Mesothelioma 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.

Summary In this proposal, we aim to revolutionise the way that pollen is measured, model the spatial and temporal deposition of different species of grass pollen and identify linkages to human health. In the UK population ~5% suffer from allergic reactions (ranging from hay fever to asthma attacks) and further 22% are sensitised to grass pollen (i.e. they have antibodies capable of causing reactions). Grass pollen is the single most important outdoor aeroallergen closely followed by tree pollen. Similar to tree pollen, sensitivity towards grass pollen varies between species. However, we have no way of detecting, modelling or forecasting the aerial-dispersion of pollen from different species of grass. These limitations are due to complete lack of detailed source maps reflecting both the presence and abundance of different species of grass and because grass pollen, contrary to tree pollen, can not be separated into species using traditional observational methods. Therefore, combinations of the approximately 150 different species of grass pollen that are monitored (using approaches that remain unchanged since World War II) are lumped into a single category and form the foundation of the pollen forecast. In this project we will both develop new models and new methods of detection that address these major shortcomings. The present situation means that hay fever suffers and health practitioners do not know what species, or combination of species cause present symptoms. Individuals can be tested for against particular grass species, but there are ca. 16 million people sensitised to grass pollen, allergic reactions are complex and testing the population against 150 different grass species species is an overwhelming task. The alternative is to take an environmental approach by developing exposure models and identify the environmental conditions that induce the allergic response, which then can be profiled to human health. Recent developments in the generation of a UK plant DNA "barcode" library and DNA sequencing technologies have provided a unique and timely opportunity to identify the species, or combinations of species of grass that are associated with the allergic response. The important development of the UK plant DNA barcode library now gives us the ability to not only target individual species in molecular genetic analyses, but also assign identities to sequences derived from very high throughput molecular meta-analyses of complex mixtures of pollen grains. Similarly, recent developments in next generation air quality models and the advancement of computing power, has enabled the extension of these models into aerobiology in order to study the release, dispersion and transformation of bioaerosols and how this affects the environment. Here, a group of multidisciplinary researchers specialising in aerobiological modelling, DNA barcoding/molecular genetic identification and environmental health have teamed up with the UK Met Office in order to (a.) develop a novel and high-throughput molecular genetic way of measuring the geographical spread and abundance of different allergenic species of grass across the summer months, (b.) develop novel pollen bio-aerosol models and (c.) identify which species, or combinations of species are linked to the most severe public health outcomes of the allergic response (i.e. asthma). The work will provide information that healthcare professionals and charities will be able to translate into helping individuals live healthier and more productive lives. The information will help those with long term health conditions effectively self-manage their conditions, contribute more effectively to the workplace and be less reliant on the health system with accompanied economic benefits. Employers will benefit from greater employer productivity and pharmaceutical companies will be able to better target the distribution of their products and therapies.

As minimally invasive surgery is being adopted in a wide range of surgical specialties, there is a growing trend in precision surgery, focussing on early malignancies with minimally invasive intervention and greater consideration on patient recovery and quality of life. This requires the development of sophisticated micro-instruments integrated with imaging, sensing, and robotic assistance for micro-surgical tasks. This facilitates management of increasingly small lesions in more remote locations with complex anatomical surroundings. The proposed programme grant seeks to harness different strands of engineering and clinical developments in micro-robotics for precision surgery to establish platform technologies in: 1) micro-fabrication and actuation; 2) micro-manipulation and cooperative robotic control; 3) in vivo microscopic imaging and sensing; 4) intra-operative vision and navigation; and 5) endoluminal platform development. By using endoluminal micro-surgical intervention for gastrointestinal, cardiovascular, lung and breast cancer as the exemplars, we aim to establish a strong technological platform with extensive industrial and wider academic collaboration to support seamless translational research and surgical innovation that are unique internationally.

The Government's 'Future of Mobility' and 'Road to Zero' strategies outline a second UK transport revolution, characterised by rapid decarbonisation, increased automation and enhanced connectivity. This radical transformation presents both opportunities and challenges for improving air quality over the next two decades, occurring in the context of disruptive changes in transport technology, increasing public environmental awareness and evolving transport behaviours. In this context, actions taken during the emerging transition phase will influence air pollutant sources and exposure patterns across indoor (i.e. vehicle, rail/bus) and outdoor (i.e. pavement, platform, bus station) land transport environments, with profound future implications for public health. We recognise this critical opportunity for encouraging policy foresight, cultivating scientific advancement and stimulating citizen engagement at the air quality, climate and health nexus. Our vision is to establish a diverse interdisciplinary network, connecting researchers across nine UK higher education and research institutions with >20 network partners, comprising commercial, public sector and non-profit organisations. We will establish sustainable connections to undertake co-definition of issues and opportunities and co-delivery of innovative, evidence-based solutions. We will deliver a varied portfolio of network activities including TRANSITION summits, problem-solving workshops, hackathons, discovery studies, site visits, policy engagement events and creative outreach activities at transport locations. Thus the network partners will achieve the ambitious but achievable goal of directly shaping future air quality, climate and transport policy, reflecting the ambitions of the UKRI SPF Clean Air Analysis and Solutions programme.

Air pollution causes 29,000 pre-mature death and cost the economy £20 billion per year in the UK alone. A majority of these impacts are associated with Vulnerable Groups (VGs), who are most strongly affected by air pollution with up to ca. 12 life years lost for the individual. Children (VGI) & people with pre-existing medical conditions (VGII) are of particular concern in terms of long-term health, societal & economic impacts. Despite this, most of the efforts in air quality improvement focuses on the general population and outdoor exposure. This leads to major gaps in understanding their exposure to key air pollutants (particularly PM1, ultrafine particles and VOCs), health risks & economic consequences, and the key challenges and mitigation options for these Vulnerable Groups. This network will be the first step towards establishing practical air pollution solutions for Vulnerable Groups tackling a major health & economic challenge that cannot be resolved within traditional, often segregated air quality communities. It will build a new truly cross-disciplinary and self-sustaining network bringing academics with a wide spectrum of expertise ranging from economics via psychology & engineering to indoor & outdoor air pollution science together with key industrial, governmental and NGO stakeholders. The long-term vision of the network is to develop innovative & cost-effective behaviour and technology interventions to reduce the Vulnerable Groups' future air pollution exposure, improve health & directly implement these interventions through policy advice, planning, and business innovations. The network will be composed of 8 streams (6 Work Packages (WPs) & 2 Scoping Groups (SGs)). Collectively, it will review the state-of-the-art in our understanding on (i) the VGs' air quality challenges at the indoor/outdoor interfaces, (ii) behaviour interventions to reduce pollution exposure, (iii) technology interventions at indoor/outdoor interfaces, (iv) health benefits of interventions, and (v) economic benefits of these interventions. They will also identify the future research priorities, particularly in terms of cross-disciplinary challenges, policy & business engagement. Each of the WPs will be co-led by academics and non-academic stakeholders, with support from a core group composed of Co-Is/stakeholders with relevant expertise and their institutional critical mass. Importantly, engagement will be co-led by the government-supported Connected Places Catapult (CPC). This will catalyse and enhance the existing engagement with decision makers and business partners to align our future research with their practical priorities. The network will carry out an initial scoping study to longlist wider contributors that can contribute expertise to networks and then shortlist key members to be directly involved in the network. The network will generate abundant opportunities for within- and cross-disciplinary exchanges through network meetings, direct face-to-face meetings with stakeholders (e.g. local authorities or key industrial partners), writing retreats, social media and webinars. The network will also illustrate potential solutions via a pilot study informed by insight gained in the engagement (WPs 1-6) as part of the interdisciplinary Cross-WP Scoping Group and the Cross-Network Scoping Group will liaise with the other five networks to link outcomes and establish opportunities for future bid development. This work will leave a lasting legacy of a collaborative, interdisciplinary network that will drive forward research and innovation in delivering the air pollution solutions for vulnerable groups, improving their health, and reducing the cost to the NHS and the economy.