Human hepatocellular carcinoma expresses specific PCNA isoforms: an in vivo and in vitro evaluation

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Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma.

BACKGROUND: Notch signalling is altered in several solid tumours and it plays a role in growth inhibition and apoptosis of hepatocellular carcinoma (HCC)-derived cell lines, bile duct development and hepatocyte regeneration. AIMS: This study aims to analyse the expression of Notch3, Notch4 and HES1 and HES6 as Notch-target genes in HCC, matched non-neoplastic tissue and HEPG2 cells. RESULTS: Notch3 and Notch4 are not expressed in normal liver and in chronic hepatitis surrounding HCC. Cirrhotic tissue stains negative for Notch3, while Notch4 is expressed by hepatocytes at the edge of regenerative nodules and in cell planes adjacent to fibrous septa. HCC tissue displays Notch3 and Notch4 abnormal accumulation, respectively, in 78% and 68% of the cases. The endothelium of hepatic veins with neoplastic permeation is frequently Notch4 positive. An upregulation of Notch3 mRNA was found in 95% of HCCs vs cirrhosis (P=0.0001), while Notch4 mRNA was downregulated in 80% of HCCs. HES6 mRNA expression was higher in HCC tissue when compared with cirrhosis (P=0.007), paralleling Notch3 mRNA expression. The HEPG2 cell line displays high Notch3 and low Notch4 protein and mRNA levels. CONCLUSIONS: These descriptive findings suggest an aberrant expression of Notch3 and Notch4 in HCC and allow the hypothesis of an activation of Notch signalling by Notch3

Chitosan and Essential Oils Combined for Beef Meat Protection against the Oviposition of Calliphora vomitoria, Water Loss, Lipid Peroxidation, and Colour Changes

Meat production has a higher economic and ecological impact than other commodities. The reduction in meat loss and waste throughout the whole supply chain is a demanding challenge. In recent years, the interest in the food-grade polysaccharide chitosan (CH) and essential oils (EOs) employed as allies in meat protection has increased. In this work, we selected five EOs obtained from plants traditionally used as spices, and after their chemical characterisation, a trained panel of expert sensorial analysts determined that, among them, Laurus nobilis (Lauraceae) and Piper nigrum (Piperaceae) EOs were the most suitable to season meat. Therefore, the effect of CH, the L. nobilis and P. nigrum EOs, and EOs-enriched CH solutions on meat was tested to assess how they deter the oviposition behaviour of the blowfly Calliphora vomitoria (Diptera: Calliphoridae) and against water loss, lipid peroxidation, and colour changes. All the applied treatments, compared to the control, did not accelerate meat dehydration but increased colour lightness, an attractive feature for consumers, and discouraged the blowfly’s oviposition. In particular, the P. nigrum EO-enriched CH was the most active in repelling C. vomitoria without negatively affecting the organoleptic qualities and shelf-life of meat

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial

BackgroundTocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients.MethodsA multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival.ResultsIn the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6-24.0, P=0.52) and 22.4% (97.5% CI: 17.2-28.3, P<0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline.ConclusionsTocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline.Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092)