UMIB IMPORTANT CONTRIBUTIONS IN THE PAST YEARS INCLUDE:
1-IDENTIFICATION OF NOVEL DISEASES OR NEW INSIGHTS ON RARE DISORDERS.
These include the description of a novel primary immunodeficiency, namely a congenital sideroblastic anemia with immunodeficiency, fevers and developmental delay (SIFD) and identification of the genetic basis of the disease (TRNT1 mutations); discovery of a novel congenital genetic disorder of glycosylation as a consequence of MAN1B1 deficiency; novel variants of primary ciliary dyskinesias that also drove to new pre-implantation genetic tests; and the recognition of FGA p.Glu545Val variant as a frequent cause of the fibrinogen A-alpha-chain amyloidosis in the Northern Portugal.
2- IDENTIFICATION OF NOVEL PHYSIOLOGICAL PATHWAYS AND MECHANISMS OF DISEASE.
Our research focusing on male reproductive function allowed to enlighten the molecular mechanisms underlying the metabolic regulation of spermatogenesis, furthermore this has allowed to understand the pathways leading to the negative impact of common metabolic disorders such as obesity and diabetes on human male fertility. These findings could have far reaching impact as set the grounds for the development of molecules targeting key factors for sperm motility, which could culminate into the design of innovative, effective and safe male contraceptive agents. Our research efforts contributed to disclose the role of endothelial cells (EC) in the pathophysiology of the thrombotic events, by using flow cytometry to quantify and characterize circulating EC and EC progenitors, of patients with recurrent thrombosis and Myeloproliferative Syndromes.
3- IDENTIFICATION OF NOVEL BIOMARKERS OF DISEASE TOWARDS A MORE PRECISE DIAGNOSIS AND CHARACTERIZATION OF PREVIOUSLY IDENTIFIED CONDITIONS.
Molecular and clinical data associated with disease physiopathology and progression was gathered from large cohorts of patients with autoimmune and neurological disorders, including Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), Behçet’s Disease (BD), Sleep Disorders (Hypersomnolence), and Epilepsy (Mesial Temporal Lobe Epilepsy – MTLE). Our study focusing on the contribution of genetic factors, such as HLA, and microRNA’s epigenetic factors, for the heterogeneity of these complex inflammation-associated diseases have allowed to uncover new biomarkers of disease susceptibility, progression and treatment response. The outcomes of this research represent a significant advance in the disease classification by allowing an earlier diagnosis, discrimination between clinical subgroups according to severity and outcomes, driving to the implementation of more effective treatments and leading to considerable improvement in disease prognosis. The impact of these findings was particularly striking in the “Non-Classical” Autoimmune/Inflammatory Diseases (AI/ID), such as Sleep Disorders cursing with daytime hypersomnolence, namely narcolepsy type 1 (N1), type 2 (N2) and Idiopathic Hypersomnia (IH) often difficult to distinguish from based on the clinical course of the disease. Our work has demonstrated that different HLA alleles allow the genetic identification between the conditions allowing such a distinction to be made. In addition, studies focusing in another “Non- Classical” AI/ID, such as MTLE, in which treatment resistance is known to be associated with CNS inflammation, we were able to demonstrate that the dysregulation of the purinergicinflammatory axis is the main contributing factor for seizure propagation and a poor response to pharmacological treatment. Major breakthroughs were made in oncology research, namely we described one of the first European series of patients with NK cell lymphomas, giving emphasis to the immunophenotypic characteristics of the neoplastic NK cells, and we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK), allowing to conclude that the CD94(hi)/HLADR phenotypic profile proved to be a useful surrogate marker for NK-cell clonality. Moreover, our research revealed that non-small cell lung cancer (NSCLC) exosomes and sorted miRNAs constitute novel tumor biomarkers that could enable earlier disease diagnosis in a near future. The identification these biomarkers could change the prognosis of NSCLC, a disease that currently has a very poor 5-year survival rate due to detection delay as most of patients are diagnosed in an advanced disease stage.
4- IDENTIFICATION OF BIOMARKERS FOR TARGETED THERAPIES
Research on the immunobiology of renal transplantation identified donor-specific antibody C1qbinding as predictors of antibody-mediated rejection in human leucocyte antigen-incompatible kidney transplantation that allows to stratify the risk of graft failure after renal transplantation and thus allowing a targeted intervention. Research on Fanconi Anemia (FA) identified Red Blood Cell distribution width as a biomarker of stress erythropoiesis and antioxidants were shown to be protective against the chromosome instability, thus offering new opportunities for treatment.
5- IDENTIFICATION OF PERSONALIZED TREATMENT APPROACHES LEADING TO IMPROVED CLINICAL OUTCOMES, INCLUDING THE DESIGN OF ALTERNATIVE HEALTHCARE STRATEGIES AND DISCLOSURE OF ADDITIONAL INDICATIONS FOR PREVIOUSLY AVAILABLE DRUGS.
Based on our studies on the role of gut hormones in controlling energy intake and glucose homeostasis, which contributed to the understanding of the molecular mechanisms underlying diabetes remission induced by weight loss surgical procedures such as gastric bypass (RYGB), a modified RYGB procedure with a longer biliopancreatic limb was devised and implemented in the clinical practice with improved anti-diabetic effects. Thus, our data has demonstrated that metabolic surgical interventions could be patient tailored to improve T2D outcomes. Moreover, aiming to achieve the best possible clinical outcomes in type 2 diabetic (T2D) patients with metabolic surgery intervention, as part of an international collaborative effort, we have established a novel diabetes remission prediction score (DiaBetter). In addition, our research focused on Hereditary Transthyretin Amyloidosis, ATTR V30M mutation allowed to identify new clinical features to the previously described hereditary disease, such as microalbuminuria as the presenting feature antedating the establishment of the neuropathy in V30M carriers; led the recommendation to perform simultaneous liver-kidney transplantation as a healthcare strategy in this patient population to enhance efficacy and safety by avoiding recurrence of nephropathy in ATTR patients with chronic renal disease; allowed to disclose and identify a new indications for a previously available drug, as the use of a transthyretin stabilizer tafamidis in kidney disease, in addition to peripheral neuropathy.