
Papworth Hospital NHS Trust
Papworth Hospital NHS Trust
2 Projects, page 1 of 1
assignment_turned_in Project2019 - 2023Partners:University of Liverpool, Papworth Hospital NHS Trust, British Lung Foundation, University of Liverpool, Papworth Hospital NHS Foundation Trust +1 partnersUniversity of Liverpool,Papworth Hospital NHS Trust,British Lung Foundation,University of Liverpool,Papworth Hospital NHS Foundation Trust,British Lung FoundationFunder: UK Research and Innovation Project Code: NC/T001631/1Funder Contribution: 430,894 GBPMesothelioma is an aggressive and largely untreatable cancer of the lung lining, mainly caused by environmental exposure to asbestos. New treatments, or new approaches to treatment, are urgently required. We can now read detailed information about genetic changes from a small sample of a patient's cancer, which can then be used to make decisions about the most effective anti-cancer drugs to give to an individual patient as "precision medicine". Recent studies have revealed the type and frequency of genetic changes that occur in mesothelioma, which may help in predicting new treatments. In many cancers, genetic changes switch on "oncogenes", which accelerate the speed with which cancer cells divide into two, driving tumour growth. Many cancer treatments use drugs that directly block the activity of oncogenes to prevent this uncontrolled tumour growth. However, mesothelioma is unusual, as there are no common oncogene mutations. Instead, genetic changes mostly occur in "tumour suppressor" genes, disabling proteins that would normally apply a brake to slow down dividing cells and so prevent tumour growth. This presents a difficult challenge for finding ways to treat mesothelioma, as we need to fully understand how each specific tumour suppressor mutation alters the cancerous behaviour of mesothelioma cells, in order to find an Achilles' heel that we might be able to target with drugs. Ultimately, we also need to develop the best laboratory models in which to test the drugs, before they can be given to mesothelioma patients. Disabling mutations of the tumour suppressor BAP1 are found in more than half of all mesotheliomas. Normally, BAP1 controls the production and destruction of other proteins within the cell. Therefore, in mesothelioma without BAP1, there are potentially changes in the amounts of many different proteins that could affect cancerous behaviour. Using cells with gene-edited mutations of BAP1, we identified many of these protein changes. We found that BAP1 mutation not only affects proteins that alter the growth of cancer cells, but also proteins that control how they move, gain access to blood vessels, and spread around the body. We are currently evaluating which of these proteins make mesothelioma cells more sensitive to specific anti-cancer drugs. However, we need to test these drugs in models that can provide a good replica of human mesothelioma growth and spread. To do this, we will develop a chick embryo model of mesothelioma, as a replacement for currently used mouse models. The chick embryo model is classified as non-protected under the Animals Scientific Procedures Act, and so is a useful technique to replace testing in animals. It has many additional advantages over mouse models, including cost effectiveness, accessibility and speed. It is an excellent model to study the growth and spread of tumour cells, as they can be easily engrafted onto the "chorioallantoic membrane". This is an accessible surface, located outside the chick embryo directly beneath the eggshell, with a good supply of blood vessels. Within a few days, a small tumour develops, which can spread across and into the membrane, potentially accessing blood vessels to spread to specific organs. Importantly, new drug treatments can be readily tested in the chick embryo model, and the tumour cells imaged over time to assess their survival and behaviour. We will use the chick embryo model to grow mesothelioma cells, with and without BAP1 mutation, and evaluate therapeutic responses to our candidate drugs. Successful outcomes will suggest new drugs for inclusion in precision medicine trials in mesothelioma patients. During the project, we will develop the first standard operating procedures to generate and monitor mesothelioma tumours in this model. We will make these protocols, and key reagents, available to the mesothelioma research community, encouraging widespread replacement of murine models.
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For further information contact us at helpdesk@openaire.euassignment_turned_in Project2017 - 2020Partners:RCS, Buro Happold Limited, University of Cambridge, Gensler, IHEEM (Inst of Health Eng & Estate Mgt) +11 partnersRCS,Buro Happold Limited,University of Cambridge,Gensler,IHEEM (Inst of Health Eng & Estate Mgt),Papworth Hospital NHS Trust,Royal College of Surgeons of England,University of Cambridge,BURO HAPPOLD LIMITED,Papworth Hospital NHS Foundation Trust,Gensler,UNIVERSITY OF CAMBRIDGE,Institute of Healthcare Engineering and Estate Management,BuroHappold (United Kingdom),CIBSE,Chartered Institution of Building Services EngineersFunder: UK Research and Innovation Project Code: AH/R001952/1Funder Contribution: 198,865 GBPExISE addresses Key Area 3 of the AHRC Antimicrobial Resistance Call, 'Creative, Collaborative and Disruptive Innovation, Experiments and Design in Indoor/Built Environments'. Its overarching Aim is to eliminate airborne acquired Surgical Site Infections (SSI) in operating theatres OTs, traditionally countered with antibiotics. Our microbiologist colleagues emphasise that any antibiotic use, suboptimal or optimal, creates AMR and so avoidance of antibiotic use, in this case post-operative, is paramount. ExISE proposes to achieve this aim through the evidence-based reinvention of the actual physical environment in which surgery is practised, the Operating Theatre OT. Eliminating airborne SSI will reduce the number of infections and the reactive use of antibiotics in recovery and recuperation and in some cases repeat surgery and renewed risk. Airborne transmission of infection has long been feared, the post war custom and practice position on its mechanisms has dominated OT design. SSI is not eliminated in contemporary OTs. The position is not wholly substantiated. Surgeons do not question OT design. Is there another way? ExISE will search for alternative approaches: its historians of science, art and architecture will research a history of Operating Theatre design, of making 'safe', appropriate environments for surgery within their designers' and patrons' theories and beliefs over some 150 years. The search will extend to exhuming still and moving images of surgery in action within its set environments. The Royal College of Surgeons believes this is an as yet unwritten history. The team will be searching for accompanying evidence for environmental intent to enable meaningful reconstructions of their theatres and environments against the original criteria for success. What did they think a healthy environment with healthy air looked like? ExISE scientists will assemble laboratory models and environments from the historical reconstructions of OTs alongside a contemporary 'Ultraclean' OT, the familiar 'cooker hood' issuing truly prodigious flows of cool air through the OT over all the occupants and contents, up to 40 air changes/hr, making a bizarre and not wholly welcome working environment for surgical teams. In parallel, ExISE will achieve greater understanding of the physical and psychological experience of being in/working in a contemporary OT for surgical teams and support staff by visiting teams and interviewing them in situ and at the Royal College. We hope to translate these insights into a meaningful critique from which design and redesign leads can be drawn, leading to a radical step change in fundamental approaches to the design of OTs. Approaches which appeal to our stakeholders and partners will be interrogated and tested physically with both analogue and theoretical models to enable wide dissemination of research outputs with real confidence and thence make significant impacts on the aspirations for and expectations of environments for surgery. Pursuing the international success of our earlier Robust Hospitals project film, we will make a 4-5minute animation out of our drawn reconstructions of OTs, our ideas for redesigning the OT superimposing the fluid flow modelling and calculated environmental performance. Our partners will post the film for their constituencies as will Cambridge University on its streaming media site and YouTube Much detailed and painstaking work will be required subsequently to implement such radically new OTs in practice but ExISE should achieve the 'great leap forward' that breaks more than 60 years of standard practice.
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