NIHRDataInsights/HRCSData huggingface dataset:
Title: Development, piloting and initial evaluation of an intervention to improve information exchange in surgical consultations for complex head and neck cancer surgery.
Funder: Department of Health (England)

Abstract: Surgeons talk to people before operating on them, but what is said during consultations is rarely studied. This project will develop an information set that surgeons can use in consultations with people with head and neck cancer. Literature reviews will assess currently-available information. Interviews with surgeons and patients, and recordings of consultations, will allow analysis of current practice of verbal information provision and identify the information needs of patients. Surveys will reduce all of this to a core information set that will be tested in real consultations. This will lead to improved standards of information provision for patients by surgeons.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Non-invasive Exhaled Breath analysis for the prediction of Oesophago-Gastric cancer
Funder: Department of Health (England)

Abstract: Despite improvements in a range of chemo-, radio- and surgical therapies, the overall survival at five years from oesophago-gastric cancer remains poor and ranges from 10% to 30%. Endoscopy is an expensive invasive test, in which cancer is not present in more than 95% of cases. Breath testing may be able to non-invasively determine the risk of cancer, to allow more appropriate allocation of further investigations, earlier treatment and improve survival. The aim of this research is to develop and validate a breath test to predict oesophago-gastric cancer therefore allowing earlier diagnosis and introduction of treatment.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C)
Funder: Department of Health (England)

Abstract: To determine whether methylation analysis of surveillance biopsies taken from ulcerative colitis patients can improve the early detection of neoplastic change this project is organised in 3 modules: 1: Optimisation of methylation biomarkers in a retrospective study of bowel mucosal samples collected from 160 cases (harbouring colorectal neoplasms and 320 controls (low risk colitis patients) from three hospitals.2: Technology Development within BUMP evaluating a high-throughput next generation bisulphite sequencing approach delivering a robust analytical pipeline.3: A prospective multicentre test accuracy cohort studyStudy Population: Chronic ulcerative colitis of over 10 years with disease beyond the splenic flexure in protocolised surveillance program.Index and reference test: Mucosal biopsies taken for histology subjected to a supplementary DNA methylation test. Methylation positive patients will undergo a further colonoscopy (reference test) at 4- 6 months as well as a random sample of twice as many methylation test negative patients.Primary outcome: The occurrence of dysplasia in mucosal biopsies taken at follow up colonoscopy at 4-6 months in patients demonstrating hypermethylation (the positive predictive value).Sample size: Undertaking the tests in a cohort of 1000 will provide over 90% power to prove that the positive predictive value is over 15% with a 5% significance level and have over 90% power to show the diagnostic odds ratio is significantly (P<0.05) different from one. .Statistical analysis: Analysis for the primary outcome will estimate positive and negative predictive values of methylation as the proportion of those methylation positive at the initial colonoscopy who are detected with CAN at the reference colonoscopy and the proportion methylation negative who are free of CAN at the reference colonoscopy respectively. Milestones:Module 1: collation of FFPE samples (– 6 months). Validation of b) our markers (- 9 months) published markers ( – 18 months). Failure to show acceptable performance of markers - No-Go decision.Module 2: assay development 15 months protocolisation of the analysis– 18 months. Failure to develop a robust assay will prompt reverting to existing pyrosequencing assay.Module 3: will be IRAS approval across all sites-15 months recruitment months 18 - 26 IDMC review at months 24 and 30.


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;ORAL AND GASTROINTESTINAL
Title: Flexible Single-Optical-Fibre Endoscope
Funder: Engineering and Physical Sciences Research Council

Abstract: Recently, researchers at Massachusetts Institute of Technology and Korean University demonstrated a single multimode-optical-fibre (MMF) imaging endoscope. Compared with conventional fibre-bundle based endoscopes, this device is ultra-slim, high-resolution, wide-field, lensless, low cost and disposable. The main drawback of such devices is that they cannot be used as flexible endoscopes due to image blurring caused by fibre-shape variation. However, flexible endoscopes are viewed as most desirable and are widely used in modern healthcare. In order to overcome this problem, this research aims to develop the world's first flexible single-fibre endoscope system by using a novel speckle monitoring technique. The monitoring module will consist of a calibration beam and associated optics to monitor the real-time changes in mode coupling induced by fibre movement and bending. The monitoring results will be used to predict MMF imaging transmission matrix for original image restoration. At the end of the project, a prototype device together with real-time software and algorithms will be developed for potential clinical trials and translational research. The project is highly interdisciplinary: it brings together expertise in the areas of optics, instrumentation, imaging, signal processing and surgery. The outcome of the proposed research has the potential to put the UK at the forefront of a crucial emerging area of new medical devices for modern endoscopy, which is likely to have a huge impact not only on research and patient well-being, but also on the UK and global economy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Definition of human intestinal mesenchymal origins and of mesenchymal epithelial cross-talk in health and disease
Funder: Medical Research Council

Abstract: Here we will use 10x genomics droplet based scRNAseq to sequence upwards of 100,000 mesenchymal and epithelial cells during human foetal development and in specific disease contexts in adults. Data will be analysed using FastQc software, the 10x genomics Cell Ranger software suit, and R for further processing. 'Seurat' R package will be used to normalise expression values. Clustering will be performed prior to dimensionality reduction using PCA and data clustered in the reduced dimension space using "Seurat" package prior to visualisation using tSNE plots and assessments of batch distributions for each dataset visualised to ensure clustering not driven by batch effects. Cluster markers will be recorded together ontology enrichment analysis for each cluster. Cell differentiation trajectories will be reconstructed using R Package "monocle". To identify putative lineage regulators we will identify factors that change between phenotypic branches using branched expression analysis modeling. We will validate our findings by confirming anatomical segregation of novel populations of cells with differing functions or in differing disease states. Here we will use immunohistochemistry (IHC), single-molecule in situ hybridisation (sm-ISH) and immunofluorescence. The relationship of individual colonic mesenchymal niche cells with specific epithelial cells will be examined using novel multiparameter imaging technologies such as Codex, imaging mass cytometry (IMC) or multiplexed ion beam imaging (MIBI). We will develop methods to isolate/sort newly identified progenitor cells and test how these differentiate into stromal cell states we know to exist in health and disease in the adult colon. We will use CRISPR/Cas9 gene targeting to remove key transcriptional determinants associated with cell differentiation stages to establish their role in shaping mesenchymal architecture in health and disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Identifying a Wnt pathway inhibitor for stem cell maintenance in IBD
Funder: Medical Research Council

Abstract: Inflammatory bowel disease (IBD) represents a major healthcare burden which affects approximately 5 million people worldwide. Ulcerative colitis (UC) is one of the main forms of IBD which affect the colon and rectum. UC involves several aberrations as defects in epithelial barrier function, overactivated host defence pathways, atypical immune regulation, and failing tissue repair. Unfortunately, less than half of UC patients do not show response to current therapies (e.g. anti-TNF agents). Additionally, UC patients exposed to chronic inflammation and in consequence to active tissue regeneration have a 1 in 3 lifetime risk of colorectal cancer. So, there is an urgent need of more successful treatments. In IBD the inflamed intestinal tissue fails to repair because chronic inflammation reduces the intestinal stem cell population which is responsible for tissue reparation. Intestinal stem cells modulated by Wnt pathway are capable of self-renew as well as produce more specialized progenies to replace damaged cells. We have found that a novel Wnt inhibitor which is upregulated in intestinal inflammation, decreases stem cell activity and in consequence impairs tissue regeneration. These findings were confirmed by using mouse models and murine 3D-organoids. In this project, we aim to discover new mechanisms to re-activate stem cells by blocking this protein function. We will study its mechanism of action; we will find the unknown receptor and we will test blocking antibodies. Our findings will characterize the mechanism of inhibition in attenuating the inflammatory response by using an innovative human UC enteroid model derived from patient's samples and healthy volunteers. Despite ongoing efforts in mouse models, clinical paradigms in IBD are still imprecise and human 3D organoids will help to understand basic mechanisms driving the disease forward and test treatment's efficiency. In conclusion, we aim to discover a novel therapeutic approach for UC patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: The role of IDH mutation in liver cell plasticity and cancer
Funder: Wellcome Trust

Abstract: The application of next generation sequencing to bile duct cancers (cholangiocarcinoma) has revealed a subgroup with mutations in the Isocitrate Dehydrogenase (IDH1, IDH2) genes, which appear non-overlapping with other drivers including TP53 and KRAS and which are associated with relatively favourable, but still poor, clinical prognosis. IDH1/2 mutations result in neomorphic production of the oncometabolite 2-hydroxyglutarate (2HG), which causes cell toxicity, DNA hypermethylation, and repression of cellular differentiation. This project tests two hypotheses. First, it seeks to determine whether 2HG production can metabolically reprogramme liver cell identity, triggering a cell fate change from a hepatocyte to a biliary phenotype, thereby promoting the formation of cholangiocarcinoma. I will seek to define the cell populations in the liver in which IDH1 mutations occur in disease and use lineage tracing techniques to establish whether IDH1 mutation results in an increase in hepatic progenitor or ductal cells in vivo, as well as which cell types give rise to these ductular reactions. Second, I shall examine whether 2HG causes non-cell-autonomous local toxicity or inflammation, and determine whether this contributes to tumorigenesis. My results will elucidate fundamental mechanisms of biliary carcinogenesis and suggest the likely efficacy of targeted 2HG inhibition or, indeed, 2HG overexpression.

Lay abstract: Cholangiocarcinoma (cancer of the bile ducts) is a highly aggressive liver cancer with currently no curative treatment options aside from major surgery, for which few patients are eligible. Cancers, including cholangiocarcinoma arise when DNA is damaged or mis-coded (mutations). This fellowship seeks to investigate the role that mutations in a gene known as IDH1 play in the development of bile duct cancer. Specifically I wish to discover whether a substance known as 2HG produced when IDH1 mutation occurs, is able to 're-programme' or change the identity of cells from liver cells (known as 'hepatocytes') into bile duct cells ('cholangiocytes') and whether this change promotes the formation of bile duct cancer. I wish to establish whether in fact IDH1 mutation occurs in liver cells or bile duct cells in disease and whether the mutation promotes local inflammation or toxic injury to cells which might be then targeted in designing new treatments.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Epidemiology and molecular pathology epidemiology of Barrett's oesophagus and oesophageal adenocarcinoma in the modern treatment era
Funder: Cancer Research UK

Abstract: Background Oesophageal cancer has been identified as a cancer of ‘unmet need’, due to its poor survival rates. There are opportunities for early detection of, and therefore better survival from, oesophageal adenocarcinoma (OAC) through detection and surveillance of Barrett’s oesophagus. Recent advances provide opportunities for prevention through novel therapies such as radiofrequency ablation (RFA) and endoscopic mucosal resection (EMR) for dysplastic Barrett’s oesophagus. Several modifiable risk factors, such as smoking and obesity, have also been identified for OAC, but our understanding of how these may influence survival is limited. There is also a lack of understanding of how modifiable risk factors interact with molecular features of OAC, and molecular pathology epidemiology (MPE) studies are required to provide insight into such relationships. Aims 1. To evaluate population trends of Barrett’s oesophagus, low and high grade dysplasia, and OAC progression and survival in the modern treatment era. 2. To conduct MPE studies of the interaction between modifiable risk factors and relevant molecular features of OAC, and their impact on survival outcomes. Methods In Aim 1, data from the Northern Ireland Barrett’s oesophagus register will be analysed. The NI Barrett’s register is the only population-based register in the UK, and will be updated to 2020, to include over 22,000 patients. Analyses will evaluate the potential impact of RFA/EMR on temporal trends in dysplasia diagnoses, and progression across the Barrett’s-dysplasia-adenocarcinoma sequence, and survival rates. For Aim 2, data and samples from over 3,000 OAC patients within the UK-wide ‘OCCAMS’ consortium, will be analysed. Using available somatic mutation data, and immunohistochemical biomarker expression, I will evaluate a number of modifiable risk factors in relation to OAC survival stratified by newly identified molecular subtypes of OAC, in order to evaluate their interactions and impact on survival. Additional analyses will evaluate: (i) smoking, TP53 mutations and p53 expression, (ii) vitamin D-related genetic variants and vitamin D receptor expression, (iii) aspirin use, COX-2 expression and PIK3CA mutations, and (iv) obesity, APOBEC genes, leptin and adiponectin expression; and their impact on survival. How the results of this research will be used Evaluation of up-to-date epidemiological trends in Barrett’s oesophagus and OAC will estimate the potential impact of new treatments and guidelines on progression and survival outcomes. Insights from MPE studies will inform whether personalised lifestyle interventions (e.g. smoking cessation, vitamin D supplementation, aspirin, weight loss) should be targeted at individuals according to molecular characteristics of their OAC detected.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Orphan GPR35 controls the quintessential sodium-potassium pump
Funder: Wellcome Trust

Abstract: We discovered that GPR35 interacts with the &alpha;1-chain of the sodium/potassium ATPase (Na/K- ATPase) and thereby controls its pump and signalling function. GPR35T108M, which confers genetic risk for ulcerative colitis and primary sclerosing cholangitis, increases Na/K-ATPase's pump function by 25%, while deletion of Gpr35 decreases it by 30%. GPR35 also activates Na/K-ATPase-dependent Src signalling, and Gpr35–/– mice are protected from developing tumours. Considering Na/K-ATPase’s quintessential role in maintaining the electrochemical gradient of a cell, we will (1) address the structural basis of GPR35’s unique interaction with Na/K-ATPase. We will use molecular biological, biochemical, and structural (cryo-EM) methods to address this. (2) We will elucidate the role of GPR35 in innate and adaptive immunity and its dependency on Na/K-ATPase. GPR35 is expressed in immune and intestinal epithelial cells. Albeit endothelial cells do not express GPR35, we observed changes in vascularisation in tumour tissue and aortic rings. This prompted us to (3) study the role of GPR35 in angiogenesis. We will test how GPR35 modulates the interaction of macrophage, fibroblasts and endothelial cells and the consequent effects on vascularisation and therefore tumour growth and size.

Lay abstract: GPR35 is a membrane receptor highly expressed in the intestine and immune system. A variant of the receptor increases risk for inflammatory diseases of the intestinal tract. We found that GPR35 uniquely forms a complex with the sodium/potassium pump (Na/K-ATPase) and promotes its pump and signalling function, which is further increased with the disease risk variant. This is important since Na/K-ATPase maintains intracellular electrolytes in all cells. GPR35 thereby plays a role in tumour promotion. In this fellowship, I will investigate (1) how GPR35 interacts with Na/K-ATPase and promotes its function. (2) How GPR35 affects the function of the immune system, to understand how it predisposes for disease. And (3), how GPR35 affects the neo-vascularisation in tumours and its role in the tumour micro-environment. This project may reveal how a receptor regulates one of the most fundamental cellular processes, thereby underpinning its role as a disease risk-gene.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: A randomised controlled trial of eicosapentaenoic acid (EPA) and/or aspirin for colorectal adenoma (or polyp) preve
Funder: Medical Research Council

Abstract: Scientific Abstract Research design: A randomised, double-blind, placebo-controlled 2 x 2 factorial trials integrated into the screening and surveillance phases of the National Bowel Cancer Screening Programme (BCSP). Study population: BCSP patients str


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Improve outcomes from oesophageal cancer through innovative screening and surveillance tests
Funder: Department of Health (England)

Abstract: Cancer of the oesophagus is a global problem with a high mortality due to late diagnosis. Dr Rebecca Fitzgerald plans to extend her novel approach for detecting precancerous cells in Barrett's oesophagus to molecular tests for early detection of squamous cell cancer of the oesophagus. For higher risk cases, Rebecca and her team are developing molecular imaging tools to define areas for biopsy and treatment.


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;ORAL AND GASTROINTESTINAL
Title: Interplay between cAMP and Ca2+ signalling cascades: focus on store-operated Ca2+ entry.
Funder: Wellcome Trust

Abstract: The relationship between cyclic adenosine monophosphate (cAMP) and Ca2+ signalling cascades will be investigated in primary pancreatic acinar cells and in established pancreatic cancer cell lines. Particular attention will be given to relationships between cAMP signalling and store-operated Ca2+ entry (SOCE). 1) To determine the effect of Ca2+ signaling on cAMP level, and on Protein Kinase A (PKA) and Exchange protein activated by cAMP (EPAC) activity. 2) To characterise the effect of cAMP increases on Ca2+ signalling mechanisms and specifically on SOCE. 3) To determine the effect of cAMP on junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) and on proteins involved in SOCE. 4) To determine the relative positioning of Ca2+ sensitive adenylate cyclases and ER-PM junctions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Title: Interplay between Nod-like receptor apoptosis inhibitory proteins and prostaglandins in colonic infection, inflammation and cancer
Funder: Wellcome Trust

Abstract: Maintenance of gut health is dependent on the complex interactions between different cell types in the intestines and the immune system. Communication between these cells ensures that the barrier between the body and the gut contents is not disrupted and enables threats, such as harmful bacteria, to be detected by one cell subset and eliminated by another. The interactions between these cell types are disrupted during inflammation and disease, such as colitis, cancer, and infection. Understanding these signals and how they are perturbed during disease is vital. Certain bacteria are detected using receptors called NAIPs; we aim to understand how activation of NAIPs subsequently affects the rest of the immune system and how this impacts disease development. We will delete NAIPs from epithelial cells in the gut and identify resultant changes in immune cells. We will test this in models of colitis, colorectal cancer and Salmonella infection. I will look at changes in gene expression following NAIP deletion and identify the soluble mediators which influence the immune response. This project will aid our understanding of NAIPs during inflammatory disease development and thus generate potential targets for treating these diseases in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of Mr.I-targeted biopsies in the diagnosis of prostate cancer
Funder: Department of Health (England)

Abstract: I will investigate Mr.I-targeted biopsy(Mr.I-TB) as an alternative to standard of care, 12-core trans-rectal biopsy, in the diagnosis of prostate cancer. I will carry out a feasibility randomised-controlled trial(RCT), PRECISION, comparing both techniques. I will carry out biopsy simulation studies, a systematic review on Mr.I-TB and clinician and service manager interviews to establish barriers for the introduction of Mr.I-TB into routine care. This project will inform conduct of a multi-centre full-phase RCT and will optimize the clinical applicability of Mr.I-TB to allow a new gold standard diagnostic test in prostate cancer to be established in the NHS within 5 years.


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;RENAL AND UROGENITAL