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COVID-19 is a new pandemic, caused by Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-Cov2) infection and characterized by a broad spectrum of clinical manifestations. Inflammation and the innate immune system have been recently recognized as pivotal players in the most severe forms, characterized by significantly elevated levels of pro-inflammatory cytokines. In this setting, several studies have also reported the presence of abnormalities in coagulation parameters and platelets count, possibly identifying a subgroup of patients with poor prognosis. Some reports of full-blown thromboembolic events are emerging. Among the possible mechanisms underlying coagulation dysfunction, the so-called "cytokine storm" seems to play a pivotal role. Other candidate factors include virus-specific mechanisms, related to the virus interaction with renin angiotensin system (RAS) and the fibrinolytic pathway, but also comorbidities affecting these patients. Coagulation dysfunction is therefore a candidate risk factor for adverse outcomes in COVID-19 and should be carefully addressed in clinical practice.

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The lymphatic vasculature is essential for tissue fluid homeostasis and cancer metastasis, although the molecular mechanisms involved remain poorly characterized. Endothelin-1 (ET-1) axis plays a crucial role in angiogenesis and tumorigenesis. Here, we first report that ET-1 acts as a lymphangiogenic mediator. We performed in vitro and in vivo studies and show that lymphatic endothelial cells produce ET-1, ET-3, and express the endothelin B receptor (ET B R). In these cells, ET-1 promotes proliferation, invasiveness, vascular-like structures formation, and phosphorylation of AKT and p42/44 mitogen-activated protein kinase through ET B

Background We evaluated whether frailty and multimorbidity predict in-hospital mortality in patients with COVID-19 beyond chronological age. Methods 165 patients admitted from March 8th to April 17th, 2020, with COVID-19 in an acute geriatric ward in Italy were included. Pre-disease frailty was assessed with the Clinical Frailty Scale (CFS). Multimorbidity was defined as the co-occurrence of ≥2 of these in the same patient. The hazard (HR) of in-hospital mortality as a function of CFS score and number of chronic diseases in the whole population and in those aged 70+ years were calculated. Results Among the 165 patients, 112 were discharged, 11 were transferred to intensive care units and 42 died. Patients who died were older (81.0 vs. 65.2 years, p<0.001), more frequently multimorbid (97.6 vs. 52.8%; p<0.001) and more likely frail (37.5 vs. 4.1%; p<0.001). Less than 2.0% of patients without multimorbidity and frailty, 28% of those with multimorbidity only and 75% of those with both multimorbidity and frailty died. Each unitary increment in the CFS was associated with a higher risk of in-hospital death in the whole sample (HR=1.3; 95%CI=1.05-1.62) and in patients aged 70+ years (HR=1.29;95%CI=1.04-1.62), whereas the number of chronic diseases was not significantly associated with higher risk of death. The CFS addition to age and sex increased mortality prediction by 9.4% in those aged 70+ years. Conclusions Frailty identifies patients with COVID-19 at risk of in-hospital death independently of age. Multimorbidity contributes to prognosis because of the very low probability of death in its absence.

Endothelial cells are important targets for herpesvirus infection. To evaluate the biological effects of human herpesvirus-6 (HHV-6) infection, adult heart microvascular and aortic endothelial cells were examined for in vitro susceptibility to HHV-6 and for the alterations induced by viral infection on the production of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8). Analysis by reverse transcription-polymerase chain reaction and by in situ polymerase chain reaction showed that HHV-6 replicates in endothelium in the absence of cytopathic effects, and that viral sequences were present in 20% umbilical vein and in 10% aortic and 1% microvascular endothelium. HHV-6 infection upregulated the production of MCP-1 and IL-8, with differences observed between aortic and microvascular endothelium. These findings demonstrate that endothelial cells represent a potential reservoir for HHV-6 infection, and the altered pattern of chemokine production can lead to attraction of immunocompetent cells and to the development of inflammatory processes.

Hepatocellular carcinoma (HCC) is one of most malignant and aggressive human tumors. Transforming growth factor-B1 (TGF-B1) and its coreceptor CD105 have been shown to contribute to HCC malignant progression. TGF-B1 and CD105 have also been implicated in angiogenesis, but their role in the vascularization of HCC has not been investigated. To fill this gap, we studied the effect of TGF-B1 and CD105 on HCC-derived endothelium. By using immunomagnetic beads, we isolated and cultured endothelial cells (ECs) from HCC (HCC-EC) and adjacent nonneoplastic tissue (nNL-ECs) obtained from 24 liver biopsies. HCC and nNL biopsies were also analyzed by immunohistochemistry for the expression of CD105, TGF-B1, Ve-cadherin (Ve-cad), CD44, B-catenin, and E-cadherin. Compared with nNL-ECs, HCC-ECs had higher expression of CD105, enhanced spontaneous motility, and greater capacity to migrate in response to TGF-B1 (5 ng/mL), particularly in the presence of a fibronectin matrix. The chemotactic effect of TGF-B1 was blocked by anti-CD105 antibodies and correlated with the grade of HCC malignancy. Histologic examination of HCC biopsies showed that HCCs with the worse malignant features had the highest expression of TGF-B1, CD105, and angiogenic markers (Ve-cad and CD44). Because CD105 was highly expressed in microvessels at the tumor periphery and TGF-B1 staining was only found in neoplastic hepatocytes, we conclude that HCC-derived TGF-B1 may act as a chemoattractant for CD105-expressing ECs and as a promoter of tumor angiogenesis. Thus, drugs that selectively target the TGF-B1/CD105 axis may interfere with HCC-related angiogenesis and HCC progression. [Cancer Res 2008;68(20):8626-34]

BackgroundSARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD).ObjectiveWith this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations.MethodsWe investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission.ResultsPatients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19.ConclusionsOur results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.