NIHRDataInsights/HRCSData huggingface dataset:
Title: Integration of physiological tissue models and machine learning to understand genomic instability from oncogene activation to cancer initiation
Funder: Medical Research Council

Abstract: Genome instability is a hallmark of cancer but the causes of genome instability that drive cancinogenesis are poorly defined. Oncogene expression during carcinogenesis is thought to induce oncogene induced replication stress (Oi-RS) which is proposed to induce subsequent mitotic defects and genome instability. However, longitudinal data supporting this hypothesis are sparse due to limited access to appropriate disease progression models. This project will investigate the current major unknowns in oncogene-induced genomic instability using a primary cell-based, physiological model of HPV establishment and oncogenic disease progression. Oncogenic human papillomaviruses (HPV) express viral oncogenes E6 and E7, which induce replication stress and genomic instability, eventually causing carcinomas of the anogenital and oropharyngeal tracts. HPV infection thus provides a tractable model system in which to decipher the pathway from initial Oi-RS to cancer. The impact of HPV infection on genomic instability has mainly been studied by overexpression of viral oncogenes in primary epithelial, or cancer cell lines, which fail to accurately recapitulate natural pathogenesis of HPV. We will now employ a state-of-the-art 3D primary human tissue model that faithfully recapitulates the HPV infection cycle to dissect the timing and mechanisms of Oi-RS, genomic instability, and oncogenesis. We will integrate state-of-the-art cell and molecular biology methods with single cell and single molecule sequencing technologies and machine learning-based detection of genomic position-resolved replication stress. In depth analysis of these models using methods established outside of the traditional cell biology arena will uncover key driving events in HPV-driven carcinogenesis that will be directly applicable in other oncogene-induced tumours. The findings will define the steps from initial oncogene-induced replication stress to cellular immortalisation and disease progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Opportunity-Led - Rapid development of a digital COVID Support Module for Cancer Carers
Funder: Public Health Agency, NI

Abstract: Objectives: The COVID-19 pandemic has greatly affected the delivery of cancer care. Due to social restrictions and reductions in health service contact it is expected that the burdens experienced by informal carers has risen. This study provides an analysis of cancer carer’s health, Quality of Life (Qol) and experiences during the first wave of the pandemic. Methods: An online mixed method longitudinal design was used. The survey included measures of health status (EQ-5D-5L), Quality of Life (WHOQoL-BREF) and impact of COVID-19, and open ended questions. Data was analysed descriptively and regression analysis used to identify predictors associated with poor Quality of Life. Open ended responses were analyzed thematically according to Miles and Huberman techniques. Results: Of the 196 respondents n=142/72.4% experienced challenges related to anxiety and depression; 35.2% rated these problems as slight with 25% rating these as moderate and 11.2% as severe. In the WHOQOL-BREF questionnaire carer scores for physical (median=71.43), psychological (mean=58.59), social relationships (mean=57.95) and environmental (mean=71.88).Qualitative analysis identified negative impacts of the pandemic on psychological health, social isolation, finance and access to health services. Conclusions: Carer’s challenges have deepened throughout the COVID pandemic. There is a need to develop innovative ways to provide support for carers to provide palliative and supportive care at home. Due to the need for infection control meaningful development and integration of digital technology might be the most feasible solution.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Experiences of diagnostic pathways and cancer care during the COVID-19 pandemic
Funder: Yorkshire Cancer Research

Abstract: The public lockdown and NHS reorganisation needed to deal with the COVID-19 pandemic had a major impact on cancer care, with far fewer people being referred to hospital for possible cancer symptoms, or receiving treatment for an existing cancer diagnosis. This study will interview patients, their caregivers, hospital doctors and GPs to find out about their experiences of diagnosis, care and treatment for cancer during the pandemic. This will help us to get a better understanding of what happened, so that we can improve how cancer care is delivered during future health pandemics such as this one.

Lay abstract: The public lockdown and NHS reorganisation needed to deal with the COVID-19 pandemic had a major impact on cancer care, with far fewer people being referred to hospital for possible cancer symptoms, or receiving treatment for an existing cancer diagnosis. This study will interview patients, their caregivers, hospital doctors and GPs to find out about their experiences of diagnosis, care and treatment for cancer during the pandemic. This will help us to get a better understanding of what happened, so that we can improve how cancer care is delivered during future health pandemics such as this one.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Addressing the double burden of HIV and cervical cancer: benefits and costs of integrating care in Kenya
Funder: Wellcome Trust

Abstract: In Kenya, cervical cancer is the leading cause of cancer deaths among women. The Ministry of Health wants to scale-up preventative screening and treatment to reduce this burden but has limited funds. It has been suggested that providing services for two diseases in one clinic is more cost-effective than providing them in separate clinics, because services share the delivery platform (clinic) and costs of inputs such as diagnostic equipment. However, joint service provision may also be less cost-effective, because the efficiency gains from sharing delivery platforms only materialize if there is spare capacity to deliver both services; otherwise, one intervention with comparably lower benefits may crowd out another with higher benefits. This means that it is unclear whether the ministry should invest in integrated or separate services for cervical cancer. Our project will test the hypothesis that integrating services for cervical cancer with services for Human Immunodeficiency Virus (HIV) is more cost-effective than providing the screening separately. We will collect data on the cost of providing care and on the number of patients seen, then compare the cost-effectiveness of integrated services to separate services. Our findings will be translated into recommendations to the Kenyan Ministry of Health.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Economic modelling of cervical cancer control interventions in sub Saharan African countries: A scenario analysis of the 2030 elimination targets for Nigeria
Funder: Wellcome Trust

Abstract: Sub-Saharan African countries continue to bear the burden of cervical cancer. High cancer incidence and high mortality rates can be decreased by available evidence-based interventions, such as vaccination, screening, and early referral for treatment, if they are implemented on a large scale. The large-scale programs though are expensive and not always affordable in low-income countries. In this study, I aim to examine the economic costs and effect of the World Health Organization cervical cancer elimination strategy in Nigerian health system by 2030. The strategy involves attaining immunisation coverage of 90% for Human papilloma virus (HPV) vaccination, cervical cancer screening coverage of 70% and 90% treatment targets for identified cases . I will review existing literature, conduct key informant interviews and simulation exercises to provide evidence on the appropriate resources and infrastructural investments required to attain the targets for HPV vaccination, cervical cancer screening and treatments of pre-invasive and invasive cervical cancer in Nigeria by 2030. The study will provide evidence to guide decision makers in Nigeria and other sub-Saharan countries in allocating resources to address cervical cancer control in a robust, evidence-based and equitable manner.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Identifying the genetic determinants of Fusobacterium associated with diarrhoeal disease and colorectal cancer in Vietnam
Funder: Wellcome Trust

Abstract: The gut microbiome and its dysbiosis play a central role in understanding infectious and non-infectious conditions. Evidence suggests Fusobacterium nucleatum, an oral anaerobic bacterial pathobiont, potentiates colonic tumourigenesis. My recent work in Vietnam indicates that Fusobacterium, including F. nucleatum, is also enriched in the gut microbiome of children during infectious diarrhoea. My aim is to define the role of Fusobacterium in the resolution of infectious diarrhoea and the development of colorectal cancer, through integrating 16S rRNA-based metagenomics in two distinct clinical studies in Vietnam. I will examine the impact of Fusobacterium gastrointestinal overgrowth and microbiome dysbiosis on diarrhoeal duration in children. Additionally, I will measure the prevalence and distribution of F. nucleatum in the microbiomes of gut mucosa taken from colorectal cancer patients. I will perform whole genome sequencing on the F. nucleatum isolated from collected saliva, diarrhoea stools, and colonic tumour mucosa. Using genomics and phylogenetic analyses, I aim to identify genetic factors associated with F. nucleatum colonization in different human body compartments (oral, colonic) and pathological states (tumour, non-tumour). These findings will enable future in-depth studies, contributing to the development of non-invasive diagnostic marker for colorectal cancer and targeted Fusobacterium therapies in these two diseases.

Lay abstract: The bacterium Fusobacterium nucleatum commonly resides in the human mouth, but its presence in the gut could contribute to the development of colorectal cancer in adults and potentially the resolution of diarrhoea in children. Here, I will investigate whether Fusobacterium overgrowth in the gut affects the duration of childhood diarrhoea and measure the prevalence of F. nucleatum in the gut of colorectal cancer patients in Vietnam. I will study the bacterial communities in clinical samples (saliva, stool, gut tissue) by analysing the composition of a bacterial barcode gene (16S rRNA). I will grow F. nucleatum from collected samples and compare these organisms’ genetic content, to assess which F. nucleatum genes are associated with colonization in colorectal tumours and different human organs (mouth, gut). My project will define the role of Fusobacterium in these two critical diseases, and help designing effective therapies to counter Fusobacterium colonization in the human gut.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Human retroviral latency: regulation and dynamics at the single-cell level
Funder: Wellcome Trust

Abstract: Latent persistence of retroviruses, including HIV-1 and the human leukaemia virus HTLV-1, remains a major barrier to their eradication from the host. HTLV-1 appears to be latent in circulating lymphocytes, but the strong, persistently activated immune response indicates that the virus is not latent in vivo. We infer that HTLV-1 undergoes intermittent bursts of gene expression. We have now obtained direct evidence of HTLV-1 gene bursts in naturally-infected cells in vitro. The central question “What regulates HTLV-1 latency?” therefore becomes “What regulates the gene expression bursts of HTLV-1?” We have developed a powerful set of materials and techniques to identify the causes and quantify the kinetics of this gene bursting at the single-cell level. A major regulator of mammalian gene expression is the key chromatin architectural protein CTCF. We recently discovered that the HTLV-1 provirus binds CTCF and alters the higher-order structure of host chromatin. In this programme we will investigate the consequences for both the virus and the host cell of this remarkable experiment of nature. The results of this work will answer fundamental questions on the persistence and pathogenesis of HTLV-1, and contribute to the growing understanding of mammalian gene bursting.

Lay abstract: The human leukaemia virus HTLV-1, related to HIV, causes an aggressive leukaemia in 5% of the people it infects, but how it does so is not understood. Like HIV, HTLV-1 integrates into the DNA of the infected cell, where it can lie dormant and so avoid elimination by the immune response. Evidence from our studies of patients’ lymphocytes and the immune response, and very recent data from our molecular biological studies of HTLV-1-infected cells in the laboratory, show that the virus is carefully regulating its activity by causing intermittent bursts of expression of its genes, after which it returns to its dormant state. We have assembled a powerful set of materials and techniques to identify the causes and quantify the kinetics of this gene bursting at the single-cell level. The results will answer fundamental questions on the persistence and pathogenesis of HTLV-1, and contribute to the growing understanding of mammalian gene bursting. We recently discovered that HTLV-1, when integrated into host DNA, can cause abnormal folding of the DNA. We aim to test the hypothesis that this abnormal folding in turn causes abnormal gene activity in the cell, which might be a significant cause of the leukaemia.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Impact of COVID-19 on breast cancer services and patients
Funder: Breast Cancer Now

Abstract: Background Globally, breast cancer screening, diagnosis and treatment services have been significantly impacted by the COVID-19 pandemic. Locally, the Northern Ireland Cancer Registry (NICR) reported a 34% reduction in pathological diagnosed breast cancers between March and June 2020 compared with the similar period 2017-2019. Aim The proposed mixed methods project aims to improve outcomes for male and female breast cancer patients by documenting the impact of COVID-19 on their care and identifying areas where service improvements are needed now and in the future. Techniques and Methodology We will in the secure (ISO 27001 accredited) environment of the NICR compare data from approximately 2,200 breast cancer patients diagnosed in Northern Ireland (NI), half from March to December 2020 (COVID-19 era) the remainder from 2018 (PRE-COVID-19). We will examine method of presentation (screening/ emergency), investigations, comorbidities (including COVID-19), molecular markers, stage, treatment and survival. We will also measure adherence to relevant National Institute for Health and Care Excellence (NICE) breast cancer guidance. To ensure the voices of patients are heard, we will supplement registry work with an ethically approved, self-completed, online survey using similar methodology to “Investigating the Impact of COVID-19 on Caregivers and Patients” (IMPaCCT) and undertake in-depth qualitative interviews about the lived experience of breast cancer patients during the pandemic. Clinicians and patients will be part of the research project via regular steering committee meetings. Impact on breast cancer research This study will provide new information on the impact of COVID-19. This will aid service recovery and safeguarding of breast cancer services in the UK should future disruptions occur and enable comparisons with similar national/international data. Anonymous datasets generated will facilitate further studies investigating the impact of COVID-19 on breast cancer patients including long term survival and will be available for use by other researchers e.g. NI biobank.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: The role of RL13 in human cytomegalovirus pathogenesis
Funder: Division for Social Care and Health Research (Wales)

Abstract: Human cytomegalovirus (HCMV) infects the majority of individuals worldwide, producing a lifelong infection that dramatically alters the immune system. If caught during pregnancy, it can lead to death of the foetus, or the foetus can be born with permanent disabilities including mental retardation, deafness or blindness. This affects >1,000 babies every year in the UK - more than Downs Syndrome. However HCMV also offers a unique possibility. By far the strongest immune response raised to any infectious agent is made to CMV, and following animal studies, CMV has unexpectedly emerged as the best candidate vaccine carrier against human immunodeficiency virus (HIV). The advent of CMV as a vaccine carrier, and the need to develop anti-HCMV vaccines, has highlighted fundamental virological issues that need to be urgently addressed. When clinical isolates are grown in the laboratory, they change. They rapidly lose the ability to infect a wide range of cell types, and become less ‘cell associated’. Consequently, it isn’t possible to accurately model how well vaccines work, and how well HCMV-based vaccine carriers protect against other diseases, using lab-grown viruses. We have determined exactly how CMV changes in the lab, and developed unique technologies to reverse these changes; clinical virus contains a gene called RL13, but virus grows poorly in the lab unless RL13 is inactivated. However once RL13 is inactivated, virus growth is dramatically altered, and virus interacts differently with the immune system. It is therefore imperative that research labs are able to work with virus containing RL13, particularly when developing vaccines and therapeutics. This project will determine why RL13 stops virus growing in the lab. It will circumvent this limitation, enabling us to grow HCMV-based vaccine vectors containing RL13, and will determine whether RL13 is required in vaccine vectors to provide optimal protection against HIV or cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Deciphering the complex mechanisms that reprogram gene expression and promote Epstein Barr Virus replication.
Funder: Medical Research Council

Abstract: The aim of this research is to determine the molecular mechanisms that determine activation and repression of gene expression by Zta. Two cell systems representing natural lineages for EBV replication will be used. (a) Modified B-lymphoma cells (Akata) that harbour latent EBV and a truncated CD2 gene under the control of an EBV lytic cycle promoter. Upon stimulation with anti-IgG, a subpopulation of cells express Zta and enter lytic cycle; those cells express the truncated surface CD2 protein that can be physically isolated using paramagnetic beads coated with anti-CD2 antibody. (b) HEK 293 cells harbouring latent EBV will be transfected with a Zta expression vector to stimulate lytic cycle. This process is efficient and no selection is necessary. Cells will be harvested for several assays: (i) Proteins and DNA will be cross-linked using formaldehyde, and chromatin prepared for chromatin precipitation assays (ChIPs) with commercial antibodies. Libraries will be generated using reagents from Illumina. Second-generation DNA sequencing, data processing and alignment to the genome will be undertaken at UCL Genomics. (ii) RNA will be prepared, and cDNA generated for the quantitation of gene expression using Q-PCR with gene-sepcific TaqMan reagents from ABI. (iii) DNA will be harvested and bisulphite converted. The Illumina Infinium Methylation Assay will be undertaken at UCL Genomics on a human gene regulatory region array. Zta carrying a HaloTag (Promega) will be expressed transiently in cells and Zta and associated proteins purified using Halo-Link resin (Promega). Mass spectrometry of the purified protein will be undertaken using nano-scale liquid chromatography MS/MS at the University of Sussex proteomics facility (Dionex Ultimate U3000/ThermoScientific LTQ-Orbitrap Hybrid FT-MS/MS). Immuneprecipitation/western blot analysis will be used to validate interactions, with further analysis using ChIP for Zta followed by re-CHiP for the associated protein.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: KIR in adaptive immunity: in vivo relevance for human disease
Funder: Medical Research Council

Abstract: We have clear and consistent evidence that the presence of a host gene, namely KIR2DL2, enhances both protective and detrimental HLA class I associations in two unrelated chronic viral infections. What is much less clear is the underlying mechanism of action. Epistatic HLA-KIR associations are typically attributed to direct NK-mediated lysis of virus-infected cells. We believe direct NK killing is not compatible with our observations and instead hypothesise that the downstream effectors of KIR2DL2-dependent enhancement are CD8+ T cells. We wish to test this hypothesis and to explore the generality of this KIR2DL2-enhancement by investigating whether KIR2DL2 also impacts on the probability of developing virus-associated malignancy. Importantly, we suggest that KIR2DL2 consistently enhances the efficiency of the CD8+ T cell response; this does not imply that KIR2DL2 is consistently beneficial to human health as KIR2DL2 also enhances the efficiency of CD8+ T cells restricted by detrimental HLA alleles. Approach. We will take an integrated theoretical and experimental approach. We will study 3 patient cohorts. 1) HCV: 60 HCV-HIV coinfected individuals with acute HCV. 2) HTLV-1 (UK): 30 individuals chronically infected with HTLV-1. 3) HTLV-1 (Japan): 240 adult T cell leukemia/lymphoma (ATLL) cases and 200 HTLV-I-infected healthy controls. To compare the strength of the CD8+ T cell response between KIR2DL2+ and KIR2DL2- individuals we will use next generation sequencing of the HCV genome (Illumina HiSeq), mathematical modelling of host-pathogen dynamics including parameter inference and model selection, ex vivo CTL and NK killing assays and HLA class I epitope prediction. To assess the impact of KIR2DL2 in adult T cell leukemia/lymphoma we will use HLA and KIR genotyping, epitope prediction, logistic regression and Monte Carlo methods in a case-control cohort.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION