Antimicrobial resistance (AMR) is one of the most critical challenges facing science in the 21st century. For decades we have benefited from the widespread availability of drugs to treat a variety of conditions using antibiotics with penicillin becoming one of the most recognizable drugs in terms of public awareness. However, through the natural evolution of pathogens, accelerated by the over-use of antimicrobial drugs, the effectiveness of current treatments to such interventions is reducing. Indeed the emergence of pathogens which are fully resistant to antimicrobial drugs, though limited, is becoming an increasing trend. As a direct result of the serious implications and threats this poses the UK has established a 5-year AMR challenge to researchers, mirrored internationally, to address these issues. In considering AMR it is important that the risk to human health from the emergence of AMR in livestock is also recognized and addressed. The use of antibiotics in this context is also widespread, and the emergence of AMR is occurring as seen in human pathogens. Given the food chain, and environmental factors such as waste treatment and run-off, there is significant risk that this may offer a pathway for the translation of AMR pathogens from animals into humans. Much of the study into AMR and its emergence has naturally been undertaken by researchers within the life sciences. However, researchers within the engineering and physical sciences (EPS) have for many years contributed strongly to the development of life and medical sciences through the development of new characterization tools, advanced mathematical modelling techniques, and through the development of increasingly smart sensors to give a few examples. There is therefore significant scope for engaging EPS researchers directly with addressing the AMR challenges with the aim of accelerating the development of new techniques and tools for identifying and addressing the problem. This project will create a space in which we will bring together researchers from the EPS community, including many leaders of their field, with those directly tackling AMR research challenges in the life sciences. We will do this through the creation of a Collaborative Hub for Advancing Interdisciplinary Research (CHAIR) at the University of Surrey. This CHAIR will be based in the newly established School of Veterinary Medicine, providing a neutral space to engage with researchers from across the EPS Departments within the University. To support and facilitate collaborations focused on addressing the AMR challenges we will run a series of integrated seminars, workshops and networking events which will lead to 'sandpits' at which researchers will work to propose short collaborative projects. Successful projects will then be eligible to apply to receive further funding with the aim of generating full research proposal submissions to funding bodies on the AMR challenges. We will also provide support in terms of research time to short projects, funds for short-term missions to support researcher interaction and information exchange, and network formation. A series of researcher development and training activities will be offered in collaboration with the University's Researcher Development Programme. We will also closely engage with a number of strategic partners including the Defra Animal and Plant Health Agency, the Veterinary Medicines Directorate (VMD), The National Physical Laboratory (NPL), The Royal Surrey County Hospital, and internationally at North Carolina State University (USA) including supporting a short-term visiting appointment, and Universidad Sao Paulo (Brazil). This will significantly extend the potential impact of the activities we will support and provide new opportunities for wider collaboration.

Oesophageal cancer is a highly aggressive cancer with five year survival rates of 15%. There are two main subtypes, squamous cell cancer and adenocarcinoma. This study is focussed on Oesophageal Adenocarcinoma as it is the commonest form in the UK. Current treatment uses chemotherapy and/or radiotherapy prior to surgery to try to cure the disease. Despite advances in these treatments there has still been no significant change in patients' outcomes. Immunotherapy opens the door to changing these results. So far, we have seen very good responses in other cancers, such as melanoma, and head and neck cancer, however results in Oesophageal cancer have been relatively disappointing. We are looking to increase our understanding of the immune reaction that occurs in Oesophageal cancer and how we can improve this to benefit patients. Using samples collected at surgery, we will use a cutting-edge imaging technique, multispectral immunohistochemistry, to examine the tumour microenvironment of Oesophageal Adenocarcinoma, specifically looking at the number and interactions of immune cells found within the tumour. We are hopeful that the knowledge that we gain from the first part of the study will allow us to identify which immune cell types we need to increase the activity of, so that our treatment will create an improved immune response to Oesophageal cancer. Our laboratory specialises in the use of oncolytic ("cancer killing") viruses to increase the immune reaction in tumours and so our second experiment will look to selectively infect and kill the tumour using an oncolytic virus whilst not affecting the normal oesophageal tissue. We have designed a novel combination immunotherapy strategy which is given directly into the tumour itself which will augment the action of the oncolytic virus. This "intratumoural immunotherapy" uses the cancer as a vaccine against itself, meaning the immune system is activated to destroy the tumour that it was previously unable to fight. There are other advantages to intratumoural immunotherapy in that we can give higher doses of drugs, which since they are acting locally, cause fewer side effects. Once the immune system is trained to kill the primary tumour it should then hunt down disease elsewhere in the body without the need for further treatments. Our combination therapy utilises the oncolytic Herpes Simplex virus-1 (HSV-1) with a novel immune stimulating agent (IL-15 Superagonist, N-803) and an immune checkpoint blocker (anti-Programmed Death-1, anti-PD-1). N-803 has been shown to increase the levels of natural killer cells as well as effector T Cells (which both kill the cancer) in other tumours. Immune checkpoint blockers stop the mechanism by which many tumours inhibit these immune cells from destroying them and previous work has shown that this mechanism is upregulated after oncolytic virus infection. We have setup a new collaboration with a research team based in Germany who have created the first mouse model of Oesophageal Adenocarcinoma in the world. This will allow us to test our immunotherapy strategy in mice. We will examine the effect that HSV-1 infection has on cells of mouse Oesophageal Adenocarcinoma. Then we will use our triple combination immunotherapy of - HSV-1, N-803 and anti-PD-1 antibody to treat Oesophageal tumours in mice. As all the agents used in this study have been safely used in patients previously, this combination intratumoural immunotherapy could be translated to a human clinical trial in the future.

Currently, radiotherapy patients are treated lying on their backs. Complex machinery weighing at least six tonnes is rotated around them. As it rotates, this machinery delivers radiation beams from different angles. Leo Cancer Care are a small British company who adopted a "design thinking" approach to re-imagine and simplify radiotherapy. Together with ergonomics experts, they developed a flexible and comfortable robotic positioning system that rotates an upright patient. The radiotherapy beam remains fixed. This project draws upon the fellow's international clinical experience and strong scientific track-record to optimise Leo Cancer Care's simplified radiotherapy solution for clinical use. This will enable the fellow and Leo Cancer Care to deliver cancer treatments that are better, cheaper, more efficient and more accessible. Better treatments: radiotherapy side-effects can be devastating. For certain types of cancer, treating patients upright will enable us to better target radiotherapy treatment beams, reducing normal-tissue damage. For breast cancer, sitting upright with a forward tilt moves the breast away from the heart and lungs, improving beam access. For prostate cancer, day-to-day variations in bladder filling and rectal gas will have less impact for upright patients. For lung cancer, lung volumes are greater and lung motion is reduced when patients are upright, enabling better sparing of the heart. Additionally, upright positioning will make many patients feel physically more comfortable (e.g. by enabling patients with lung cancer to breathe more easily) helping them to tolerate their treatment. Cheaper treatments: the cost of a LCC upright X-ray treatment room is half that of a conventional, supine treatment: £2m compared to £4m. More efficient treatments: LCC's simpler technology will lead to (1) reduced equipment maintenance costs (2) easier upgrades of beam delivery technology (3) simpler machine QA & therefore lower expertise barriers (4) substantial reductions in shielded treatment room volume (5) improved patient throughput due to upright positioning. More accessible treatments: worldwide access to radiotherapy is unacceptably low. There is potential to save one million lives per year by 2035 through optimal access to radiotherapy. 80% of cancer patients live in low- and middle-income countries which host only around 5% of the world's RT resources. By halving the cost of an X-ray treatment room and also delivering more efficient RT, LCC solutions stand to make RT more affordable and accessible, improving cancer survival worldwide. To conduct this research the fellow will build new partnerships between Leo Cancer Care, the NHS and universities/hospitals worldwide. Partners include: University College London NHS Foundation Trust, Clatterbridge Cancer Centre, the Royal Surrey NHS Foundation Trust, Massachusetts General Hospital, Centre Léon-Bérard, University College London, the University of Surrey, Sheffield Hallam University, Loughborough University and the University of Sydney. The shared goal is to rapidly deliver the benefits of upright radiotherapy to patients. To do this, a number of key scientific challenges will be addressed: Challenge 1: patient immobilisation systems must be developed. These must enable the patient to sit/stand comfortably for ~20 mins for each radiotherapy treatment. Radiotherapy is delivered daily, in up to 30 treatment 'fractions', each lasting ~20 mins. Challenge 2: upright radiotherapy workflows (for patient treatments and machine testing) must be streamlined. Streamlined workflows will reduce the expertise barrier associated with treatments, improving access. Challenge 3: algorithms must be developed to transfer biological data from MRI/PET to upright radiotherapy. Challenge 4: to incorporate tomorrow's imaging technologies into upright RT, bringing live MRI-guidance to our treatment rooms. This will further improve tumour targeting.

Black and South Asian communities are more likely to die at higher rate during the COVID-19 pandemic. Many people in the community, community leaders, government and the health services are concerned, and we need culturally specific, targeted messages to reduce COVID-19 risk and change behaviours to protect the community. Our initial work has suggested that we need to educate diverse communities to understand their risk and how to protect themselves. We have a track record in coproducing digital, culturally specific health messages for BAME groups and this project will do this in the context of COVID-19 and deliver these messages with the help of the community nationally. We will work with community groups, community and faith leaders and professionals from public health and allied health to produce written/pictorial guidance, short films and mobile app. We will work with these groups to ensure that the messages reach minority groups and will also evaluate the effectiveness of our health messages. We will share information and experience gained from the project quickly via community leaders, policy makers, including NHS England and Public Health England.

This project aims to investigate key mechanisms maintaining the health of the articular cartilage, the tissue covering the edges of the long bones in the joint, allowing a smooth sliding of the bones while we move. The articular cartilage is affected by severe structural damage during the development of a disease called osteoarthritis. Osteoarthritis affects millions of people worldwide. People affected suffer chronic pain and disability with a severe decrease in the quality of life. The only available treatment is pain relief until cartilage damage is so severe that surgery is required. Surgery usually consists of surgical removal of the joint and its replacement with a prosthetic. By understanding the mechanisms keeping the cartilage healthy, we could design new drugs to re-establish the cartilage in cases where it is lost or damaged. We already have evidence showing that a class of proteins called Wnts (pronounced Wenz) are important to maintain cartilage integrity. Thus, the final goal of this application is to understand how these Wnts work. We have three aims: 1) to clarify which other proteins might work with the Wnts within a group of receptors, called frizzled receptors, which are present on cartilage cells; 2) to identify whether very small molecules called microRNAs can modify the function of the Wnts from within the cell; 3) determine whether the function of the Wnts is altered during OA development and whether re-establishing their original activity could be exploited in the future via development of a drug as a therapeutic treatment.