Bladder cancer (BC) ranks as the tenth most prevalent cancer in the world (IARC, WHO), with a steady rise in its incidence and prevalence, and is accompanied by a high morbidity and mortality. Absence of reliable screening methods, invasiveness of diagnostic modalities, and high recurrence rates, makes BC one of the most challenging and expensive cancers to diagnose and treat. Cystoscopic examination is considered as the gold standard for BC assessment, but although the detection rate is high, the technique/equipment is expensive, invasive, not available worldwide, and most importantly uncomfortable and associated with risk of complications. Therefore, there is a critical need to develop a non-invasive, low cost, and sensitive method for the early detection and monitoring of BC. Each of our groups have developed promising, simple and low-cost urine-based diagnostic tests for the non-invasive early detection of BC through preclinical exploratory studies. In this project, we aim to investigate the robustness of these biomarkers in our reciprocal populations through a large international multicentric study (Canada, France, Germany), and determine the diagnostic accuracy of each test and combined ones. This would demonstrate the applicability of each of our tests to be used as universal non-invasive biomarkers for early detection and surveillance of BC in different populations, and determine whether a multi-analyte urine biomarker through a combination of these tests could increase the performance for the detection of primary or recurrent BC. For this purpose, we bring together an international group of experts who will collaborate to comprehensively assess the robustness of these biomarkers and their applicability worldwide in order to provide sufficient evidence towards the clinical implementation of these tests for the non-invasive detection of BC.

The importance of the lymphatic circulation to human biology and health is hugely underestimated. A major reason for this is an absence of ways to investigate the lymphatics in humans. Veins on the back of the hand are easily seen, but the lymph vessels are invisible. Standard methods of analysing them such as x-ray, ultrasound, CT and MRI cannot easily detect the lymphatic vessels. Consequently, the lymphatic system has been largely underrated and its role in disease not widely appreciated. Through cellular and animal research we now know that the lymphatics play an important part in heart disease, cancer, infection, and fat metabolism; the four main challenges in healthcare today. Knowledge of how lymphatics do and do not work in humans has not kept pace, largely because of difficulties with investigation. While circulating blood is the main supply system for the body (providing water, nutrients, and oxygen to all cells), lymphatics are the returning, recycling and cleansing system. Lymphatic vessels are like veins but instead carry lymph fluid from tissues to lymph glands. The lymphatic system houses most of our immune cells such as lymphocytes. Infections, including Covid, must enter the lymph vessels and reach the lymph glands to activate lymphocytes. This develops effective immunity against that infection. The main consequence of a failure of lymphatic function is a condition called lymphoedema - where swelling occurs due to fluid accumulation, often in a limb and more commonly the legs. People with the condition also have reduced circulation of immune cells, which leads to an increased risk of infection that can be recurrent and life threatening. Lymphoedema is common (with 400,000 people in the UK, and 250 million people affected worldwide) but is not often diagnosed due to lack of awareness amongst clinicians. There are two different types - secondary lymphoedema (a result of damage to a previously healthy lymphatic system), and the much rarer primary lymphoedema (due to a genetic fault). Unlike cardiovascular disease and cancer, not one drug is licensed to treat lymphoedema and no universally successful surgical treatment exists. Thus, currently, lymphoedema cannot be cured and is managed through a range of physical therapies such as massage and compression to improve swelling. At St George's Hospital we operate a primary and paediatric lymphoedema clinic to which patients are referred from across the UK. More than 20 years of seeing patients with primary lymphoedema and lymphatic malformations, collectively known as primary lymphatic anomaly (PLA), has resulted in the discovery of several causal genes. Consequently, the St George's Hospital lymphoedema clinic is internationally renowned and has been appointed a Centre of Excellence, and has the largest collection of patients with lymphoedema anywhere in the world. The research proposed here is designed to improve our understanding of the mechanisms that lead to lymphoedema in humans through use of newly developed and more powerful investigatory methods. Patients with PLA - because of an inborn fault in lymphatic function caused by a gene mutation - will be studied so we can piece together how these faults are a driver of lymphoedema. This process has already begun in one type of PLA where the gene (PIK3CA) fault is not inherited but develops only in some cells and tissues of the body, a so-called somatic mosaic disorder. A drug now exists to block the effects of the faulty gene causing this lymphatic problem. Trials using this drug are now underway with St George's as one of a few centres for recruitment. Knowledge of other causal genes and the mechanisms producing the lymphoedema as planned in this research project, will create opportunities for new treatments. We believe the results of our work can be extended to other types of lymphoedema, such as those secondary to for example breast cancer treatment.

What is being done? We will study patients with a life-threatening condition called cardiogenic shock. This type of shock happens when the heart is suddenly unable to pump sufficient blood around the body to meet the needs of vital organs such as the brain, lungs, liver and kidney, thereby impairing their ability to function normally. Cardiogenic shock is often a consequence of a sudden and unexpected event, for example a heart attack Our study is aimed at understanding how the body responds to the inadequate blood supply caused by cardiogenic shock and to find out how and why this response varies from one patient to another. Our long-term goal is to improve survival from cardiogenic shock by developing a better understanding of which patients will benefit from specific treatments and how we can ensure that the right patients are getting the right treatment at the right time. We also hope to identify new targets for drug treatment aimed at modifying the body's response to cardiogenic shock. Why is this needed? Every year across Europe over 50000 patients are diagnosed with cardiogenic shock. Despite improvements in how we deliver care to patients with acute heart problems, death rates from cardiogenic shock have remained unacceptably high at between 30% and 50% for the last two decades. Current treatments use drugs and mechanical pumps to temporarily restore or replace the function of the heart, to "buy-time" for the heart to recover. Most of the patients who die, do so due to failure of other vital organs, often despite some recovery of heart function. We believe that in many cases death is a consequence of inflammation caused by a dysfunctional response of the immune system to the initial insult. Of those who survive, 30% will suffer the effects of long-term heart damage (heart failure), as well as the consequences of critical illness, including extreme weakness, fatigue, depression, chronic ill health with repeated hospital attendances and admissions, being unable to return to work and a poor quality of life. How will this be done? We believe that a dysregulated and inappropriate immune response to cardiogenic shock results in widespread inflammation, organ failure and often death. Further we think that the nature and drivers of the patient response to cardiogenic shock differ between individuals. We will take a novel approach to studying cardiogenic shock by measuring the levels of gene activity and mediators of inflammation in blood from patients with this condition. Using these data, we will: - better understand the reasons why people develop cardiogenic shock and die from it - identify why there is variation between patients in severity of disease and the response to current therapies - work out which patients are likely to benefit most from current and new treatments and why - work with doctors undertaking clinical trials of new treatments for cardiogenic shock to use the knowledge gained from this study to improve the design of such trials Where will the work be done? The work will be undertaken at Queen Mary University London, the University of Oxford and the Wellcome Sanger Institute using blood samples from patients in the UK and Germany. When will this work take place? We will complete this work between 2022 and 2025.