Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

GENDER PECULIARITIES OF BRONCHIAL ASTHMA COURSE IN PATIENTS WITH BODY MASS DIFFERENCE

Bronchial asthma is among the most common diseases of the respiratory system. Increased incidence of bronchial asthma can be associated with obesity that is more common nowadays. Fatty tissue plays a special role in the formation of systemic inflammation, which differs depending on gender. The aim of the research was to compare peculiarities of clinical course and spirometry indices in patients with bronchial asthma and body mass difference depending on gender. A complete clinical examination of 104 patients with persistent BA in an inpatient department has been performed. Depending on body mass index, all patients were divided into three subgroups: the first one included 36 patients with normal body mass, the second subgroup 34 overweight patients, and the third subgroup 34 patients with obesity. In each subgroup, most patients suffered from persistent BA of moderate degree, mild course was usually observed in overweight patients. Severe course was more common in patients with obesity and normal body mass. To detect gender peculiarities, we analyzed data of case histories and peculiarities of clinical course. It was revealed that 91.6% of women with obesity had reported onset of the disease in middle age, and 40% of men had suffered since childhood. In the subgroup with normal body mass, 59.1% of men and 57.1% of women suffered less than 10 years. Thus, the disease progressed more rapidly in obese women, while there was not gender difference in disease duration under conditions of normal body mass. Complicated course was much more common in women. However, men more often suffered from type 2 diabetes mellitus. Gender differences in the spirometry indices were analyzed separately in women and men depending on body mass. In obese women, of all spirometry indices, only MEF75 decreased. It proves that more marked obstructive changes are observed at the level of tiny branches of the bronchial tree in obese women. In overweight men, FVC, IVC, FEV1 and PEF were lower than in the subgroup with normal mass. These indices were also significantly lower in the subgroup of patients with obesity. Thus, in men, increase in body mass has more influence on speed and volume of air in spirometry indices. To perform thorough gender analysis, we compared spirometry indices in overweight men and women and obese individuals together and revealed some peculiarities. In men, the majority of spirometry indices are significantly lower than in women, indicating more severe course of the disease. Among them, all indices confirm restrictive changes in the lungs and FEV1 is the main marker of broncho-obstructive syndrome. Besides, more manifested obstructive changes were observed in men both at the level of the main, secondary and tertiary bronchi. Conclusion. Excessive body mass in men has more manifested influence on speed and volume of air in spirometry indices. Such marked changes in respiratory function can be explained by the fact that abdominal obesity is more common in men, which contributes to the decrease in volume and speed indices due to restrictive diaphragmatic excursion and, as a result, deterioration of broncho-obstructive syndrome

Decreased expression levels of PIWIL1, PIWIL2, and PIWIL4 are associated with worse survival in renal cell carcinoma patients

Robert Iliev,1,2 Michal Stanik,3 Michal Fedorko,4 Alexandr Poprach,1 Petra Vychytilova-Faltejskova,1,2 Katerina Slaba,2 Marek Svoboda,1 Pavel Fabian,5 Dalibor Pacik,1 Jan Dolezel,2 Ondrej Slaby3,4 1Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 2Central European Institute of Technology, Masaryk University, 3Department of Urologic Oncology, Masaryk Memorial Cancer Institute, 4Department of Urology, University Hospital Brno, Masaryk University Brno, 5Department of Diagnostic and Experimental Pathology, Masaryk Memorial Cancer Institute, Brno, Czech RepublicAbstract: Piwi-interacting RNAs (piRNAs) are a newly discovered class of small non-coding RNAs involved in silencing of transposable elements and in sequence-specific chromatin modifications. PIWI proteins (PIWIL) belong to the family of Argonaute genes/proteins, bind piRNAs and their functioning have been described mainly in germ-line cells and more recently also in stem cells and cancer cells. There are four PIWI proteins PIWIL1, PIWIL2, PIWIL3, and PIWIL4 discovered in human till now. Recent studies suggested that deregulated the expression of Piwi proteins and selected piRNAs is common to many types of cancers. We found significantly lower expression of PIWIL1 (P<0.0001) and piR-823 (P=0.0001) in tumor tissue in comparison to paired renal parenchyma. Further, we observed progressive decrease in PIWIL1 (P=0.0228), PIWIL2 (P=0.0015), and PIWIL4 (P=0.0028) expression levels together with increasing clinical stage. PIWIL2 (P=0.0073) and PIWIL4 (P=0.0001) expression progressively decreased also with increasing Fuhrman grade. Most importantly, low-expression levels of PIWIL1 (P=0.009), PIWIL2 (P<0.0001), and PIWIL4 (P=0.0065) were significantly associated with worse overall survival in renal cell carcinoma (RCC) patients. Our results suggest the involvement of PIWIL genes and piR-823 in RCC pathogenesis, and indicate PIWIL1, PIWIL2, and PIWIL4 as potential prognostic biomarkers in patients with RCC. Keywords: kidney cancer, PIWIL, piRN