IL-22 promotes liver regeneration after portal vein ligation.

Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. Conclusion: IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

Obesity and diabetes mellitus are associated with SARS-CoV-2 outcomes without influencing signature genes of extrapulmonary immune compartments at the RNA level.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is responsible for eliciting Coronavirus disease 2019 (COVID-19) still challenges healthcare services worldwide. While many patients only suffer from mild symptoms, patients with some pre-existing medical conditions are at a higher risk for a detrimental course of disease. However, the underlying mechanisms determining disease course are only partially understood. One key factor influencing disease severity is described to be immune-mediated. In this report, we describe a post-mortem analysis of 45 individuals who died from SARS-CoV-2 infection. We could show that although sociodemographic factors and premedical conditions such as obesity and diabetes mellitus reduced survival time in our cohort, they were not associated with changes in the expression of immune-related signature genes at the RNA level in the blood, the gut, or the liver between these different groups. Our data indicate that obesity and diabetes mellitus influence SARS-CoV-2-related mortality, without influencing the extrapulmonary gene expression of immunity-related signature genes at the RNA level.

TNFα aggravates detrimental effects of SARS-CoV-2 infection in the liver.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFα production. Further analysis revealed that TNFα signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFα signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time.

Cardiac pre-competiton screening in Swiss athletes. Current situation in competitive athletes and short-time assessment of an exemplary local screening program.

AIM OF THE STUDY: In Switzerland, screening concepts for the prevention of sports-associated sudden cardiac death are still insufficiently established in the large group of competitive athletes who are not integrated in an Olympic- or other high-level squad. The aim of the present study was to objectively determine the current situation in this particular group of athletes concerning cardiac pre-competition screening and define specific features of an "ideal" Swiss screening concept. Based on these data, the feasibility and validity was tested by the implementation of an exemplary local screening programme. METHODS: A standardised questionnaire was completed by 1,047 competitive athletes of different ages and gender. The individual, sports-specific profile of an athlete and furthermore, the personal attitude towards and the vision of a "perfect" cardiac screening were assessed. Based on the results, an exemplary local screening programme for competitive athletes was implemented at the "Academic Sports Association Zurich" (ASVZ) in Zurich, Switzerland and evaluated 1 year after its introduction. RESULTS: Only 9% of the 1,047 interviewed competitive athletes (aged 13 to 64 years; median age 22 years, SD = 5.87) had previously undergone a cardiac screening. Only 47% of the interviewed competitive athletes expressed their interest to undergo a cardiac screening at all. Male and older athletes showed a significantly higher acceptance rate for the screening programme than women and younger athletes. All athletes accepted to bear the expenses for the baseline screening programme, adapted to international standards (minimal accepted fee of 60 Swiss Francs). Almost half of the athletes (49.2%) preferred easy accessibility to a sports cardiologist (max. distance of 10 kilometres). The exemplary local screening programme proved to be feasible and successful. However, only 30% of the 102 screened individuals were female and most of the athletes (80%) who made use of the screening had a specific concern or symptom (selection bias). A total of 5 athletes (4.9%) were, at least temporarily, declared as not eligible for competitive sports due to a relevant cardiac pathology. CONCLUSION: The fact that only 9% of the interviewed competitive athletes had previously undergone cardiac screening is alarming, but underlines the necessity and urgency of implementing a cost-effective and adequate screening concept in the enormous group of competitive athletes who are not integrated in an Olympic- or other high-level squad. The need for a certain self-determination and personal responsibility of the athletes should be respected. Therefore, the screening should not be mandatory. However, adequate information about the issue is crucial for an informed decision.