NIHRDataInsights/HRCSData huggingface dataset:
Title: A feasibility study of early identification, assessment and support for informal carers in primary care
Funder: Marie Curie

Abstract: This project addresses the need to identify and better support informal carers of people with cancer and other conditions who are approaching the end of life. It proposes and tests a novel primary-care based intervention, supported by Voices of Carers Across Lothian (VOCAL), that will overcome the barriers to the prospective identification of carers who either may not be aware that the person they care for is approaching death, or may not identify themselves as carers. Systematic carer identification, assessment and targeted support will empower carers as the cared-for person’s illness advances, and will in turn enhance the quality of care that the patient receives. The objectives of this project are: 1) to develop and refine a preliminary model of carer identification, assessment, support and referral; and 2) To pilot and evaluate the intervention in four general practices. The project will be conducted in two stages reflecting the MRC new guidance on developing and evaluating complex interventions (MRC, 2008). During the design stage we will conduct two literature reviews; synthesize in-house studies of carer experiences; and conduct four focus groups. This will allow us to model the key outcomes and processes that will form part of our intervention and determine how it will be delivered. During the second stage our model will be piloted in four general practices. The intervention will involve: the identification of a carer co-ordinator in each practice; the development and operationalization of a set of strategies for systematically identifying informal carers (who are registered with the practice) of people approaching the end of their lives; the use of practice registers to identify both informal carers and patients who may be the recipients of informal care; the development of criteria to identify vulnerable carers and the mapping of referral pathways to local carer organizations. We will also test and refine patient-centered outcomes suitable for the subsequent study. This intervention has the potential to greatly increase the number of informal carers that are identified, enhance the support they are offered and strengthen the links between GPs and local carer services. Having conducted and learned from this proposed feasibility study, we plan in future to conduct a large multi-centered trial to roll-out our model of carer identification, assessment, support and referral in a large number of Primary Care Teams and carer organizations UK-wide, so that such good practice can be made routine care in the UK.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.2 END OF LIFE CARE;7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: New Porphycene Macrocycles for Applications in Two-Photon Absorption: Optimisation and Synthesis
Funder: Engineering and Physical Sciences Research Council

Abstract: This proposal combines advanced state-of-the-art response theoretical computation with efficient, modern synthesis of structurally variable dibenzoporphycenes, and non-linear laser spectroscopy to probe structural and electronic parameters in a class of molecules that show very promising two-photon absorption (TPA) behaviour. The use of TPA shows many advantages over conventional excitation techniques, however, applications of these techniques are still in their infancy. We will model, prepare and study a new class of promising compounds for potential use in the treatment of cancer via what is known as photodynamic therapy. Here, TPA has the potential overcome many issues in this field, for example exploiting the tissue transparency window. This proposal is thus timely as it brings together the three strands of research required to investigate this new class of compounds. Compounds within this promising subset of aromatic macrocycles with optimal TPA properties will be discovered computationally and then prepared by flexible, convergent synthetic routes. This proposal will thus bring together a multi-disciplinary team to study this important topic.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Predictive modelling of ligand binding to flexible proteins
Funder: Engineering and Physical Sciences Research Council

Abstract: It is now recognised that a large fraction of the human proteome is made of extremely flexible proteins whose structure cannot be characterized by a unique fold. These intrinsically disordered proteins (IDPs) play key roles in cells and have been implicated in a striking range of diseases such as cancers, neurodegenerative disorders and diabetes. These diseases will become increasingly prevalent in an aging UK population. It is therefore highly desirable to develop small drug-like molecules that could bind to IDPs and modulate their function. Yet it is very difficult to determine the range and nature of conformations adopted by an IDP using experimental techniques. IDPs are therefore generally considered "undruggable" by the pharmaceutical industry. It is important to develop new techniques and technologies to address the national and global health challenges caused by IDPs. Computer simulations have the potential to provide detailed structural models of IDP/small molecule interactions to guide rational structure-based drug design efforts. However standard simulation techniques are unable to perform this task. Their description of intermolecular interactions is too approximate. The exploration of the complicated energy landscape of IDPs is too time consuming. It is therefore essential to develop novel simulation methodologies that can handle the high flexibility of IDPs. We propose the development of new molecular simulation algorithms that will enable the rapid computation of the structural, thermodynamic and kinetic properties of IDPs in complex with drug-like molecules. Our research is structured around three objectives: 1. We will develop a force-field optimisation method that iterates biased molecular dynamics simulations and energy reweighting to minimize systematic errors in the prediction of molecular observables for IDP/small molecule complexes (e.g. NMR chemical shifts). 2. We will develop a simulation method to steer "on-the-fly" computational efforts towards the exploration of molecular conformations that contribute the most to overall uncertainties in predicting the dynamics of IDP/small molecule complexes. 3. We will perform simulation studies to elucidate the mechanisms of small molecule binding to selected IDPs. Such interactions currently challenge our understanding of molecular recognition. Test systems will include for instance the IDPs c-myc and p53 that play key roles in the progression of several cancers. The primary goal of this research is therefore to develop new computational methodologies that will enable preclinical drug discovery efforts to target intrinsically disordered proteins with structure-based approaches. In addition the algorithms and software developed during this research will be widely applicable and this research will also enable applications in a broad range of soft-condensed matter research areas.


Research activity codes: 5.1 PHARMACEUTICALS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: The Mechanism of Myc Function in Cell Proliferation and Cancer
Funder: Medical Research Council

Abstract: The Mechanism of Myc Function in Cell Proliferation and Cancer c-Myc expression is elevated in a significant proportion of cancers, and experimental Myc overexpression promotes tumour formation. Myc is also essential for cell proliferation. Despite the fact that Myc has a critical role in cell proliferation and transformation, we know little about the function of Myc during these processes. Myc is a transcription factor and it is via transactivation of target genes that Myc is presumed to function. Recently, I have found a novel biochemical function of Myc which is to promote mRNA cap methylation, a modification necessary for mRNA translation. To my knowledge, this is the first observation that a transcription factor can upregulate gene expression by increasing mRNA cap methylation. My research focus will be to biochemically characterise this novel Myc function and to investigate its role in Myc-induced cell proliferation and transformation. I will address: 1. What is the mechanism by which Myc promotes mRNA cap methylation? 2. What is the physiological significance of Myc-induced mRNA cap methylation? 3. Are Myc mutants found in cancers hyperactive for mRNA cap methylation? Mechanistic characterisation of this pathway will be carried out using co-immunoprecipitations, chromatin immunoprecipitations and by manipulating expression of pathway components using siRNA. Global identification of Myc-induced cap methylated mRNA will be carried out by purification of these mRNAs by immunoprecipitation and affinity chromatography followed by microarray analysis. This will reveal the extent of cap methylation in response to Myc and identify which mRNAs are methylated in response to Myc. My preliminary studies have demonstrated that Myc can upregulate two genes by simultaneous upregulation of transcription and mRNA cap methylation. The proposed microarray studies will reveal whether the majority of Myc transcriptional target genes are also subject to Myc-induced cap methylation. I will investigate the significance of Myc-induced cap methylation in Myc-induced cell proliferation and transformation. Following identification of Myc-induced cap methylated mRNAs, I will investigate whether particular cellular pathways relevant to cell proliferation and transformation are targetted by this mechanism. I will select candidate mRNAs and determine whether they are required for Myc-induced cell proliferation and transformation in cell-based assays. I will also investigate whether Myc-induced cap methylation is hyperactivated by Myc mutants found in cancer. The objective of this study is to better define the role of Myc in cancer with the long term goal of targetting Myc function in cancer therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Antagonism of PI 3-kinase signalling by PTEN and SHIP2
Funder: Medical Research Council

Abstract: Class I phosphoinositide 3-kinases (PI 3-kinases) synthesise phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3), a lipid second messenger which controls cell growth, motility, survival and metabolism in response to a wide variety of hormonal and environmental cues. Defects in this regulatory system contribute to the pathology of important human diseases including many forms of cancer, type II diabetes and inflammatory disorders. The integrity of PI 3-kinase signalling depends upon the correct temporal and spatial distribution of inositol lipid second messengers determined by the regulation and targeting of Class I PI 3-kinases and PtdInsP3 phosphatases. Moreover, the metabolism of PtdInsP3 serves at least two distinct purposes. Firstly, the termination of PtdInsP3 signalling via removal of the 3-phosphate by the tumour suppressor phosphatase, PTEN. Secondly, the co-ordinated synthesis of additional lipid signals, including phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) and phosphatidylinositol 3-phosphate via removal of the 5-phosphate by one or more members of the phosphoinositide 5-phosphatase family such as SHIP and SHIP2. Whilst the functions and molecular targets of PtdInsP3 are well understood, the relative contributions of PtdInsP3 and/or PtdIns(3,4)P2 to PI 3-kinase signalling and which, if any of these functions are driven primarily by PtdIns(3,4)P2 remain ill-defined. We aim to develop our understanding of the distinct biological functions of PtdInsP3 metabolism under four thematic headings. (i) How do cells exert independent temporal and spatial control of PtdInsP3 versus PtdIns(3,4)P2 when the latter is a metabolic product of the former? (ii) The identification, characterisation and biological functions of PtdIns(3,4)P2 effector proteins. (iii) The roles of PTEN and SHIP2 in the development and maintenance of cell polarity in epithelial cells and other relevant models. How does loss of PTEN or oncogenic mutation of p110alpha affect PtdInsP3 distribution and cell polarity? (iv) What, if any, is the role of PTEN s specificity for both PtdInsP3 and phosphopeptide substrates in mediating its tumour suppressor function? Our approach is multidisciplinary, involving molecular characterisation of expressed and purified components; studies of endogenous and exogenously expressed components in cell lines, 3D epithelial cell cultures and other model systems; and the generation of unique mouse models arising from original discoveries in our laboratory concerning substrate recognition by PTEN. We will continue to collaborate with major pharmaceutical companies via the Division of Signal Transduction Therapy of which CPD is a co-director and which aims to accelerate drug discovery in the area of protein and lipid kinases and phosphatases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: The E2F pathway: new levels of control and regulation
Funder: Medical Research Council

Abstract: E2F transcription factors are widely viewed as essential regulators of cell cycle progression through their ability to co-ordinate and integrate cell cycle events with the transcription machinery. E2F activity has been connected with a variety of cell fates, including differentiation, apoptosis, senescence and autophagy, and is attributed with a major role in driving tumourigenesis. Since the original definition of E2F DNA binding complexes in mammalian cells, it has become apparent that E2F is a family of transcription factors with diverse physiological roles that has been highly conserved throughout evolution. It remains a major challenge to decipher the biology of individual E2F family members, and understand the physiological cues that drive the diverse outcomes that have been assigned to E2F activity. Knowledge about the regulatory events that influence E2F activity is therefore of considerable importance in understanding the complexity of cell cycle control and abnormalities that contribute to cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Marie Curie Palliative Care Research Centre
Funder: Marie Curie

Abstract: Aim 1. Undertaking high quality research of national priority and directly relevant to patient and carer needs. Specific objectives are to: - attract high value external research funding into Wales and UK as lead investigators - act as co-investigators on high value studies led from elsewhere - provide leadership across our host institution, the UK and internationally in study development - embed patient and carer experience at the centre of our work - demonstrate continued national leadership and innovation in Patient and Public Involvement (PPI) - apply for project grants, studentships, fellowships and the delivery of professorial academic leadership - contribute to education via undergraduate medical teaching, and postdoctoral supervision - support capacity building and grant capture in the area of social care - Aim 2. Demonstrating impact through knowledge transfer and mobilization, effecting the translation of research findings into clinical practice and policy implementation. Specific objectives are to: - develop our senior academic leadership at professorial level - publish our research in high quality scientific and clinical journals - present our research at national and international scientific and clinical meetings - use our innovative model of PPI to mobilise evidence into practice in co-production with patients and public - consolidate our leadership roles within Wales Cancer Research Centre and collaboration with Welsh Government - work beyond traditional dissemination boundaries to include popular and social media in engaging with care providers, patients and the wider public - work with the Centre for Medical Education to build capacity and disseminate our research evidence via its undergraduate and postgraduate medical education programmes - raise the profile of research evidence to clinical audiences through the WCRC PaCERS (Palliative Care Evidence Review) Rapid Review service, and pursue evidence of impact on care provision - work with Marie Curie, government and other third sector partners to influence policy making at the highest levels.


Research activity codes: 7.2 END OF LIFE CARE;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Costs and effectiveness of UK palliative care day services: a three-centre mixed methods study of impact upon patients and family carers
Funder: Marie Curie

Abstract: In response to the changing demographics and the increasing number of people with cancer and other chronic illnesses, there is an increased demand for palliative care. Limitations of inpatient care have led to a reliance on day services in an outpatient model of hospice care. There is a very wide variety of interventions provided within Palliative Care Day Services provided to people with cancer and other life limiting illnesses in the UK. Despite clear need and rapid expansion of services, there is little evidence to guide practice. Qualitative data suggests that Day Services are highly valued as having a positive influence across the four domains of palliative care. There is some evidence that attending day services results in fewer referrals to more expensive health care services. We aim to provide evidence of the cost-effectiveness of palliative care day services in improving quality of life. This study will be guided by the Medical Research Council’s Framework for evaluating complex interventions, within which the Donabedian Model will be used as a conceptual framework to examine day hospice services in three categories: structure, process and outcomes, across the palliative care domains. Evidence will be drawn from various sources to obtain cost-effectiveness as follows: (1) a systematic review of published evidence; (2) collection and analysis of secondary data, retrospective review of 100 records and nine focus groups; (3) a three-site prospective cohort study (N=120) of naturally-occurring variation with benchmarking of service outputs. By understanding the structure, processes and outcomes of three palliative care day services, service models can be influenced to achieve better outcomes for people in need of palliative day services, their carers and family members.


Research activity codes: 7.2 END OF LIFE CARE;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: The role of E3 ubiquitin ligases in cancer pathogenesis and treatment with Ionising Radiation (IR)
Funder: Medical Research Council

Abstract: The mission of the D'Angiolella laboratory is to decipher the role of E3 ubiquitin ligases in the pathogenesis and radiotherapy response of cancers. Our long-term ambition is to develop novel drugs targeting E3 ubiquitin ligases for the improvement of cancer treatment. The ubiquitin system plays a crucial role in controlling cell survival after IR and provides a large repertoire of targets that could be exploited to increase the efficacy of radiotherapy in cancers, such as GB. However, a comprehensive analysis of the ubiquitin system after IR is lacking. We systematically queried the ubiquitin system in GB after IR by performing a pooled high-resolution CRISPR screen. We were able to identify known determinants of IR response and novel exploitable targets like cyclin F and Fbxo42. Using 'state of art' LC/MS we have identified the main substrates of Fbxo42 and cyclin F. We propose to investigate how cyclin F impact on the repair of Double Strand Breaks (Objective 1). We have identified cyclin F as a suppressor of inflammatory responses after IR and we would like to establish the underlying molecular mechanisms (Objective 2). We aim to understand Fbxo42 function and mechanism of action as previously done for cyclin F and other F-box proteins (Aim3). Finally, given the ideal set up for CRISPR screens in my laboratory and the unique set-up within the unit to deliver FLASH radiation we intend to extend our screens to relevant in vivo models with conventional and novel radiotherapy modalities (FLASH) (Aim 4). In addition to the fundamental implications for cell biology, our study has strong translational potential: the study is highlighting novel pathways which could be targeted to improve radiotherapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Analysis of PP1 isoform functions at the metaphase-to-anaphase transition
Funder: Wellcome Trust

Abstract: When a cell divides, the genetic material, DNA, has to be duplicated and split between resulting daughter cells. This highly regulated process, which involves cells passing through ‘checkpoints’, is designed to prevent errors, which can result in cell death or initiation of cancer. The ‘spindle assembly checkpoint’ (SAC) checks that chromosomes are correctly aligned and attached to the mitotic spindle before they are split into daughter cells. This checkpoint is controlled by tags called phosphorylations which are added by kinases and removed by phosphatases. My project aims to understand the function of one such phosphatase - protein phosphatase 1 (PP1). Previous research suggests that PP1 may be important in switching off the SAC when cells are ready to divide. Beyond that we have little understanding of its function. I hope to investigate how, when and on which substrates the different forms of PP1 act. To do this I will use molecular biology to edit or remove PP1 and its substrates from cells and then fluorescence microscopy to analyse the impact this has on successful cell division. This knowledge will enable better understanding of cell division and the development of therapeutic approaches for diseases where errors in cell division have occurred.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS