Coronavirus, uses the Angiotensin Converting Enzyme-2 Receptor to enter airway cells. Viral endocytosis is mediated by several factors, including clathrin, the adaptor protein-2 complex (AP2) and the adaptor-associated kinase-1 (AAK1). 2 According to a recent report, 3 COVID-19, the disease caused by SARS-CoV-2, is characterized by three clinical patterns: no symptoms, mild to moderate disease, severe pneumonia requiring admission to Intensive Care Unit (ICU) in up to 31% of the patients. 3 Thus far, there is no specific therapy for COVID-19 infection. No benefit of lopinavir-ritonavir treatment resulted in a recent trial. 4 Hydroxychloroquine, currently used in view of its "in vitro" observed effect of reduction of viral replication, seems unsatisfactory. 5 Elevated proinflammatory cytokine/chemokine responses seem associated with respiratory failure. 3 Recently, tocilizumab, an interleukin-6 inhibitor, was reported as effective in patients with severe COVID-19 pneumonia. 6 Baricitinib, another inhibitor of cytokine-release, seems an interesting anti-inflammatory drug. It is a Janus kinase inhibitor (anti-JAK) licensed for the treatment of rheumatoid arthritis (RA) with good efficacy and safety records. 7 Moreover it seems to have anti-viral effects by its affinity for AP2-associated protein AAK1, reducing SARS-CoV-2 endocytosis. 8 On this basis, we assessed the safety of baricitinib therapy combined with lopinavir-ritonavir in moderate COVID-19 pneumonia patients and we evaluated its clinical impact.All consecutive hospitalized patients (March 16th −30th) with moderate COVID-19 pneumonia, older than 18 years, were treated for 2 weeks with baricitinib tablets 4 mg/day added to ritonavir-lopinavir therapy. The last consecutive patients with moderate COVID-19 pneumonia receiving standard of care therapy (lopinavir/ritonavir tablets 250 mg/bid and hydroxychloroquine 400 mg/day/orally for 2 weeks) admitted before the date of the first baricitinib-treated patient served as controls. Antibiotics were scheduled only in the case of suspected bacterial infection.Inclusion criteria were: a. SARS-Co-V2 positivity in the nasal/oral swabs; b. presence of at least 3 of the following symptoms: fever, cough, myalgia, fatigue; c. evidence of radiological pneumonia . After discharge, patients treated with baricitinib were planned to be followed for additional 6 weeks. Exclusion criteria: history of thrombophlebitis (TP), latent tuberculosis infection (QuantiFERON Plus-test positivity, Qiagen, Germany 9 ), pregnancy and lactation.Mild to moderate COVID-19 disease definition: presence of bilateral pneumonia with or without ground glass opacity and in absence of consolidation, not requiring intubation at enrollment; arterial oxygen saturation (SpO2) > 92% at room-air, and ratio arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) 10 0-30 0 mmHg. Parameters daily accessed were: fever, pulmonary function, Modified Early Warning Score (MEWS), 10 pulse rate, blood pressure. After the initial execution, r...

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Background: Interleukin-6 (IL-6), a proinflammatory cytokine, has been reported to be associated with disease severity and mortality in patients with coronavirus disease 2019 (COVID-19). Yet, dynamic changes in IL-6 levels and their prognostic value as an indicator of lung injury in COVID-19 patients have not been fully elucidated. Objective: To validate whether IL-6 levels are associated with disease severity and mortality and to investigate whether dynamic changes in IL-6 levels might be a predictive factor for lung injury in COVID-19 patients. Methods: This retrospective, single-center study included 728 adult COVID-19 patients and used data extracted from electronic medical records for analyses. Results: The mortality rate was higher in the elevated IL-6 group than in the normal IL-6 group (0.16 vs 5%). Cox proportional hazards and logistic regression analyses for survival (adjusted hazard ratio, 10.39; 95% confidence interval [CI], 1.09-99.23; p = 0.042) and disease severity (adjusted odds ratio, 3.56; 95% CI, 2.06-6.19; p < 0.001) revealed similar trends. Curve-fitting analyses indicated that patient computed tomography (CT) scores peaked on days 22 and 24. An initial decline in IL-6 levels on day 16 was followed by resurgence to a peak, nearly in tandem with the CT scores. Conclusion: Increased IL-6 level may be an independent risk factor for disease severity and in-hospital mortality and dynamic IL-6 changes may serve as a potential predictor for lung injury in Chinese COVID-19 patients. These findings may guide future treatment of COVID-19 patients.

Autophagy is reported to be involved in the formation of skin hypertrophic scar (HTS). However, the role of autophagy in the process of fibrosis remains unclear, therefore an improved understanding of the molecular mechanisms associated with autophagy may accelerate the development of effective therapeutic strategies against HTS. The present study evaluated the roles of autophagy mediated by transcription factor EB (TFEB), a pivotal regulator of lysosome biogenesis and autophagy, in transforming growth factor-β1 (TGF-β1)-induced fibroblast differentiation and collagen production. Fibroblasts were treated with TGF-β1, TGF-β1 + tauroursodeoxycholic acid (TUDCA) or TGF-β1 + TFEB-small interfering RNA (siRNA). TGF-β1 induced phenotypic transformation of fibro-blasts, as well as collagen synthesis and secretion in fibroblasts in a dose-dependent manner. Western blotting and immuno-fluorescence analyses demonstrated that TGF-β1 upregulated the expression of autophagy-related proteins through the endoplasmic reticulum (ER) stress pathway, whereas TUDCA reversed TGF-β1-induced changes. Reverse transcription-quantitative PCR (RT-qPCR), western blotting and RFP-GFP-LC3 double fluorescence analyses demonstrated that knockdown of TFEB by TFEB-siRNA decreased autophagic flux, upregulated the expression of proteins involved in the apoptotic pathway, such as phosphorylated-α subunit of eukaryotic initiation factor 2, C/EBP homologous protein and cysteinyl aspartate specific proteinase 3, and also downregulated the expression of α-smooth muscle actin and collagen I (COL I) in fibroblasts. Immunofluorescence confocal analyses and enzyme-linked immunosorbent assay indicated that TGF-β1 increased the colocalization of COL I with lysosomal-associated membrane protein 1 and Ras-related protein Rab-8A, a marker of secretory vesicles, in fibroblasts, as well as the secretion of pro-COL Iα1 in culture supernatants. Meanwhile, these effects were abolished by TFEB knockdown. The present results suggested that autophagy reduced ER stress, decreased cell apoptosis and maintained fibroblast activation not only through degradation of misfolded or unfolded proteins, but also through promotion of COL I release from the autolysosome to the extracellular environment.

Minimal extrathyroidal extension (ETE) is defined as tumor cells extending to the sternothyroid muscle or perithyroidal soft tissue. However, there is controversy regarding whether the magnitude of ETE (minimal or gross) should be considered in assigning a precise TNM stage to patients with thyroid cancer in the seventh/eighth editions of the AJCC system. The present study evaluated Surveillance, Epidemiology, and End Results data from 107,114 patients with differentiated thyroid cancer (2004–2013) to determine whether the magnitude of ETE (thyroid confinement, minimal, or gross) influenced the ability to predict cancer-specific survival (CSS) and overall survival (OS). Patient mortality was evaluated using Cox proportional hazards regression analyses and Kaplan-Meier analyses with log-rank tests. The cancer-specific mortality rates per 1,000 person-years were 1.407 for the thyroid confinement group (95% CI: 1.288–1.536), 5.133 for the minimal ETE group (95% CI: 4.301–6.124), and 29.735 for the gross ETE group (95% CI: 28.147–31.412). Relative to the thyroid confinement group, patients with minimal ETE and gross ETE had significantly poorer CSS and OS in the univariate and multivariate analyses (both P<0.001). After propensity-score matching according to age, sex, and race, we found that thyroid confinement was associated with better CSS and OS rates than minimal ETE (P<0.001) and gross ETE (P<0.001). These results from a population-based cohort provide a reference for precise personalized treatment and management of patients with minimal ETE. Furthermore, it may be prudent to revisit the magnitude of ETE as advocated by the AJCC and currently used for treatment recommendation by the American Thyroid Association.