Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma

Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.

Proteolytic enzyme and adiponectin receptors as potential targets for COVID-19 therapy

The coronavirus disease 2019 (COVID-19) pandemic requires not only the creation of vaccines to prevent the spread of the disease, but also the development of novel drugs aimed at reducing viral load, suppressing an excessive immune response and preventing the severe complications such as lung fibrosis and acute respiratory distress syndrome. One of the promising targets for studying the development of pneumonia, systemic inflammation and disseminated intravascular coagulation in COVID-19 is the plasminogen activator system. In patients with a severe disease course, impaired activity or expression of plasminogen activators significantly increases the blood level of D-dimer and fibrinogen, as well as correlates with intravascular coagulation and thrombus formation. The second promising target for studying the pathogenesis of COVID-19 is the adiponectin/T-cadherin system: adiponectin is able to reduce the content of pro-inflammatory cytokines, the increase of which is characteristic of COVID-19, and stimulate the production of an anti-inflammatory cytokine interleukin-10. The review describes the role of plasminogen and T-cadherin activators in their possible participation in the development of pulmonary fibrosis in COVID-19 and hemostasis regulation, as well as cardio- and vasculoprotective function of adiponectin and its receptor, T-cadherin.

From Pregnancy Loss to COVID 19 Cytokine Storm: A Matter of Inflammation and Coagulation

Large scientific evidence achieved during the second half of the past century points to a leading role of inflammation in the pathogenic mechanism of the main pregnancy complications, such as abortion, pregnancy loss, premature delivery, infection, fetal encephalopathy, enterocolitis, pulmonary hyaline membrane diseases and death. Thinking about pregnancy inflammation, one must refer today to the umbalance of the normal mediators of organic functions: cytokins, peptides, nucleosides, prostanoids. Indeed, according to the order and quantity of their release, they are involved either in physiology or in pathology of pregnancy. At this regard, it has been shown that Th1-type immunity is incompatible with successful pregnancy. Regulation of the mediators of maternal functions is largely under fetal genetic control. Assessment of the fetal role derives from studies showing an umbalance of cytokines and plasminogen activator system, an increase of endothelin, a downregulation of adenosine receptors, in the fetal compartment, in aneuploid pregnancies. The resulting functional deviations deal with inflammation, imfection, coagulation, impaired utero-placental perfusion, possibly leading to fetal demise and ominus maternal complications. SARS-COV-2 infection, on the other hand, is characterized by a similar umbalance of the inflammatory mediators, leading to hyperactivation of a type-1 lymphobyte T-helper response, which ends in a possibly fatal cytokine storm syndrome. While SARS-COV-2 infection recognizes a viral etiology, the cause of pregnancy inflammation must be recognized in the inability of the fetus to control the maternal immune response. Therefore, the preventive measures are quite different, although both benefit of a similar anti-inflammatory, antibiotic and anti-coagulant therapy.