The impact of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms on apixaban trough concentration and bleeding risk in patients with atrial fibrillation.

OBJECTIVES: Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of CYP3A4*22, CYP3A5*3 and ABCB1 polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding. METHODS: A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5 mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. RESULTS: The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133 µmol/L, F(1)=6.7, p=0.01124). ABCB1 (rs1045642 and rs4148738), CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding. CONCLUSIONS: We report no significant association between ABCB1 gene polymorphisms (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.

Genetic changes in the FH gene cause vagal paraganglioma.

Vagal paraganglioma (VPGL) is a rare neuroendocrine tumor that originates from the paraganglion associated with the vagus nerve. VPGLs present challenges in terms of diagnostics and treatment. VPGL can occur as a hereditary tumor and, like other head and neck paragangliomas, is most frequently associated with mutations in the SDHx genes. However, data regarding the genetics of VPGL are limited. Herein, we report a rare case of a 41-year-old woman with VPGL carrying a germline variant in the FH gene. Using whole-exome sequencing, a variant, FH p.S249R, was identified; no variants were found in other PPGL susceptibility and candidate genes. Loss of heterozygosity analysis revealed the loss of the wild-type allele of the FH gene in the tumor. The pathogenic effect of the p.S249R variant on FH activity was confirmed by immunohistochemistry for S-(2-succino)cysteine (2SC). Potentially deleterious somatic variants were found in three genes, SLC7A7, ZNF225, and MED23. The latter two encode transcriptional regulators that can impact gene expression deregulation and are involved in tumor development and progression. Moreover, FH-mutated VPGL was characterized by a molecular phenotype different from SDHx-mutated PPGLs. In conclusion, the association of genetic changes in the FH gene with the development of VPGL was demonstrated. The germline variant FH: p.S249R and somatic deletion of the second allele can lead to biallelic gene damage that promotes tumor initiation. These results expand the clinical and mutation spectra of FH-related disorders and improve our understanding of the molecular genetic mechanisms underlying the pathogenesis of VPGL.

Presepsin as a biomarker of bacterial translocation and an indicator for the prescription of probiotics in cirrhosis.

BACKGROUND: The gut-liver axis and bacterial translocation are important in cirrhosis, but there is no available universal biomarker of cellular bacterial translocation, for which presepsin may be a candidate. AIM: To evaluate the relationship of the blood presepsin levels with the state of the gut microbiota in cirrhosis in the absence of obvious infection. METHODS: This study included 48 patients with Child-Pugh cirrhosis classes B and C and 15 healthy controls. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of presepsin were measured. A total of 22 patients received a probiotic (Saccharomyces boulardii) for 3 months. RESULTS: Presepsin levels were higher in patients with cirrhosis than in healthy individuals [342 (91-2875) vs 120 (102-141) pg/mL; P = 0.048]. Patients with elevated presepsin levels accounted for 56.3% of all included patients. They had lower levels of serum albumin and higher levels of serum total bilirubin and overall severity of cirrhosis as assessed using the Child-Pugh scale. Patients with elevated presepsin levels had an increased abundance of the main taxa responsible for bacterial translocation, namely Bacilli and Proteobacteria (including the main class Gammaproteobacteria and the minor taxa Xanthobacteraceae and Stenotrophomonas), and a low abundance of bacteria from the family Lachnospiraceae (including the minor genus Fusicatenibacter), which produce short-chain fatty acids that have a positive effect on intestinal barrier function. The presepsin level directly correlated with the relative abundance of Bacilli, Proteobacteria, and inversely correlated with the abundance of Lachnospiraceae and Propionibacteriaceae. After 3 months of taking the probiotic, the severity of cirrhosis on the Child-Pugh scale decreased significantly only in the group with elevated presepsin levels [from 9 (8-11) to 7 (6-9); P = 0.004], while there were no significant changes in the group with normal presepsin levels [from 8 (7-8) to 7 (6-8); P = 0.123]. A high level of presepsin before the prescription of the probiotic was an independent predictor of a greater decrease in Child-Pugh scores (P = 0.046), as well as a higher level of the Child-Pugh scale (P = 0.042), but not the C-reactive protein level (P = 0.679) according to multivariate linear regression analysis. CONCLUSION: The level of presepsin directly correlates with the abundance in the gut microbiota of the main taxa that are substrates of bacterial translocation in cirrhosis. This biomarker, in the absence of obvious infection, seems important for assessing the state of the gut-liver axis in cirrhosis and deciding on therapy targeted at the gut microbiota in this disease.

Gut Microbiota and Biomarkers of Intestinal Barrier Damage in Cirrhosis.

Gut dysbiosis and subclinical intestinal damage are common in cirrhosis. The aim of this study was to examine the association of intestinal damage biomarkers (diamine oxidase [DAO], claudin 3, and intestinal fatty acid binding protein [I-FABP; FABP2]) with the state of the gut microbiota in cirrhosis. The blood levels of DAO were inversely correlated with blood levels of claudin 3, lipopolysaccharide (LPS), presepsin, TNF-α, and the severity of cirrhosis according to Child-Pugh scores. The blood level of I-FABP was directly correlated with the blood level of claudin 3 but not with that of DAO. Patients with small intestinal bacterial overgrowth (SIBO) had lower DAO levels than patients without SIBO. There was no significant difference in claudin 3 levels and I-FABP detection rates between patients with and without SIBO. The DAO level was directly correlated with the abundance of Akkermansiaceae, Akkermansia, Allisonella, Clostridiaceae, Dialister, Lactobacillus, Muribaculaceae, Negativibacillus, Ruminococcus, Thiomicrospiraceae, Verrucomicrobiae, and Verrucomicrobiota; and it was inversely correlated with the abundance of Anaerostipes, Erysipelatoclostridium, and Vibrio. The I-FABP level was directly correlated with Anaerostipes, Bacteroidia, Bacteroidota, Bilophila, Megamonas, and Selenomonadaceae; and it was inversely correlated with the abundance of Brucella, Pseudomonadaceae, Pseudomonas, and Vibrionaceae. The claudin 3 level was directly correlated with Anaerostipes abundance and was inversely correlated with the abundance of Brucella, Coriobacteriia, Eggerthellaceae, and Lactobacillus.

Gut Microbiota and Biomarkers of Endothelial Dysfunction in Cirrhosis.

Our aim was to study the association of endothelial dysfunction biomarkers with cirrhosis manifestations, bacterial translocation, and gut microbiota taxa. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of nitrite, big endothelin-1, asymmetric dimethylarginine (ADMA), presepsin, and claudin were measured as biomarkers of endothelial dysfunction, bacterial translocation, and intestinal barrier dysfunction. An echocardiography with simultaneous determination of blood pressure and heart rate was performed to evaluate hemodynamic parameters. Presepsin, claudin 3, nitrite, and ADMA levels were higher in cirrhosis patients than in controls. Elevated nitrite levels were associated with high levels of presepsin and claudin 3, the development of hemodynamic circulation, hypoalbuminemia, grade 2-3 ascites, overt hepatic encephalopathy, high mean pulmonary artery pressure, increased abundance of Proteobacteria and Erysipelatoclostridium, and decreased abundance of Oscillospiraceae, Subdoligranulum, Rikenellaceae, Acidaminococcaceae, Christensenellaceae, and Anaerovoracaceae. Elevated ADMA levels were associated with higher Child-Pugh scores, lower serum sodium levels, hypoalbuminemia, grade 2-3 ascites, milder esophageal varices, overt hepatic encephalopathy, lower mean pulmonary artery pressure, and low abundance of Erysipelotrichia and Erysipelatoclostridiaceae. High big endothelin-1 levels were associated with high levels of presepsin and sodium, low levels of fibrinogen and cholesterol, hypocoagulation, increased Bilophila and Coprobacillus abundances, and decreased Alloprevotella abundance.

Editing Metabolism, Sex, and Microbiome: How Can We Help Poplar Resist Pathogens?

Poplar (Populus) is a genus of woody plants of great economic value. Due to the growing economic importance of poplar, there is a need to ensure its stable growth by increasing its resistance to pathogens. Genetic engineering can create organisms with improved traits faster than traditional methods, and with the development of CRISPR/Cas-based genome editing systems, scientists have a new highly effective tool for creating valuable genotypes. In this review, we summarize the latest research data on poplar diseases, the biology of their pathogens and how these plants resist pathogens. In the final section, we propose to plant male or mixed poplar populations; consider the genes of the MLO group, transcription factors of the WRKY and MYB families and defensive proteins BbChit1, LJAMP2, MsrA2 and PtDef as the most promising targets for genetic engineering; and also pay attention to the possibility of microbiome engineering.

Decelerated Epigenetic Aging in Long Livers.

Epigenetic aging is a hot topic in the field of aging research. The present study estimated epigenetic age in long-lived individuals, who are currently actively being studied worldwide as an example of successful aging due to their longevity. We used Bekaert's blood-based age prediction model to estimate the epigenetic age of 50 conditionally "healthy" and 45 frail long-livers over 90 years old. Frailty assessment in long-livers was conducted using the Frailty Index. The control group was composed of 32 healthy individuals aged 20-60 years. The DNA methylation status of 4 CpG sites (ASPA CpG1, PDE4C CpG1, ELOVL2 CpG6, and EDARADD CpG1) included in the epigenetic clock was assessed through pyrosequencing. According to the model calculations, the epigenetic age of long-livers was significantly lower than their chronological age (on average by 21 years) compared with data from the group of people aged 20 to 60 years. This suggests a slowing of epigenetic and potentially biological aging in long livers. At the same time, the obtained results showed no statistically significant differences in delta age (difference between the predicted and chronological age) between "healthy" long livers and long livers with frailty. We also failed to detect sex differences in epigenetic age either in the group of long livers or in the control group. It is possible that the predictive power of epigenetic clocks based on a small number of CpG sites is insufficient to detect such differences. Nevertheless, this study underscores the need for further research on the epigenetic status of centenarians to gain a deeper understanding of the factors contributing to delayed aging in this population.

Culturable Bacterial Endophytes of Wild White Poplar (Populus alba L.) Roots: A First Insight into Their Plant Growth-Stimulating and Bioaugmentation Potential.

The white poplar (Populus alba L.) has good potential for a green economy and phytoremediation. Bioaugmentation using endophytic bacteria can be considered as a safe strategy to increase poplar productivity and its resistance to toxic urban conditions. The aim of our work was to find the most promising strains of bacterial endophytes to enhance the growth of white poplar in unfavorable environmental conditions. To this end, for the first time, we performed whole-genome sequencing of 14 bacterial strains isolated from the tissues of the roots of white poplar in different geographical locations. We then performed a bioinformatics search to identify genes that may be useful for poplar growth and resistance to environmental pollutants and pathogens. Almost all endophytic bacteria obtained from white poplar roots are new strains of known species belonging to the genera Bacillus, Corynebacterium, Kocuria, Micrococcus, Peribacillus, Pseudomonas, and Staphylococcus. The genomes of the strains contain genes involved in the enhanced metabolism of nitrogen, phosphorus, and metals, the synthesis of valuable secondary metabolites, and the detoxification of heavy metals and organic pollutants. All the strains are able to grow on media without nitrogen sources, which indicates their ability to fix atmospheric nitrogen. It is concluded that the strains belonging to the genus Pseudomonas and bacteria of the species Kocuria rosea have the best poplar growth-stimulating and bioaugmentation potential, and the roots of white poplar are a valuable source for isolation of endophytic bacteria for possible application in ecobiotechnology.

Non-Coding RNAs and the Development of Chemoresistance to Docetaxel in Prostate Cancer: Regulatory Interactions and Approaches Based on Machine Learning Methods.

Chemotherapy based on taxane-class drugs is the gold standard for treating advanced stages of various oncological diseases. However, despite the favorable response trends, most patients eventually develop resistance to this therapy. Drug resistance is the result of a combination of different events in the tumor cells under the influence of the drug, a comprehensive understanding of which has yet to be determined. In this review, we examine the role of the major classes of non-coding RNAs in the development of chemoresistance in the case of prostate cancer, one of the most common and socially significant types of cancer in men worldwide. We will focus on recent findings from experimental studies regarding the prognostic potential of the identified non-coding RNAs. Additionally, we will explore novel approaches based on machine learning to study these regulatory molecules, including their role in the development of drug resistance.

Sex-determining region complements traditionally used in phylogenetic studies nuclear and chloroplast sequences in investigation of Aigeiros Duby and Tacamahaca Spach poplars (genus Populus L., Salicaceae).

Members of the genus Populus L. play an important role in the formation of forests in the northern hemisphere and are used in urban landscaping and timber production. Populus species of closely related sections show extensive hybridization. Therefore, the systematics of the genus is rather complicated, especially for poplars of hybrid origin. We aimed to assess the efficiency of application of the sex-determining region (SDR) in addition to the nuclear and chloroplast genome loci traditionally used in phylogenetic studies of poplars to investigate relationships in sections Aigeiros Duby and Tacamahaca Spach. Targeted deep sequencing of NTS 5S rDNA, ITS, DSH 2, DSH 5, DSH 8, DSH 12, DSH 29, 6, 15, 16, X18, trnG-psbK-psbI, rps2-rpoC2, rpoC2-rpoC1, as well as SDR and ARR17 gene was performed for 379 poplars. The SDR and ARR17 gene together with traditionally used multicopy and single-copy loci of nuclear and chloroplast DNA allowed us to obtain a clustering that is most consistent with poplar systematics based on morphological data and to shed light on several controversial hypotheses about the origin of the studied taxa (for example, the inexpediency of separating P. koreana, P. maximowiczii, and P. suaveolens into different species). We present a scheme of relationships between species and hybrids of sections Aigeiros and Tacamahaca based on molecular genetic, morphological, and geographical data. The geographical proximity of species and, therefore, the possibility of hybridization between them appear to be more important than the affiliation of species to the same section. We speculate that sections Aigeiros and Tacamahaca are distinguished primarily on an ecological principle (plain and mountain poplars) rather than on a genetic basis. Joint analysis of sequencing data for the SDR and chloroplast genome loci allowed us to determine the ancestors of P. × petrovskoe - P. laurifolia (female tree) × P. × canadensis (male tree), and P. × rasumovskoe - P. nigra (female tree) × P. suaveolens (male tree). Thus, the efficiency of using the SDR for the study of poplars of sections Aigeiros and Tacamahaca and the prospects of its use for the investigation of species of the genus Populus were shown.

Intestinal Barrier and Gut Microbiota in Patients with Overlapping Irritable Bowel Syndrome and Functional Dyspepsia.

BACKGROUND: Disturbances in the intestinal barrier and gut dysbiosis have been observed in patients with functional bowel diseases. AIMS: To investigate the correlation between biomarkers of intestinal barrier disorders at different layers and the severity of symptoms in patients with overlapping diarrhea-predominant irritable bowel syndrome and functional dyspepsia (IDFO), as well as with gut microbiota taxa. METHODS: This study included 45 patients with IDFO and 16 healthy controls. Endoscopy with biopsy of the duodenum and sigmoid colon (SC) was performed to count intraepithelial lymphocytes (IELs) and mucosal eosinophils (subepithelial layer), assess fatty acid binding protein (FABP; epithelial layer) level, and stain for mucin-2 (MUC-2; pre-epithelial layer). Composition of the gut microbiota was evaluated using 16S rRNA gene sequencing. RESULTS: Patients with IDFO exhibited an increase in biomarkers of intestinal barrier disorders at all layers studied. IEL count in the duodenum was correlated with the severity of bloating (r = 0.336; p = 0.024) and, in the SC, was correlated with tenesmus severity (r = 0.303; p = 0.042). FABP-1 level in the SC was correlated with the severity of diarrhea (r = 0.577; p = 0.001), and FABP-5 concentration in the SC was correlated with abdominal distension (r = 0.477; p = 0.010). MUC-2 concentration in the duodenum was correlated with the severity of heartburn (r = 0.572; p = 0.025) and burning sensation in the epigastrium (r = 0.518; p = 0.048). All biomarkers of intestinal barrier permeability were correlated with the abundance of some gut microbiota taxa. CONCLUSION: Patients with IDFO exhibited disrupted intestinal barrier function in all layers, which was associated with clinical symptom severity and changes in the gut microbiota.

Gut Dysbiosis and Hemodynamic Changes as Links of the Pathogenesis of Complications of Cirrhosis.

The aim was to evaluate the relationship between gut dysbiosis and hemodynamic changes (hyperdynamic circulation) in cirrhosis, and between hemodynamic changes and complications of this disease. This study included 47 patients with cirrhosis. Stool microbiome was assessed using 16S rRNA gene sequencing. Echocardiography with a simultaneous assessment of blood pressure and heart rate was performed to assess systemic hemodynamics. Patients with hyperdynamic circulation had more severe cirrhosis, lower albumin, sodium and prothrombin levels, higher C-reactive protein, aspartate aminotransferase and total bilirubin levels, and higher incidences of portopulmonary hypertension, ascites, overt hepatic encephalopathy, hypoalbuminemia, hypoprothrombinemia, systemic inflammation, and severe hyperbilirubinemia than patients with normodynamic circulation. Patients with hyperdynamic circulation compared with those with normodynamic circulation had increased abundance of Proteobacteria, Enterobacteriaceae, Bacilli, Streptococcaceae, Lactobacillaceae, Fusobacteria, Micrococcaceae, Intestinobacter, Clostridium sensu stricto, Proteus and Rumicoccus, and decreased abundance of Bacteroidetes, Bacteroidaceae, Holdemanella, and Butyrivibrio. The systemic vascular resistance and cardiac output values correlated with the abundance of Proteobacteria, Enterobacteriaceae, Bacilli, Streptococcaceae, Lactobacillaceae, Micrococcaceae, and Fusobacteria. Heart rate and cardiac output value were negatively correlated with the abundance of Bacteroidetes. The mean pulmonary artery pressure value was positively correlated with the abundance of Proteobacteria and Micrococcaceae, and negatively with the abundance of Holdemanella.

Effect of Rebamipide on the Intestinal Barrier, Gut Microbiota Structure and Function, and Symptom Severity Associated with Irritable Bowel Syndrome and Functional Dyspepsia Overlap: A Randomized Controlled Trial.

Treatment of functional digestive disorders is not always effective. Therefore, a search for new application points for potential drugs is perspective. Our aim is to evaluate the effect of rebamipide on symptom severity, intestinal barrier status, and intestinal microbiota composition and function in patients with diarrheal variant of irritable bowel syndrome overlapping with functional dyspepsia (D-IBSoFD). Sixty patients were randomized to receive trimebutine (TRI group), trimebutine + rebamipide (T + R group), or rebamipide (REB group) for 2 months. At the beginning and end of the study, patients were assessed for general health (SF-36), severity of digestive symptoms (Gastrointestinal Symptom Rating and 7 × 7 scales), state of the intestinal barrier, and composition (16S rRNA gene sequencing) and function (short-chain fatty acid fecal content) of the gut microbiota. The severity of most digestive symptoms was reduced in the REB and T + R groups to levels similar to that observed in the TRI group. The duodenal and sigmoidal lymphocytic and sigmoidal eosinophilic infiltration was decreased only in the REB and T + R groups, not in the TRI group. Serum zonulin levels were significantly decreased only in the REB group. A decrease in intraepithelial lymphocytic infiltration in the duodenum correlated with a decrease in the severity of rumbling and flatulence, while a decrease in infiltration within the sigmoid colon correlated with improved stool consistency and decreased severity of the sensation of incomplete bowel emptying. In conclusion, rebamipide improves the intestinal barrier condition and symptoms in D-IBSoFD. The rebamipide effects are not inferior to those of trimebutine.

Transcriptome Profiling of Prostate Cancer, Considering Risk Groups and the TMPRSS2-ERG Molecular Subtype.

Molecular heterogeneity in prostate cancer (PCa) is one of the key reasons underlying the differing likelihoods of recurrence after surgical treatment in individual patients of the same clinical category. In this study, we performed RNA-Seq profiling of 58 localized PCa and 43 locally advanced PCa tissue samples obtained as a result of radical prostatectomy on a cohort of Russian patients. Based on bioinformatics analysis, we examined features of the transcriptome profiles within the high-risk group, including within the most commonly represented molecular subtype, TMPRSS2-ERG. The most significantly affected biological processes in the samples were also identified, so that they may be further studied in the search for new potential therapeutic targets for the categories of PCa under consideration. The highest predictive potential was found with the EEF1A1P5, RPLP0P6, ZNF483, CIBAR1, HECTD2, OGN, and CLIC4 genes. We also reviewed the main transcriptome changes in the groups at intermediate risk of PCa-Gleason Score 7 (groups 2 and 3 according to the ISUP classification)-on the basis of which the LPL, MYC, and TWIST1 genes were identified as promising additional prognostic markers, the statistical significance of which was confirmed using qPCR validation.

Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster.

Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents some negative side effects of rapamycin. Moreover, it inhibits the rapamycin-resistant TORC2 complex. In this work, we evaluated transcriptomic changes in D. melanogaster heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included D. melanogaster of three ages (2, 4, and 6 weeks old), separately for males and females. Torin-2, taken at the lowest concentration being tested (0.5 µM per 1 L of nutrient paste), had a slight positive effect on the lifespan of D. melanogaster males (+4% on the average) and no positive effect on females. At the same time, RNA-Seq analysis revealed interesting and previously undiscussed effects of Torin-2, which differed between sexes as well as in flies of different ages. Among the cellular pathways mostly altered by Torin-2 at the gene expression level, we identified immune response, protein folding (heat shock proteins), histone modification, actin cytoskeleton organization, phototransduction and sexual behavior. Additionally, we revealed that Torin-2 predominantly reduced the expression of Srr gene responsible for the conversion of L-serine to D-serine and thus regulating activity of NMDA receptor. Via western blot analysis, we showed than in old males Torin-2 tends to increase the ratio of the active phosphorylated form of ERK, the lowest node of the MAPK cascade, which may play a significant role in neuroprotection. Thus, the complex effect of Torin-2 may be due to the interplay of the immune system, hormonal background, and metabolism. Our work is of interest for further research in the field of NMDA-mediated neurodegeneration.

Transcriptome Analysis of Redox Systems and Polyamine Metabolic Pathway in Hepatoma and Non-Tumor Hepatocyte-like Cells.

Reactive oxygen species (ROS) play a major role in the regulation of various processes in the cell. The increase in their production is a factor contributing to the development of numerous pathologies, including inflammation, fibrosis, and cancer. Accordingly, the study of ROS production and neutralization, as well as redox-dependent processes and the post-translational modifications of proteins, is warranted. Here, we present a transcriptomic analysis of the gene expression of various redox systems and related metabolic processes, such as polyamine and proline metabolism and the urea cycle in Huh7.5 hepatoma cells and the HepaRG liver progenitor cell line, that are widely used in hepatitis research. In addition, changes in response to the activation of polyamine catabolism that contribute to oxidative stress were studied. In particular, differences in the gene expression of various ROS-producing and ROS-neutralizing proteins, the enzymes of polyamine metabolisms and proline and urea cycles, as well as calcium ion transporters between cell lines, are shown. The data obtained are important for understanding the redox biology of viral hepatitis and elucidating the influence of the laboratory models used.

Comprehensive Genetic Study of Malignant Cervical Paraganglioma.

Malignant middle ear paraganglioma (MEPGL) is an exceedingly rare tumor of the neuroendocrine system. In general, MEPGLs represent as slow growing and hypervascularized benign neoplasms. The genetic basis of MEPGL tumorigenesis has been poorly investigated. We report a case of malignant MEPGL accompanied by the comprehensive genetic analysis of the primary tumor and metastasis. Based on whole-exome sequencing data, the germline pathogenic mutation p.R230H in the SDHB gene, encoding for subunit B of mitochondrial complex II, was found in a patient. Analysis of somatic mutation spectra revealed five novel variants in different genes, including a potentially deleterious variant in UNC13C that was common for the tumor and metastasis. Identified somatic variants clustered into SBS1 and SBS5 mutational signatures. Of note, the primary tumor was characterized by Ki-67 4% and had an elevated mutational load (1.4/Mb); the metastasis' mutational load was about 4.5 times higher (6.4/Mb). In addition, we revealed somatic loss of the wild-type SDHB allele, as well as loss of heterozygosity (LOH) at the 11p locus. Thus, germline mutation in SDHB combined with somatic LOH seem to be drivers that lead to the tumor's initiation and progression. Other somatic changes identified can be additional disease-causing factors. Obtained results expand our understanding of molecular genetic mechanisms associated with the development of this rare tumor.

Broadness and specificity: ArdB, ArdA, and Ocr against various restriction-modification systems.

ArdB, ArdA, and Ocr proteins inhibit the endonuclease activity of the type I restriction-modification enzymes (RMI). In this study, we evaluated the ability of ArdB, ArdA, and Ocr to inhibit different subtypes of Escherichia coli RMI systems (IA, IB, and IC) as well as two Bacillus licheniformis RMI systems. Furthermore we explored, the antirestriction activity of ArdA, ArdB, and Ocr against a type III restriction-modification system (RMIII) EcoPI and BREX. We found that DNA-mimic proteins, ArdA and Ocr exhibit different inhibition activity, depending on which RM system tested. This effect might be linked to the DNA mimicry nature of these proteins. In theory, DNA-mimic might competitively inhibit any DNA-binding proteins; however, the efficiency of inhibition depend on the ability to imitate the recognition site in DNA or its preferred conformation. In contrast, ArdB protein with an undescribed mechanism of action, demonstrated greater versatility against various RMI systems and provided similar antirestriction efficiency regardless of the recognition site. However, ArdB protein could not affect restriction systems that are radically different from the RMI such as BREX or RMIII. Thus, we assume that the structure of DNA-mimic proteins allows for selective inhibition of any DNA-binding proteins depending on the recognition site. In contrast, ArdB-like proteins inhibit RMI systems independently of the DNA recognition site.

Eubiotic effect of rifaximin is associated with decreasing abdominal pain in symptomatic uncomplicated diverticular disease: results from an observational cohort study.

BACKGROUND: Rifaximin effectively treats symptomatic uncomplicated diverticular disease (SUDD) and has shown eubiotic potential (i.e., an increase in resident microbial elements with potential beneficial effects) in other diseases. This study investigated changes in the fecal microbiome of patients with SUDD after repeated monthly treatment with rifaximin and the association of these changes with the severity of abdominal pain. METHODS: This was a single-center, prospective, observational, uncontrolled cohort study. Patients received rifaximin 400 mg twice a day for 7 days per month for 6 months. Abdominal pain (assessed on a 4-point scale from 0 [no pain] to 3 [severe pain]) and fecal microbiome (assessed using 16 S rRNA gene sequencing) were assessed at inclusion (baseline) and 3 and 6 months. The Spearman's rank test analyzed the relationship between changes in the gut microbiome and the severity of abdominal pain. A p-value ≤ 0.05 was considered statistically significant. RESULTS: Of the 23 patients enrolled, 12 patients completed the study and were included in the analysis. Baseline abdominal pain levels decreased significantly after 3 (p = 0.036) and 6 (p = 0.008) months of treatment with rifaximin. The abundance of Akkermansia in the fecal microbiome was significantly higher at 3 (p = 0.017) and 6 (p = 0.015) months versus baseline. The abundance of Ruminococcaceae (p = 0.034), Veillonellaceae (p = 0.028), and Dialister (p = 0.036) were significantly increased at 6 months versus baseline, whereas Anaerostipes (p = 0.049) was significantly decreased. The severity of abdominal pain was negatively correlated with the abundance of Akkermansia (r=-0.482; p = 0.003) and Ruminococcaceae (r=-0.371; p = 0.026) but not with Veillonellaceae, Dialister, or Anaerostipes. After 3 months of rifaximin, abdominal pain was significantly less in patients with Akkermansia in their fecal microbiome than in patients without Akkermansia (p = 0.022). CONCLUSION: The eubiotic effect of rifaximin was associated with decreased abdominal pain in patients with SUDD.

Lymphatic Dissemination in Prostate Cancer: Features of the Transcriptomic Profile and Prognostic Models.

Radical prostatectomy is the gold standard treatment for prostate cancer (PCa); however, it does not always completely cure PCa, and patients often experience a recurrence of the disease. In addition, the clinical and pathological parameters used to assess the prognosis and choose further tactics for treating a patient are insufficiently informative and need to be supplemented with new markers. In this study, we performed RNA-Seq of PCa tissue samples, aimed at identifying potential prognostic markers at the level of gene expression and miRNAs associated with one of the key signs of cancer aggressiveness-lymphatic dissemination. The relative expression of candidate markers was validated by quantitative PCR, including an independent sample of patients based on archival material. Statistically significant results, derived from an independent set of samples, were confirmed for miR-148a-3p and miR-615-3p, as well as for the CST2, OCLN, and PCAT4 genes. Considering the obtained validation data, we also analyzed the predictive value of models based on various combinations of identified markers using algorithms based on machine learning. The highest predictive potential was shown for the "CST2 + OCLN + pT" model (AUC = 0.863) based on the CatBoost Classifier algorithm.