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.

The Effect of Meclofenoxate on the Transcriptome of Aging Brain of Nothobranchius guentheri Annual Killifish.

Annual fish of the genus Nothobranchius are promising models for aging research. Nothobranchius reproduces typical aspects of vertebrate aging, including hallmarks of brain aging. Meclofenoxate (MF) is a well-known compound that can enhance cognitive performance. The drug is prescribed for asthenic conditions, trauma, and vascular diseases of the brain. It is believed that MF is able to delay age-dependent changes in the human brain. However, until now, there has been no study of the MF effect on the brain transcriptome. In the present work, we performed an RNA-Seq study of brain tissues from aged Nothobranchius guentheri, which were almost lifetime administered with MF, as well as young and aged control fish. As expected, in response to MF, we revealed significant overexpression of neuron-specific genes including genes involved in synaptic activity and plasticity, neurotransmitter secretion, and neuron projection. The effect was more pronounced in female fish. In this aspect, MF alleviated age-dependent decreased expression of genes involved in neuronal activity. In both treated and untreated animals, we observed strong aging-associated overexpression of immune and inflammatory response genes. MF treatment did not prevent this effect, and moreover, some of these genes tended to be slightly upregulated under MF treatment. Additionally, we noticed upregulation of some genes associated with aging and cellular senescence, including isoforms of putative vascular cell adhesion molecule 1 (VCAM1), protein O-GlcNAcase (OGA), protein kinase C alpha type (KPCA), prolow-density lipoprotein receptor-related protein 1 (LRP1). Noteworthy, MF treatment was also associated with the elevated transcription of transposons, which are highly abundant in the N. guentheri genome. In conclusion, MF compensates for the age-dependent downregulation of neuronal activity genes, but its effect on aging brain transcriptome still cannot be considered unambiguously positive.

De Novo Transcriptome Profiling of Brain Tissue from the Annual Killifish Nothobranchius guentheri.

Nothobranchius is a genus of small annual killifish found in Africa. Due to the relatively short lifespan, as well as easy breeding and care, Nothobranchius fish are becoming widely used as a vertebrate model system. Studying the genome and transcriptome of these fish is essential for advancing the field. In this study, we performed de novo transcriptome assembly of brain tissues from Nothobranchius guentheri using Trinity. Annotation of 104,271 potential genes (with transcripts longer than 500 bp) was carried out; for 24,967 genes (53,654 transcripts), in which at least one GO annotation was derived. We also analyzed the effect of a long-term food supplement with Torin 2, second-generation ATP-competitive inhibitor of mTOR, on the gene expression changes in brain tissue of adult N. guentheri. Overall, 1491 genes in females and 249 genes in males were differently expressed under Torin 2-supplemented diet. According to the Gene Set Enrichment Analysis (GSEA), the majority of identified genes were predominantly involved in the regulation of metabolic process, dendritic spine maintenance, circadian rhythms, retrotransposition, and immune response. Thus, we have provided the first transcriptome assembly and assessed the differential gene expression in response to exposure to Torin 2, which allow a better understanding of molecular changes in the brain tissues of adult fish in the mTOR pathway inhibition.