Genetic and therapeutic landscapes in cohort of pancreatic adenocarcinomas: next-generation sequencing and machine learning for full tumor exome analysis.

About 7% of all cancer deaths are caused by pancreatic cancer (PCa). PCa is known for its lowest survival rates among all oncological diseases and heterogenic molecular profile. Enormous amount of genetic changes, including somatic mutations, exceeds the limits of routine clinical genetic laboratory tests and further stagnates the development of personalized treatments. We aimed to build a mutational landscape of PCa in the Russian population based on full exome next-generation sequencing (NGS) of the limited group of patients. Applying a machine learning model on full exome individual data we received personalized recommendations for targeted treatment options for each clinical case and summarized them in the unique therapeutic landscape.

[Change of transcription level of photoreceptor-specific CRX gene in the peripheral blood of the participants of an arctic world oceanic international flight]. / Izmenenie urovnya transkriptsii fotoretseptor-spetsifichnogo gena CRX u uchastnikov arkticheskogo krugosvetnogo pereleta.

The CRX gene encoding the cone-rod homeobox protein is a specific photoreceptor transcription factor crucial for retinal function. Persons temporarily residing in the Arctic zone during the polar summer may suffer from disturbances associated with extremely high ambient illumination. These environmental changes are mediated by retinal photoreceptors; therefore, it is important to study the expression of retinal genes in order to assess individual capacities of sensory adaptation to polar day conditions. PURPOSE: To reveal the dynamics of CRX expression level in humans after a prolonged temporary exposure to polar day conditions. MATERIAL AND METHODS: The study included 6 pilots (males from 39 to 69 y.o.) who participated in the Arctic World Oceanic International Flight Sever Vash (West to East, from 62°N 74°E to 72°N 114°E). Samples of peripheral blood for RNA isolation were collected at the start and at the end of the flight. The level of mRNA in the samples was evaluated based on the data of quantitative real-time PCR of the CRX gene, as well as the b2M and TBP housekeeping genes (reference). RESULTS: Expression of the CRX gene in the studied group (p<0.01) was revealed; the total average level of mRNA was about 3 times higher prior to, and approximately 7 times higher after normalization to the b2M gene. Five pilots had increased expression of the CRX gene within the range of -1.53 to -3.07 (Z-score of <0 before the flight and >0 after the flight). In one pilot, the level of CRX expression was higher at the start, but it reduced by the end of the circumnavigation flight. CONCLUSIONS: The results confirm the hypothesis that the CRX gene is expressed after a prolonged temporary exposure to polar day conditions. It was also revealed that during rapid adaptation, equal changes in the illumination of retinal photoreceptors lead to different individual dynamics of CRX expression.

Comparative Whole-Transcriptome Profiling of Liver Tissue from Wistar Rats Fed with Diets Containing Different Amounts of Fat, Fructose, and Cholesterol.

Differential expression of 30,003 genes was studied in the liver of female Wistar rats fed with isocaloric diets with the excess of fat, fructose, or cholesterol, or their combinations for 62 days using the method of whole-transcriptome profiling on a microchip. Relative mRNA expression levels of the Asah2, Crot, Crtc2, Fmo3, GSTA2, LOC1009122026, LOC102551184, NpY, NqO1, Prom1, Retsat, RGD1305464, Tmem104, and Whsc1 genes were also determined by RT-qPCR. All the tested diets affected differently the key metabolic pathways (KEGGs). Significant changes in the expression of steroid metabolism gene were observed in the liver of animals fed with the tested diets (except the high-fat high fructose diet). Both high-fat and high-fructose diets caused a significant decrease in the expression of squalene synthase (FDFT1 gene) responsible for the initial stage of cholesterol synthesis. On the contrary, in animals fed with the high-cholesterol diet (0.5% cholesterol), expression of the FDFT1 gene did not differ from the control group; however, these animals were characterized by changes in the expression of glucose and glycogen synthesis genes, which could lead to the suppression of glycogen synthesis and gluconeogenesis. At the same time, this group demonstrated different liver tissue morphology in comparison with the animals fed with the high-fructose high-fat diet, manifested as the presence of lipid vacuoles of a smaller size in hepatocytes. The high-fructose and high-fructose high-fat diets affected the metabolic pathways associated with intracellular protein catabolism (endocytosis, phagocytosis, proteasomal degradation, protein processing in the endoplasmic reticulum), tight junctions and intercellular contacts, adhesion molecules, and intracellular RNA transport. Rats fed with the high-fructose high-fat or high-cholesterol diets demonstrated consistent changes in the expression of the Crot, Prom1, and RGD1305464 genes, which reflected a coordinated shift in the regulation of lipid and carbohydrate metabolisms.