Tinnitus is the perception of a phantom sound and the patient’s reaction to it. Tinnitus remains a scientific and clinical enigma of iTinnitus is the perception of a phantom sound and the patient’s reaction to it. Although much progress has been made, tinnitus remains a scientific and clinical enigma of high prevalence and high economic burden. It affects more than 10% of the general population, whereas 1% of the population considers tinnitus their major health issue. Recent cohort studies show that tinnitus prevalence tends to increase over time and with older age. Assuming that there is no cure to be found, the prevalence estimates in Europe would double by 2050. A large variety of patient characteristics - including genotyping, aetiology, and phenotyping - are poorly understood, because integrated systems approaches are still missing to correlate patient`s characteristics to predict responses to combinatorial therapies. Although genetic causes of tinnitus have been neglected for decades, recent findings of genetic analysis in specific subgroups (gender and phenotype) have highlighted that bilateral tinnitus in men reached a heritability of 0.68. This heritability is close to autism, schizophrenia and Attention Deficit Hyperactive Disorder (ADHD). There is no current consensus on tinnitus treatment. UNITI’s overall aim is to deliver a predictive computational model based on existing and longitudinal data attempting to address the question which treatment approach is optimal for a specific patient based on specific parameters. Clinical, epidemiological, medical, genetic and audiological data, including signals reflecting ear-brain communication, will be analysed from existing databases. Predictive factors for different patient groups will be extracted and their prognostic relevance will be tested in a randomized controlled trial (RCT) in which different groups of patients will undergo a combination of therapies targeting the auditory and central nervous systems.

Allogeneic stem cell transplantation (allo-SCT) is the most common cellular immunotherapy for hematologic malignancies, but beneficial outcomes are limited by severe morbidity and mortality by graft-vs.-host disease (GVHD) and by relapse as a consequence of insufficient antitumor immune response (graft-vs-leukemia, GVL). In allo-SCT patients, a diverse gut microbiome is associated with beneficial clinical outcomes and fecal microbiota transplantation (FMT) emerges as a promising therapeutic option for acute gastrointestinal GVHD patients. Yet, how the gut and tissue-associated microbiome governs immune function and tissue homeostasis remains poorly understood. We identified microbial signatures - i.e., configurations of microbial communities and their associated immune-modulatory metabolites - in allo-SCT patients that (i) favourably associate with clinical outcomes, (ii) can engage an Interferon (IFN)-I inducing pathway to induce tissue regeneration, and (iii) protect mice from immune-mediated tissue damage. We therefore hypothesize that gut and tissue-associated microbial consortia and their immune-modulatory metabolites serve as a game changer for allo-SCT. “MICROBOTS” will test this by (i) providing a thorough characterization of microbiome/metabolome-host interaction at the epithelial interface in allo-SCT patients with or without GVHD, relapse and undergoing FMT and (ii) evaluating the functional impact of identified microbial signatures in advanced preclinical models of GVL and GVHD. These novel insights will provide a template for the design of a Precision FMT approach with defined microbial-metabolite cocktails aimed to achieve robust and durable antitumor responses in allo-SCT patients as well as to improve tissue regeneration and minimize immune-mediated side effects (GVHD). This may induce a paradigm-shift in clinical allo-SCT protocols and potentially other T cell transfer therapies (CAR/TCR T cells) in cancer treatment as a whole.

MEFISTO will develop two novel solutions to treat meniscus loss as a strategy for preventing the onset of an epidemic of post-meniscectomy knee osteoarthritis (OA) in Europe. Morphological profiling will identify the population of patients who, after meniscal resection, are at higher risk of early compartment degeneration, providing a personalized approach for the patient. The two different reconstructive strategies are: i) a controlled vascularized bioactive biodegradable meniscal scaffold, which will regenerate the native meniscus. This strategy will address younger patients with early osteoarthritic changes. ii) a bioactive non-biodegradable meniscal prosthesis, which will act as a mechanical unloading device and a drug delivery system, with the capacity to modulate the inflammatory environment. This strategy will address patients with advanced OA. A socio-economic analysis of the efficacy of existing meniscal substitutes will complete the project. This analysis is of vital importance for the European healthcare system, as it will provide a clear understanding of the costs and benefits of current clinical practice and predict the impact of the two new interventions. The technological innovation lies in the development of biologically active functionalized nanobiomaterials that can interact with the surrounding articular tissues. The biodegradable scaffold will promote revascularization in the peripheral zone, while leaving the inner zone avascular, reflecting the native meniscal tissue and functionalization with drug delivery micro/nanoparticles of the non-biodegradable device will provide modulation of inflammation. The impact is expected to be significant as so many patients have undergone or will undergo meniscectomy. The interventions developed in MEFISTO will prevent these patients from receiving joint-sacrificing procedures such as metal prosthesis whilst reducing the social burden, associated costs and high levels of morbidity resulting from OA.