Lymphoid leukemias and lymphomas represent frequent areas of the tumour pathology. Recent Integrative clinical and molecular studies allows to identify concrete disorders where a precise recognition leads to a specific treatment with a minimum toxicity and maximum clinical benefit. Even though there have been many progress during last years, there still persist numerous conditions with low survival probability and high side effects of the received treatments. The introduction of the precision medicine in lymphoid neoplasms is new and challenging due to the scarce knowledge about disease pathogenesis, targeted therapies and predictor markers, immunotherapy role and poor experimental models. T-cell lymphoma tumors present a dismal survival probability dismal (25% for Peripheral T-cell lymphoma) in patients, and the molecular mechanism underlying their high rate of lack response to treatments and relapse is poorly understood. Furthermore, patients with lymphoproliferative disorders often have complex (multiclonal) or mixed lymphoproliferative disorders. This project aim the consolidation of the precision medicine in the diagnosis and therapy of these disorders, thus facilitating the treatment of each patient according its disease, with specific therapy according to the integral characterization of its disease, thus reducing toxicity and improving the therapy efficacy. The project focuses on complex lymphoproliferative diseases characterized by clinical aggressiveness with low therapeutic response, tumor heterogeneity and patterns of dependency / interaction with the microenvironment. The success of the project requires in first instance to improve in the knowledge of the molecular basis of the disease and subsequently in the identification of precise tumour types and patient stratification, thus facilitating the identification of markers for targeted therapy, using gene expression and mutational signatures.

Cardiac toxicity is one of the most frequent serious side effects of cancer therapy, affecting up to 30% of treated patients. Cancer treatment-induced cardiotoxicity (CTiCT) can result in severe heart failure. The trade-off between cancer and chronic heart failure is an immense personal burden with physical and psychological consequences. Current therapies for CTiCT are suboptimal, featuring poor early detection algorithms and nonspecific heart failure treatments. Based on our recently published results and additional preliminary data presented here, we propose that CTiCT is associated with altered mitochondrial dynamics, triggering a cardiomyocyte metabolic reprogramming. MATRIX represents a holistic approach to tackling mitochondrial dysfunction in CTiCT. Our hypothesis is that reverting metabolic reprogramming by shifting mitochondrial substrate utilization could represent a new paradigm in the treatment of early-stage CTiCT. By refining a novel imaging-based algorithm recently developed in our group, we will achieve very early detection of myocardial damage in patients treated with commonly prescribed cancer therapies, long before clinically used parameters become abnormal. Such early detection, not available currently, is crucial for implementation of early therapies. We also hypothesize that in end-stage CTiCT, mitochondrial dysfunction has passed a no-return point, and the failing heart will only be rescued by a strategy to replenish the myocardium with fresh healthy mitochondria. This will be achieved with a radical new therapeutic option: in-vivo mitochondrial transplantation. The MATRIX project has broad translational potential, including a new therapeutic approach to a clinically relevant condition, the development of technology for early diagnosis, and advances in knowledge of basic disease mechanisms.

Acute kidney injury (AKI) is a life-threatening disease with high mortality characterized by an abrupt decrease of the kidney glomerular filtration rate, extra-kidney consequences (cardiovascular diseases, lung injury, neurological impairment) and high risk of secondary chronic kidney disease. The cost of AKI is very high and substantial cost savings may be yielded by the development of new preventive and management strategies. SpareKid aims to predict the development of AKI to allow dedicated primary prevention. AKI is an extremely complex disease perfectly exemplified by the current inability to successfully predict the development of AKI before the attack, even in a well-controlled clinical setting such as cardiac surgery or chemotherapy. The complexity of AKI leads to a huge heterogeneity of the kidney response even after an insult of similar intensity, which strongly impedes the personalized management of individuals in AKI at-risk situations. These data also suggest that AKI should be better described as a maladaptive kidney response to the insult. Therefore, the first innovative concept of SpareKid is to define a so-called non-invasive Kidney Resilience Index (KRI). The second innovative concept of SpareKid is to define the KRI based on in-depth and multiscale molecular and clinical data using a holistic big data-based strategy to integrate high throughput urinary and plasma proteomic, immunologic signatures (bulk-RNA sequencing and characterization of immune cell populations), and genetic signatures (whole-genome sequencing) and detailed clinical parameters. Last, using data from the National Systems of Health to model the potential cost-effectiveness of new predictive algorithms developed, we will assess the cost of each clinical trajectory according to the outcomes (AKI, CKD, death) of patients, the cost sparing of a preventive strategy and ultimately proposed a new methodology for randomized clinical trials in AKI to improve their cost-effectiveness.