. Nanoparticle Tracking Analysis will determine the physical characteristics of EV. Antibody-coated magnetic beads (Dynabeads) will be used to isolate EV. Western blot of EV protein markers and transmission electron microscopy (TEM) will confirm isolation. RNA will be extracted from EV with concentration and quality determined by Bioanalyzer. Samples from each group will be selected for RNA sequencing to identify the most differentially abundant miRNA and larger transcripts. These findings will be validated in all samples by qPCR. Comparison will be made between saliva and tissue culture derived EV with the above methods. Blocks of archived FFPE OED and OSCC tissue will be retrieved and EVs isolated by melting the blocks, incubation of tissue in an extraction buffer before Dynabead isolation of EV. Isolation will be confirmed by nanoparticle tracking analysis, transmission electron microscopy and western blot. Future work Characteristics specific to saliva EV in patients with OED will be used in larger confirmatory studies before translation to clinical practise as OED biomarkers. Similarities between saliva EV and those isolated in tissue culture will support future in-vitro work. Isolation of EV from FFPE tissues will allow future retrospective investigation using archived tissues.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Preventing and reducing obesity in Wales
Funder: Cancer Research UK

Abstract: Background: Obesity is a leading health concern in Wales. Obesity increases the risk of conditions like type 2 diabetes, cancer and heart diseases. Many of these people are living with multi-morbidities. Coronavirus has accelerated the obesity epidemic, which in turn will increase the risk of serious long-term health conditions. We need to act now by supporting people whose health is being seriously impacted by obesity and being overweight. We know that obesity is complex, and socio-economic factors alongside lifestyle choices contribute to the obesity epidemic. We must work in partnership. In 2019, the Welsh Government launched Healthy Weight: Healthy Wales, a ten-year strategy to reduce and prevent obesity in Wales. The Obesity Alliance Cymru (OAC) a group of charities and health bodies, including Diabetes UK, Cancer Research UK, Royal College of Paediatrics and Child Health, BHF and others played a pivotal role in the development of Healthy Weight: Healthy Wales and continued to be a trusted partner and critical friend in its implementation. By bringing together a coalition of organisations supporting the implementation of this strategy and policy change, we have a greater voice together. The impact of this coalition will be felt across multiple long-term health conditions. Coronavirus severely affected the capacity of our member organisations, limiting our impact and threatening the coalition’s sustainability. We have identified an approach to rebuild this. This will involve hosting a part-time coordinator role to increase capacity. Aims: • Funding a dedicated post with Diabetes UK, Diabetes UK as a secretariat for OAC • Increasing the momentum for change across government policy and health agendas targeting obesity • Working with coalition members to achieve the common goal of reducing obesity and increasing health outcomes of the people in Wales. Responsibilities: • Lead on any OAC outputs, including briefings, consultation responses, involving member organisations to ensure a united voice on obesity policy • Develop plans to influence the passage of the Food Environment Bill in the Senedd - lead implementation • Ahead of the bill, begin engagement with MSs maintain cross-party support for Healthy Weight: Healthy Wales • Establish a Cross Party Group on Obesity, providing the secretariat function • Re-establish the membership of the OAC and lead on communication and engagement • Lead on OAC governance The value our programme of work will deliver: This work will benefit people with long-term health conditions by implementation of legislation that will promote better health benefits.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS
Title: Development of CURATE (TT702) a first in class adenosine A2B Receptor selective antagonist, for a Phase I trial in advanced prostate cancer (mCRPC)
Funder: Cancer Research UK

Abstract: Adenosine is a purine nucleoside which confers potent immunosuppressive as well as direct tumour-promoting effects in the tumour microenvironment (TME). Approaches to block adenosine signalling in the TME by either blockade of adenosine generating enzymes (e.g. CD39, CD73 and CD38) or antagonism of adenosine receptors A2AR and A2BR are attractive therapeutic interventions. A2BR is a G protein-coupled receptor which, unlike other adenosine receptor subtypes, is only activated by high concentrations of adenosine found under pathophysiological conditions. It is also hypoxia-induced leading to high expression in the TME. It is expressed on both tumour and immune cells, promoting cancer cell proliferation and mediating immunosuppressive effects via regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs). Selective small molecule antagonists of A2BR have proved challenging due to low aqueous solubility, including TT-478, a highly selective A2BR antagonist. TT-478 has been shown to be safe in clinical trials. TT-702 is a pro-drug of TT-478 with improved water solubility. It shows greater oral exposure than TT-478 in vivo and is rapidly converted to TT-478. Current clinical data from other adenosine receptor antagonists support the importance of A2BR as a therapeutic target in metastatic prostate and possibly colorectal cancer. TT-702 is being developed initially for the treatment of metastatic castration-resistant prostate cancer (mCRPC) as well as a range of other tumour types including triple negative breast cancer (TNBC) and microsatellite high (MSI) and mismatch repair deficient (MMR) tumours. A2BR is upregulated by androgen receptor activation and its expression correlates with poor survival in mCRPC. TT-702 alone improves anti-tumour immune response and, in combination with enzalutamide, synergistically inhibits the growth of human prostate cancer cells. TT-702 therefore has the potential to be a novel therapy for mCRPC by enhancing anti-cancer immunity and inhibiting prostate cancer proliferation. A phase I/II first in human trial of TT-702 given alone and in combination with both anti-PD1/anti-PDL1 and AR antagonist (CURATE) is proposed. Starting dose will be defined based on preclinical data and dose escalation will proceed using a Bayesian continual reassessment model (CRM).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Cross Risk Factors Collaboration
Funder: Cancer Research UK

Abstract: Background It is estimated that around four in ten cancers are preventable, with exposure to the key risk factors of tobacco, alcohol and overweight/obesity responsible for over 120,000 cases of cancer in the UK every year. Public health issues are highly visible in the current environment and there is an opportunity to speed progress in addressing preventable cancers through the Government’s ‘levelling up’ agenda. However, this will require a comprehensive and sustained approach to bring about systemic change. This project is a novel collaboration between the Alcohol Health Alliance, Obesity Health Alliance and Smokefree Action Coalition, bringing together significant public health and advocacy expertise from across these alliances. Aims Collectively the three alliances have objectives to substantially reduce or eliminate the harm caused by smoking, alcohol consumption and excess weight. These distinct missions will be more likely to succeed in a policy environment supportive of the public health agenda and aware of the common commercial drivers of these risk factors. This collaboration will maximise this opportunity and create a stronger voice for action to avoid preventable illness and death. Methods We will establish a small stakeholder group to oversee the activity of the project and provide expert insights to shape the outputs. The main outputs will be a: 1. Policy report that will: • Set out a strong case for action • Articulate a shared policy framework • Describe a shared narrative for tackling leading causes of preventable ill health and death • Set out public opinion data in support of action • Include new analysis to support joint action focused on the impact of risk factors on health disparities 2. Dissemination and engagement strategy • Develop and implement a dissemination strategy for the report with proactive parliamentary engagement • Develop localised materials based on report findings and insights • Broaden the remit of existing communication channels within alliances, notably ASH Daily News. • Develop a shared communications approach for the networks within AHA, OHA and SFAC including Smokefree Pregnancy Network, Mental Health and Smoking Network, Smokefree Councillor Network. 3. Roadmap to sustainability • Produce a plan for future collaboration following the end of this project.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Electronic cigarette packaging in context: an exploratory study
Funder: Cancer Research UK

Abstract: Background Smoking is the greatest modifiable risk factor for cancer. Electronic cigarettes may reduce cancer risk by increasing the number of people who stop smoking successfully and/or replacing smoking for people who would otherwise have smoked. However, despite evidence showing minimal regular use of e-cigarettes amongst under-eighteens, there have been concerns that children may be attracted to vaping and calls for a precautionary ban on e-cigarette descriptors which reference popular confectionery, and packaging which includes cartoon images popular with children. Conversely, there have been concerns that the mandatory health warnings on e-cigarette packaging may put off smokers looking to switch. Aims This study will explore: 1) how e-cigarette packaging is perceived by young people and adults, smokers, vapers, dual users and never-smokers 2) the role of packaging in decisions to try e-cigarettes or to use them regularly, or to use one device or liquid rather than another 3) whether young people are particularly likely to try or use devices or liquids with names that reference popular confectionery, or packaging which includes children’s cartoon characters 4) awareness of the current health warnings on e-cigarette packaging, whether this plays a role in beliefs about relative risks of smoking and vaping, and likelihood of switching from smoking to vaping, and whether a modified health warning would increase this. Methods We will interview 40 people aged 16 to 40 in four areas of deprivation and high smoking prevalence in the North of England, Scotland and Wales about their experience of e-cigarettes in their immediate environment. We will ask which products they know, which they or their family and friends use, which do they regard as attractive or off-putting, what they and people around them purchase and why, whether they have seen the health warnings on e-cigarettes, how they understand the relative risk of smoking and vaping, how they perceive e-cigarette packaging and how they understand its role. For context, we will interview 10 staff in independent vape businesses in the fieldwork areas about customer preferences on packaging. Value The study will build our understanding of e-cigarette packaging in the UK to help determine whether further regulations on e-cigarette packaging are needed, and if so, provide recommendations to help the Government in developing guidelines that help make e-cigarette packaging both more appealing to their intended audience (people who smoke) but also less appealing to young people and people who don’t smoke.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS
Title: Novel combination therapeutic approaches to improve outcome in patients with pancreatic cancer
Funder: Cancer Research UK

Abstract: Aim: To develop innovative, multimodality approaches to improve the outcome for patients diagnosed with pancreatic adenocarcinoma (PDAC) The Jodrell Lab is developing new multimodality, therapeutic combinations in models of pancreatic ductal adeno¬carcinoma (PDAC). Rapid translation of discoveries from the laboratory into the clinic is facilitated by Jodrell’s leadership of the Cambridge ECMC, including an NCRI listed CTU and Early Phase Trials’ Team. Studies of DNA Damage Response (DDR) inhibitors and gemcitabine have identified new mechanisms of synergy and led to a clinical Phase I trial of the ATR inhibitor, AZD6738 with gemcitabine (ATRiUM), commencing in Q4 2018. ATRiUM will utilise an innovative, model based combination Phase 1 design (developed in collaboration with the MRC Biostatistics Unit), evaluating both dose and schedule, simultaneously. Correlative studies, performed in the Jodrell Lab, will include detailed evaluation of the immune tumour microenvironment (iTME), following treatment, to assess the potential for adding immuno-therapeutics to future combinations. The expansion phase of the ATRiUM trial will recruit patients with PDAC from collaborating centres in the Precision-Panc consortium, which shares our aim to accelerate translation of scientific discoveries, to improve outcomes for patients with PDAC. The Lab has also identified and characterised the phenomenon of “immune privilege” in PDAC, related to the chemokine CXCL12’s interaction with the chemokine receptor, CXCR4. We have shown that this can be overcome by the administration of the CXCR4 inhibitor, AMD3100, leading to an ongoing proof of concept study, CAMPLEX (supported by SU2C and the Lustgarten Foundation). Correlative studies (performed in the CRUK Cambridge Institute (CI)) have demonstrated (by RNAseq) in patients with micro-satellite stable colorectal cancer, evidence of immune activation. These data support (and planned preclinical scheduling studies will inform) the design of a phase 2 study of AMD3100, in combination with an immune checkpoint inhibitor (e.g. anti-PD1 Ab), CAMPLEX-2. The excellent CRUK CI core facilities support our preclinical studies, including genomic analyses (e.g. WGS, RNAseq), advanced microscopy, PK and bioanalysis, preclinical imaging (e.g. PET) and a radiotherapy platform. The latter, supports our multimodality combination approaches, including irradiation, small molecule DDR inhibitors, findings which will be translated into clinic trials (PORTICO). Novel therapeutics are acquired through collaboration (e.g. AstraZeneca/ MedImmune DDR-targeting and immuno-therapeutic assets). Novel technologies e.g. MS Imaging (collaboration with AZ) for drug distribution/PD effects, and mass cytometry (CyTOF Hyperion Imaging System), to map the immune landscape spatially, are accessed through collaboration with CRUK Grand Challenge Teams.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS