Reply to Erren et al. Chronodisruption: Origin, Roots, and Developments of an 18-Year-Old Concept. Comment on “Desmet et al. Time-Restricted Feeding in Mice Prevents the Disruption of the Peripheral Circadian Clocks and Its Metabolic Impact during Chronic Jetlag. Nutrients 2021, 13, 3846”

We would like to thank Erren et al. [...

Preneoplastic lesions in human hepatocarcinogenesis

The early stages of hepatocarcinogenesis in human chronic liver diseases are characterized by the emergence of preneoplastic lesions of which some will eventually develop into hepatocellular carcinoma (HCC). Basic studies on the genetic and epigenetic alterations of these preneoplastic lesions may eventually lead to new therapeutic strategies. Clinicopathological studies are also important in order to determine optimal management of patients with a preneoplastic lesion. This article aims to provide a comprehensive review of the current concepts of preneoplastic lesion in chronic liver diseases. The microscopical small-cell dysplastic focus is the smallest morphologically recognizable precursor lesion of HCC and therefore is a logical target of study to elucidate the earliest events in hepatocarcinogenesis. In contrast, large-cell dysplasia is not a precursor lesion, but appears to be of clinical value because of its good predictive value for development of HCC. Dysplastic nodules (DNs) are macroscopically recognizable precursor lesions of HCC and high-grade DNs (HGDNs) have a risk of malignant transformation. Detection of DNs and correct differentiation from small HCC (<2 cm) is sometimes difficult, especially when only imaging techniques are used. Additional clinicopathological studies on identification and optimal treatment of DNs are necessary. Molecular studies on HGDNs and small HCCs may yield much information on the genetic mechanisms involved in the transition from severe dysplasia to early malignancy. In contrast, currently available data indicate that (large) regenerative nodules do not represent a distinct step in hepatocarcinogenesis. Animal models will be helpful in the further unravelling of human HCC development, provided that studies are performed on models that are good representatives of human hepatocarcinogenesis. We propose three criteria by which good mimickers can be identified

Judges versus jurors: biased attributions in the courtroom

The fundamental purpose of a tort trial is to allocate responsibility. However, attributing fault is difficult, and decades of research in psychology have shown that human beings are prone to make systematic errors in performing this task. What can be done about this? The United States and countries in continental Europe adopt diametrically opposed strategies to reduce errors in the attribution of responsibility in the courtroom. American law delegates fact-finding to jurors and makes some type of evidence inadmissible in court to protect jurors from potentially biasing information, such as character evidence. European legal systems, instead, employ almost exclusively judges to perform fact-finding and allow character evidence at trial, under the assumption that judges are better than laypeople in weighing the probative value of this type of evidence. There is a longstanding debate among legal scholars on whether the American or the European approach reduces more trial errors, but the relative performance of the two legal systems remains largely untested. This article is the first to provide evidence on the relative performance of these two systems. Our results suggest that jurors fail to correctly apply European rules of character evidence. The American rules on the inadmissibility of character evidence seem therefore a more appropriate choice when fact-finding is performed by jurors. We find also that, contrary to jurors, judges apply European rules correctly and thus reduce the risk of errors in the attribution of responsibility. Overall, this result indicates that the American and the European evidence rules to improve fact-finding are well set up. Nonetheless, we also find that neither of the two systems is able to prevent factfinders' errors in the attribution responsibility when these mistakes are not due to the type of evidence presented at trial but to (unconscious) beliefs held by factfinders themselves. We thus propose a set of policies that could improve factfinders' ability to avoid mistakes in attributing responsibility.</p

Expression of neural cell adhesion molecule in human liver development and in congenital and acquired liver diseases

In the liver, neural cell adhesion molecule (NCAM) is a marker of immature cells committed to the biliary lineage and is expressed by reactive bile ductules in human liver diseases. We investigated the possible role of NCAM in the development of intrahepatic bile ducts and aimed at determining whether immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases. Therefore, we performed immunohistochemistry for NCAM and bile duct cell markers cytokeratin 7 and cytokeratin 19 on frozen sections of 85 liver specimens taken from 14 fetuses, 10 donor livers, 18 patients with congenital liver diseases characterized by ductal plate malformations (DPMs), and 43 cirrhotic explant livers. Duplicated ductal plates and incorporating, bile ducts during development showed a patchy immunoreactivity for NCAM, while DPMs were continuously positive for NCAM. Bile ducts showing complete or patchy immunoreactivity for NCA M were found in cirrhotic livers, with higher frequency in biliary than in posthepatitic cirrhosis. Our results suggest that NCAM may have a function in the development of the intrahepatic bile ducts and that NCAM-positive immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases

Progenitor cells in diseased human liver

Hepatic progenitor cells are immature epithelial cells that reside in the smallest ramifications of the billary tree in human liver. These cells are capable of differentiating toward the biliary and the hepatocytic lineages and represent the human counterpart of the oval cells in murine liver. An increased number of progenitor cells (referred to as "activation") and differentiation of the same toward hepatocytes or bile duct epithelial cells, or both, is a component of virtually all human liver diseases. The extent of progenitor cell activation and the direction of differentiation are correlated with the severity of the disease and the type of mature epithelial cell (hepatocyte or bile duct epithelial cell), respectively, that is damaged. Analogous to findings in animal models of hepatocarcinogenesis, human hepatic progenitor cells most likely can give rise to hepatocellular carcinoma. The factors that govern human hepatic progenitor cell activation and differentiation are beginning to be identified

The correlation between portal myofibroblasts and development of intrahepatic bile ducts and arterial branches in human liver

Background/Aims: The development of the intrahepatic bile ducts most likely requires interactions between epithelial and mesenchymal cells. In view of the epithelial-mesenchymal interactions between portal myofibroblasts (pMFs) and biliary epithelial cells in adult diseases of the bile ducts, we investigated the presence and function of pMFs during the development of intrahepatic bile ducts, as well as the development of intrahepatic branches of the hepatic artery. Methods: We performed haematoxylin-eosin-stainings and immunohistochemistry for alpha-smooth-muscle actin, cytokeratin 19 and vimentin on serial sections of 45 fetal and postnatal liver biopsies. Results: The mesenchyme of portal tracts in the ductal plate stage devoid of a hepatic artery branch, contained numerous and diffusely scattered pMFs. Portal tracts with a hepatic artery branch were always larger than those without and showed a decreasing number of pMFs. In the remodeling stage, all portal tracts contained a hepatic artery branch, and pMFs were restricted to the periductal mesenchyme. These periductal pMFs disappeared after full incorporation of the bile duct. Conclusion: Our findings strongly suggest interactions between pMFs and epithelial cells of the developing bile ducts. The development of the intrahepatic arterial branches always precedes the incorporation of the tubular segments of the ductal plate