NIHRDataInsights/HRCSData huggingface dataset:
Title: Cervical HPV infection in vaccinated and unvaccinated women– new markers of infection, immunity and disease.
Funder: Chief Scientist Office (Scotland)

Abstract: There is currently a unique window of opportunity in Scotland to assess variance in immunity between women vaccinated against HPV infection to prevent cervical cancer and non-vaccinated HPV infected women. This would be the first time any national vaccine programme has been evaluated for the type of immunity induced and will allow markers of protective immunity to be determined. We will utilise specimens from the National HPV archive and a prospective cohort of women with high grade cervical disease to assess which kinds of anti-HPV antibodies are induced in serum and in the cervix. We will further assess which cytokines, chemokines and cancer stem cell markers are detectable in cervical cytology specimens and whether these might be used to predict clinically significant HPV-related disease. We will further determine whether dried blood spots are a suitable minimally invasive biospecimen to determine antibody levels to HPV in future population based studies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;3.4 VACCINES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Development of CINCk (CIN Chemokine panel) as an objective laboratory triage test for HPV infected women with clinically significant cervical disease.
Funder: Chief Scientist Office (Scotland)

Abstract: "Cervical infection with High Risk strains of Human PapillomaVirus (HR-HPV) is common. Most infections clear but persistent infection can cause lesions which, if untreated, can become cancerous. Scottish girls have been vaccinated against two of the fifteen HR strains since 2008 but immunisation does not confer 100% protection and cervical screening is still required. Internationally, screening programmes are moving towards HR-HPV-DNA testing as the primary screening modality. However, as existing tests do not distinguish clinically insignificant from significant infection, there will be a numerical discrepancy between infections detected and women who need follow-up and treatment and there is a need for further triage tests. We have initial evidence that a chemokine signature measurable in routine, HR-HPV positive cervical screening samples differentiates significant from insignificant disease. We aim to translate these findings to develop a diagnostic assay for triage of HR-HPV-positive women that would be practicable to NHS service laboratory settings. "


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Generating epidemiological, economic and attitudinal evidence to inform policy-making about HPV vaccine introduction in India and Ethiopia
Funder: Department for International Development

Abstract: Cervical cancer is a major public health problem that is much worse in developing countries due to the lack of effective cervical screening. About 40% of the world's cervical cancer burden occurs in two countries, India and Ethiopia. Most cervical cancers, and a range of less common genital and oropharyngeal cancers, are preventable with the currently available Human Papilloma Virus (HPV) vaccines. Both India and Ethiopia have started small scale HPV vaccination, but major barriers to effective national roll-out of HPV vaccine exist, and in both countries there are other important health problems competing for the limited health budget, so a strengthened economic and epidemiological case for vaccine introduction is needed to support vaccine introduction. In India, where population based cancer registries exist in 32 areas, we will undertake studies of HPV infection prevalence in young women in two age strata in settings of high, intermediate and low cervical cancer risk. These data, along with concurrently collected sociological information covering sexual attitudes and practices and other risk factors, will enable the development of mathematical models to estimate cancer risk based on HPV epidemiology. These models will enable authorities in India to focus vaccine introduction on the highest risk communities, and to generate and maintain momentum for the program. In Ethiopia we will collect HPV prevalence and sociological data to better predict cancer risk and to strengthen the government's efforts to introduce HPV vaccine. In addition, we will also conduct studies of the cost of cervical cancer disease, both in financial and human terms to better understand the value of vaccination. We will also strengthen (in India) and establish (in Ethiopia) laboratory capacity for HPV detection, while at the same time establishing baseline data to enable future measurement of HPV vaccine effectiveness in the two countries.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Defining the mechanisms driving genomic variation and virulence in Helicobacter pylori and identifying the genes / alleles responsible.
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Infection with the bacterium Helicobacter pylori (H. pylori) is the main risk factor associated with stomach cancer. This risk can result from infection with any type (‘strain’) of H. pylori. However, different strains have different disease-causing potential. This variation may be due to specific mechanisms by which H. pylori causes DNA damage in the stomach. We have begun to identify strains with different potential to cause cancer and the genes responsible for this. We have a collection of 100 European H. pylori isolates; in addition, we are currently inviting patients undergoing routine gastroscopy (a clinical procedure in which samples of tissue are collected via a tube into the stomach) to participate in research and, following informed consent, collect stomach tissue samples in the Endoscopy Unit, Singleton Hospital. These biopsies are required to grow H. pylori in the laboratory at Swansea University. We will then study the entire genetic code of the bacteria and assess DNA damage in the stomach of each participants’ stomach tissue. The isolates with potential to cause cancer need further investigation to better understand the mechanism of how they cause cancer. This involves growing them with stomach cell lines. We also have the potential to explore the genes identified in such experiments, in the stomach tissue collected from each participant. The age-standardised incidence for stomach cancer is slightly higher in Wales compared to England (Cancer Research UK, 2010) .This project is a collaboration between Abertawe Bro Morgannwg University Health Board and the internationally recognised Medical Microbiology and Infectious Disease and DNA damage groups in the College of Medicine, Swansea University. Ethical approval has been granted. This project will identify which H. pylori strains have the greatest potential to cause stomach cancer, to enable more aggressive treatment, improve our knowledge of stomach cancer and lead to better treatments.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Identification of early & late transformation events in adult T-cell leukaemia/lymphoma
Funder: Leuka

Abstract: Adult T-cell leukaemia/lymphoma (ATL) is a highly aggressive type of blood cancer that only occurs in individuals who are infected with the human T-lymphotropic virus type 1 (HTLV-1). Despite many advances in cancer treatment the survival of patients with this blood cancer remains poor. Patients typically surviving just 6-9 months following diagnosis. However, the majority of individuals with this viral infection are completely well and do not develop ATL. As yet we do not have ways to identify the people with the virus who are at most risk of developing the disease. In this project we aim to understand the process from infection of a cell to a blood cancer. The aim is then to develop the tools to identify individuals at highest risk of disease. This will allow us to offer early treatment of ATL and ideally to take steps to prevent this leukaemia. This is particularly important because current treatments rarely cure this disease. The research will be undertaken at Imperial College London, supervised by a group of scientists who are internationally regarded as experts in this field. I will be using state of the art technology to identify the damage that the virus is causing to the cell before cancer develops. The research will be carried out using stored blood samples donated by patients infected with HTLV-1 who attend the National Centre for Human Retrovirology at Imperial College Healthcare NHS Trust, London.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Cellular immunity and genetic restriction of Influenza, Hepatitis C virus infection and Hepatitis B associated heptocellular carcinoma.
Funder: Medical Research Council

Abstract: Influenza remains a global threat. The avian influenza H7N9 outbreak in China has a high death rate and is able to transmit from human-to-human. We recently established that people with a particular genetic variant of IFITM3-rs12252-C are six times more likely to suffer from severe influenza infection than those without. This variant gene is very rare in Northern European populations, but is common in the Chinese population. The IFITM3 protein is known to inhibit the entry of many RNA viruses including influenza virus into cells and it is assumed that the variant is unable to do this. The first aim of our program is to assess if a lower level of IFITM3 expression is responsible for this association and determine which immune signalling pathway and proteins are affected. The impact of this genetic variation on the efficacy of the seasonal influenza and live attenuated vaccinations will also be evaluated. HBV-associated Hepatocellular Carcinoma (HCC) is one of the leading causes of death from cancer worldwide. Of the 1 million new cases of liver cancer cases globally every year, 50% are in China. The second aim is to address whether differences in HCC microenvironment modulate the quality of HCC-specific T cells and if this is affected by the presence or absence of chronic infection by HBV. To pursue these aims, we will continue to use the cohorts established through collaborations in China and will expand to include additional cohorts in the UK and abroad. Overall, we anticipate that the two main components of our programme - to study the impact of virus restriction by IFITM3 on the nature and risk of severe influenza infection and on HCV infection, and to explore new ways of manipulating tumour associated antigen-specific (TAA) T cells in HBV-associated HCC as well as HPV and EBV associated cancers, including viral and non-viral antigens –will inform vaccine development and therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Adoptive Immunotherapy with CD25/71 allodepleted donor T-cells to improve immunity after unrelated donor stem cell transplant
Funder: Medical Research Council

Abstract: The use of matched unrelated donors (MUD) has considerably broadened the applicability of stem cell transplantation (SCT), but the T-cell depletion used to prevent graft-versus-host disease (GVHD) in this setting results in a high rate of viral complications, which are a leading cause of death after MUD SCT. We have investigated a strategy to improve immunity after SCT by giving back T-cells from the donor, having specifically removed the cells that cause GVHD by targeting activated cells expressing CD25, whilst preserving anti-viral responses. The principal advantage of this approach is that it augments immunity to multiple pathogens simultaneously with a low risk of GVHD. We have shown in a previous clinical study in children that immunotherapy with such "allodepleted" T-cells does improve immunity after transplants from half-matched parents. We now wish to extend this approach to the MUD setting in adults to maximise its clinical applicability. We have refined our method by studying the biology of the alloreactive T-cells, enabling us to design better ways of removing these cells, so that we believe we can give back more T-cells safely. We have developed a simple, robust, cost-effective and broadly applicable methodology for production of allodepleted T-cells based on immunomagnetic CD25/71 depletion and shown in clinical-scale dry runs under GMP conditions that it works effectively in the unrelated donor setting. We now propose a Phase II randomised clinical study to determine if giving allodepleted T-cells can safely improve T-cell immunity and anti-viral responses after MUD SCT in adults with acute leukaemia. If successful, this study will lay the groundwork for a larger Phase III study in collaboration with an industrial partner, to determine if this strategy reduces transplant-related mortality after MUD SCT. This approach may be of major clinical benefit to patients undergoing SCT by reducing the morbidity/mortality associated with viral infections.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: A Dose Reduction Immunobridging Study of two HPV vaccines in Tanzanian girls
Funder: Medical Research Council

Abstract: Sub-Saharan Africa (SSA) has the highest cervical cancer incidence and mortality rates in the world; however, few countries have HPV vaccination programmes to prevent cervical cancer because of the costs involved. It is considerably more expensive to deliver HPV vaccine than the traditional infant EPI vaccines. If a single dose of HPV vaccine can be shown to elicit an immune response that is likely to be effective in preventing cervical cancer, it would simplify and greatly reduce the cost of vaccine delivery. Although a 2 dose regimen in girls under 15 years was recently approved based on antibody levels from studies in high and upper middle income countries, there is increasing recognition that vaccine efficacy depends on both quantity and quality of the antibodies induced. The quality of the immune response with reduced dose regimens may be affected by intercurrent infections such as malaria or helminths. Furthermore, HPV vaccines use different adjuvants which may affect their immunogenicity, theoretically meaning that some vaccines may be more suitable for dose reduction. We will enrol 900 healthy Tanzanian girls aged 9-14 years into an unblinded, randomised, immunobridging trial with 6 arms. Girls will be randomised to receive 1, 2 or 3 doses of the bivalent (2-v) HPV vaccine or the new 9-valent (9-v) vaccine. We will examine the quality and sustainability of the vaccine immune response up to 36 months, by measuring antibody titre, neutralising antibody, antibody avidity and memory B cell responses, and comparing immune responses between arms. We will bridge our immunogenicity results to those in adult women in whom efficacy has been demonstrated, in order to infer efficacy for single and 2 dose regimens in girls under 15 years in SSA. The WHO has highlighted the need for head-to-head comparisons of reduced dose schedules of different HPV vaccines as a research priority. This trial will provide rigorous evidence for the feasibility of dose reduction in Africa.


Research activity codes: 3.4 VACCINES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Quantitative proteomic and CRISPR-based genetic approaches to latent and active KSHV infection
Funder: Medical Research Council

Abstract: Kaposi's Sarcoma associated herpesvirus (KSHV) is the causative agent of three human malignancies: Kaposi's sarcoma, a tumour of endothelial cells together with B cell-associated primary effusion lymphoma (PEL) and multicentric Castelman's disease. Kaposi's Sarcoma often leads to life-threatening complications in immunocompromised, particularly HIV-infected individuals. Like other herpesviruses, infection with KSHV is persistent and lifelong, with the virus remaining latent with occasional reactivations. KSHV must therefore remodel the host cell proteome to enable its lifestyle: in latent infection, changes are particularly related to angiogenesis and cell proliferation, while upon reactivation the virus targets host immune molecules to evade recognition from the host immune system. In a preliminary proteomic analysis we identified a number of novel KSHV targets, suggesting that our understanding of KSHV-induced pathogenesis and viral immune evasion strategies are far from complete. Here we propose to apply quantitative proteomic approaches to gain a comprehensive and unbiased overview of how KSHV remodels the host cell proteome in latency and the temporal changes that occur upon viral reactivation. We will initially focus on endothelial cells and then examine B cells, two physiologically relevant cell types for KSHV infection. We will use a novel KSHV genome-wide CRISPR library screening approach to identify the viral genes responsible for the observed phenotypic cellular changes and to understand their mechanism of action. We will assess the impact of these changes on the maintenance of virus latency, the ability of the virus to manipulate the host immune system, and KSHV-induced pathogenesis. Our goal is to generate and disseminate important findings and knowledge about infection with KSHV. This will stimulate further research in this area, and in the longer term will inform the design of novel therapeutic strategies for the treatment of KSHV-associated disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Targeting Twist: Single-molecule insights into supercoiled DNA-topoisomerase interactions for drug discovery
Funder: Medical Research Council

Abstract: Topoisomerases are molecular machines that perform vital rearrangement of DNA, unknotting and decatenating it in order that transcription machinery can pass along genomic DNA unhindered. Topoisomerases are targeted by antibiotic and anti-cancer therapeutics that trap them on DNA, reducing their activity. This mechanism of action, discovered for topoisomerase inhibitors, also extends to PARP inhibitors used in anti-cancer therapies, and may be applied to target transcription factors. There remains much room for development in this field; anti-cancer therapeutics that target topoisomerases currently suffer from a lack of selectivity, and there remain a number of unexplored antibacterial targets (including topoisomerases I and III), which have significant potential, but are as yet untargeted. This is due to both a lack of structural information and fundamental gaps in our knowledge of their mechanism of action. Using single molecule techniques, I will provide valuable insight into the mechanism of action for topoisomerases and their inhibitors, with the aim of informing the rational design of novel therapeutics. This work will bring together an international multidisciplinary collaboration. Using Atomic Force Microscopy techniques I have pioneered, I will determine the conformation of DNA molecules, as they interact with topoisomerases, at double-helical resolution in aqueous solution. Using magnetic tweezers and single molecule fluorescence, I will interrogate topoisomerase-DNA interactions at millisecond time scales, providing dynamic insights into the binding of these enzymes, and how this is modulated by novel therapeutics such as anticancer drugs and antibiotics. These pioneering studies will allow for the determination of the supercoiling dependence of topoisomerases, and provide insight into the mechanism of topoisomerase-DNA interactions, and how these are modulated by topoisomerase inhibitors, a key class of therapeutics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: K. Kyeremeh - Development of Novel Therapeutics for Parasite Infections and Cancer by Multi-step Microbial Biodiscovery Processes and iChip
Funder: Medical Research Council

Abstract: Detailed chemical profiling of 150 pre-isolated strains with HRESI-LC-MS of miniaturized crude microbial extracts will be conducted. Using compound molecular ions, fragmentation patterns and UV in combination with different databases new and novel metabolites will be identified to justify the inclusion of each microbe in this project. High-throughput microbial cultivation in situ with the isolation chip (iChip) for additional 150 strains to be isolated and their chemical profile investigated as stated previously. Crude extracts from each microbe will be evaluated in all relevant bioassays under this project. Interesting chemical profile and bioactivity will be characteristic of prioritized strains that will be large scale fermented followed by purification of compounds. Structure determination of the compounds will be achieved through spectroscopy and spectrometry. Test pure compounds in assays and whole genome sequence the source microbes with priority for novel backbones. Prioritized strains cultured in several customized media and culture conditions, co-culture with co-associating fungi, and presence of chemical cues known to activate transcription of silent genes. Already established chemical profile will enable identification of differences in metabolite production in new cultures. Evaluate new extracts to identify novel metabolites which will be isolated and submitted for bioactivity tests. Identify gene clusters responsible for the production of novel metabolites and confirm with knock-out and heterologous expression. Identify silent gene clusters encoding for molecules with antibiotic, antiparasitic and anticancer properties by identification of enzymes in the genomes or the presence of certain well known molecular markers. Followed by genetic manipulation to activate/express endogenous genes or their (re)construction in a form which is suitable for expression and production of compounds in sufficient quantities for structure-activity studies and MOA.


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