Tobacco use is the leading cause of preventable death in the world. Globally, smoking kills more people every year than HIV, tuberculosis and malaria combined. By 2030, more than 80% of the world's tobacco-related deaths will occur in low and middle income countries (LMICs). Preventing people from starting to use tobacco, and encouraging users to stop, is a global priority. The World Health Organisation is addressing this through an international treaty, the Framework Convention on Tobacco Control (FCTC), which has been signed by 181 countries and sets out the policies countries should adopt to prevent smoking. The United Nations (UN) sees the FCTC as so important that when it set up 'Sustainable Development Goals' it included the FCTC in Goal 3, which is about improving health and wellbeing for all the world's people. Goal 3.10 says that the implementation of the FCTC should be strengthened in all countries. However, while a number of high income countries (HICs) have made good progress in FCTC implementation, this is not the case in all LMICs. Signing the treaty is not enough: governments need to be helped to introduce good policies and enforce them. However, few LMICs have the capacity, or in some cases the staff with the right skills, to carry out the research and advocacy necessary to design, implement and achieve compliance with good tobacco control policies. Also, most existing research on tobacco has been conducted in HICs, and is not always relevant to LMICs. Thus we need to train and support researchers in tobacco prevention in LMICs, with skills in economics, clinical medicine, public health and the social sciences, for example. This proposal is about filling these gaps, building on some good work already under way. Our proposed programme will be undertaken in two parts of the world (South Asia and Sub-Saharan Africa) where progress on tobacco control has not always been good, and where the tobacco industry is active in attempting to undermine measures that work. We propose to build research capacity in several LMICs, thought a programme of research designed to address local priorities in each country, supported by a programme of training in research and impact. It will focus in particular on three issues relevant to UN SDG 3 but also other UN goals on peace, justice and strong institutions (SDG 16) and partnerships (SDG 17). These are: tobacco taxation (which helps reduce tobacco use and provides money for governments to build the economy); preventing illicit trade in tobacco (by protecting tax revenue, reducing corruption and helping to reduce crime) and preventing tobacco industry interference (which aims to prevent or undermine national implementation of FCTC measures). Studies will be conducted on these topics as well as additional priorities chosen by countries (like building evidence for 'smokefree' clean air policies, putting health warnings on tobacco packets and services to help people stop smoking). To do this work we have put together a team including UK academics, researchers in LMICs, and charities working to reduce harm from tobacco. The programme will be led by the UK Centre for Tobacco and Alcohol Studies, a UK Centre for Public Health Excellence. The team also includes research organisations in Bangladesh, Ethiopia, The Gambia, Ghana, India, South Africa and Uganda, and can be expanded to include other LMICs if resources allow. Support is included from Cancer Research UK, the world's largest independent cancer charity. Additional help will come from other supporters including the FCTC's Framework Convention Alliance and the American Cancer Society. Funding will be used to support a network of early career (post-doctoral) researchers and teams in LMICs and the UK. Extensive training opportunities and support to carry out high quality research on policy and practice in each country and internationally, and to establish strong research partnerships for the future, will be provided.

The hypothesis at the root of this study is that a healthy immune system will recognise a cell when it becomes malignant and destroy it thus preventing the growth and spread of cancer. Therefore cancer can only occur when this process goes wrong. If we could find out how the immune system interacts with cancer cells and what abnormalities are occurring in this interaction we may then be able to develop strategies to improve the immune response to cancer. This would represent a potentially novel form of treatment and would be expected to improve the response to vaccination therapies that are already undergoing clinical trials in some cancers. This study will look at T cell function in blood samples from patients with leukaemia and lymphoma and then go on to look at mechanisms of improving that function in a mouse model. Finally, attempts will be made to generate a patient tumour-specific T cell response in vitro using the information gained in the earlier parts of the study. This research will be carried out by a clinical research fellow in the Institute of Cancer, Charterhouse Square, London.

Building upon our existing flagship industry-linked EPSRC & MRC CDT in Systems Approaches to Biomedical Science (SABS), the new EPSRC CDT in Sustainable Approaches to Biomedical Science: Responsible and Reproducible Research - SABS:R^3 - will train a further five cohorts, each of 15 students, in cutting-edge systems approaches to biomedical research and, uniquely within the UK, in advanced practices in software engineering. Our renewed goal is to bring about a transformation of the research culture in computational biomedical science. Computational methods are now at the heart of biomedical research. From the simulation of the behaviour of complex systems, through the design and automation of laboratory experiments, to the analysis of both small and large-scale data, well-engineered software has proved capable of transforming biomedical science. Biomedical science is therefore dependent as never before on research software. Industries reliant on this continued innovation in biomedical science play a critical role in the UK economy. The biopharmaceutical and medical technology industrial sectors alone generate an annual turnover of over £63 billion and employ 233,000 scientists and staff. In his foreword to the 2017 Life Sciences Industrial Strategy, Sir John Bell noted that, "The global life sciences industry is expected to reach >$2 trillion in gross value by 2023... there are few, if any, sectors more important to support as part of the industrial strategy." The report identifies the need to provide training in skills in "informatics, computational, mathematical and statistics areas" as being of major concern for the life sciences industry. Over the last 9 years, the existing SABS CDT has been working with its consortium of now 22 industrial and institutional partners to meet these training needs. Over this same period, continued advances in information technology have accelerated the shift in the biomedical research landscape in an increasingly quantitative and predictive direction. As a result, computational and hence software-driven approaches now underpin all aspects of the research pipeline. In spite of this central importance, the development of research software is typically a by-product of the research process, with the research publication being the primary output. Research software is typically not made available to the research community, or even to peer reviewers, and therefore cannot be verified. Vast amounts of research time is lost (usually by PhD students with no formal training in software development) in re-implementing already-existing solutions from the literature. Even if successful, the re-implemented software is again not released to the community, and the cycle repeats. No consideration is made of the huge benefits of model verification, re-use, extension, and maintainability, nor of the implications for the reproducibility of the published research. Progress in biomedical science is thus impeded, with knock-on effects into clinical translation and knowledge transfer into industry. There is therefore an urgent need for a radically different approach. The SABS:R^3 CDT will build on the existing SABS Programme to equip a new generation of biomedical research scientists with not only the knowledge and methods necessary to take a quantitative and interdisciplinary approach, but also with advanced software engineering skills. By embedding this strong focus on sustainable and open computational methods, together with responsible and reproducible approaches, into all aspects of the new programme, our computationally-literate scientists will be equipped to act as ambassadors to bring about a transformation of biomedical research.

To achieve productive infection, HIV must insert a DNA copy of its genome into a chromosome of a human cell. This complex process is orchestrated by integrase, an enzyme carried by the virus. Once integration is complete, the viral genome becomes a permanent resident in a cellular chromosome. From there it will initiate production of new infectious particles or it might stay dormant and undetected for a long period of time. The integration is partly responsible for the notable persistence of retroviral infections. Yet, the dependence of HIV on integration is also an exploitable weakness. A new class of drugs, disrupting enzymatic activity of integrase, called strand transfer inhibitors, takes advantage of this weakness to fight HIV infection. The three-dimensional atomic structure of HIV integrase is not known and even less understood is the architecture of its active form during integration process. Currently, the lack of structural information is the major impediment to the development of strand transfer inhibitors. This project aims to elucidate the three-dimensional structure of integrase. We will determine atomic structures of this protein separately and in active, DNA-bound, form. To achieve our goals we will use X-ray crystallography, which allows visualization of protein molecules, although requiring a significant amount of preparatory work. In particular, to determine high-resolution structures, we will have to obtain crystals of integrase in complex with accessory proteins and/or DNA. Our results will be published in open access journals and the data will be accessible to the scientific community via public databases. Our research will generate dat, which will be of great value for drug discovery by both academic and private groups, and will serve to reduce the costs and improve availability of the eventual treatments.

Cells migrate by attaching themselves to their surroundings and generating traction forces by rearranging their internal structure. The effectiveness of these tractions depend on the relative rigidity of the cells internal structure (its cytoskeleton) and that of the surrounding material. This can be probed by measuring the elastic properties (stiffness) of a cell and how these properties vary across the cell during migration. There is some evidence that as cells transform from the normal to the cancerous state, their stifness is reduced, and as these cells become progressively more invasive the stiffness is reduced further. Thus by developing methods to probe the mechanical properties of cells we can investigate some fundamental aspects of cell biology and cancer cell biology. In this proposal we will investigate the use of ultra-high frequency acoustic imaging to study the mechanical properties of individual cells. In an acoustic microscope specimens are imaged by acoustic waves in the frequency range 100 MHz - 1 GHz. Image contrast occurs from local differences in the speed of sound, which in turn is a function of the elastic stiffness of the material being imaged. Thus, by measuring the contrast of images of cells at a range of acoustic frequencies it is possible to determine local mechanical properties with a spatial resolution of around 1 micron. However, for this technique to be applicable to the study of the biochemical and physical processes that occur during cell migration, it is necessary to further develop the technique to allow the rapid acquisition of data through images taken every few seconds. The technique will be demonstrated through the investigation of the migration of cell lines that can be controlled by altering one of the proteins used during the migration process thus allowing us to compare cells that migrate rapidly with those that are more static. We will also work in collabnoration with Cancer Research UK who will provide examples of cell lines of known invasive capability for us to characterize their mechanical properties.