Leyla V. Tskhovrebova

Relevance. Familial hypercholesterolemia (FH) is a monogenic hereditary disorder characterized by impaired lipid metabolism. The prevalence of FH in the general population averages 0.32% (95% CI: 0.26-0.39%). The disease can have both autosomal dominant and autosomal recessive inheritance patterns. Eight FH phenotypes associated with mutations in the LDLRAP1, PCSK9, APOA2, APOB, GHR, GSBS, EPHX2, and LDLR genes are known, which can lead to early manifestation of the pathology. The aim of this review is to comprehensively analyze current literature data on the molecular genetics, biological, and psychological aspects of FH. Analysis of signaling pathways in FH revealed three clusters of genes and their encoded proteins responsible for the following processes: assembly, remodeling, and clearance of plasma lipoproteins (genes: LDLR, LDLRAP1, VLDLR, NPC1L1, APOC1, LPA, CETP, MTTP, APOB, PCSK9); cholesterol metabolism (gene: PPP1R17);regulation of plasma lipoprotein particle levels (gene: ANGPTL3). The proteins PCSK9, APOB, and MTTP were identified as key elements (central hubs) of these metabolic networks. The PPP1R17 protein is involved in the mechanisms of long-term depression, a form of synaptic plasticity. Furthermore, the literature describes an association of FH with five other genes: ABCG5, ABCG8, STAP1, CYP7A1, LIPA, and PNPLA5. Conclusion. Thus, for the early diagnosis and effective management of patients with FH, it is necessary to consider not only the expanded spectrum of associated genes and proteins but also the psychological state of patients, particularly their levels of anxiety, depression, and stress.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. Abnormal methylation can be one reason for this cancer. This study aimed to investigate the DNA promotor methylation status of cancer-associated genes (ATM, APC, CDO1, RB1, TP53, and WIF1) in patients with HNSCC. Methods: Bisulfite conversion and methylation-sensitive high-resolution melting were used to analyze the DNA methylation levels in normal and tumor tissues in 44 patients. Results: Significant differences in DNA methylation were observed between tumor and normal tissues for CDO1 and WIF1 genes in all subjects and subgroups (p < 0.05). In the T3 subgroup, a significant correlation was found between CDO1 gene methylation and age in normal tissue. The same correlation was detected for the WIF1 gene methylation in tumor tissue samples in the subgroup with T3 and normal tissue samples in the subgroup with T4 (p < 0.05). In all genes, no significant differences were found between the patient subgroups (T2, T3, T4 stage, primary/recurrent lesion, non-keratinizing/keratinizing SCC, age before/after 50, and smokers/non-smokers). Conclusion: Changes in the expressions of CDO1 and WIF1 genes can affect the mechanisms of the occurrence and development of HNSCC. Methylation in the ATM, APC, RB1, and TP53 genes is not specific to HNSCC.

Аномальные маточные кровотечения при ожирении в репродуктивном периоде как проявление универсального гипоксического синдрома

Head and neck squamous cell carcinoma (HNSCC) takes the sixth place among the most common cancers in the world. Abnormal methylation can be one of the reasons for this cancer. The aim of this study was to investigate the DNA promotor methylation status of cancer-associated genes (ATM, APC, CDO1, RB1, TP53, WIF1) in patients with HNSCC. Bisulfite Conversion and Methylation-Sensitive High-Resolution Melting was used for analysis of the DNA methylation level of normal and tumor tissues in 44 patients. There were significant differences in DNA methylation level between patient’s tumor and normal tissues for CDO1 and WIF1 genes in all subjects and subgroups (p<0.05). In T3 subgroup there was significant correlation between CDO1 gene methylation and age in the normal tissue. The same correlation was detected also for the WIF1 gene methylation in tumor tissue samples in the subgroup with T3 and in normal tissue samples in the subgroup with T4 (p<0,05). In all genes no significant differences were found between the subgroups (T2, T3, T4 stage, primary/recurrent lesion, non-keratinizing/keratinizing SCC, age before/ after 50, smokers/non-smokers) of the patients. Thus, changes in the expression of the CDO1 and WIF1 genes can affect mechanisms of the occurrence and development of HNSCC.

Аномальные маточные кровотечения у пациенток с ожирением и полиморфизм генов eNOS, VEGF-A и HIF-1A

Introduction. Head and neck cancer is a heterogenous group of malignant tumors of different etiologies, molecular mechanisms of which are still insufficiently studied.Aim. Investigation of DNA methylation status of some tumor associated genes (RASSF1A, RASSF2, RASSF5, CDO1, MEST and WIF1) in patients with head and neck squamous cell carcinoma.Materials and methods. The DNA methylation level of normal and tumor tissues was analyzed using bisulfite conversion and methylation-sensitive high-resolution melting in 25 patients (21 men and 4 women) diagnosed with neck squamous cell carcinoma.Results. There were significant differences in levels of DNA methylation between tumor and normal tissues in the CDO1 and WIF1 genes in all groups and subgroups of patients (larynx and other cancers, squamous cell carcinoma keratinizing and non-keratinizing, primary and recurrent tumor, smokers and non-smokers). The methylation level in the CDO1 gene in tumor tissue was significantly increased in the T4 and T3 stage subgroups compared to T2.Conclusion. The increased level of methylation of the CDO1 and WIF1 genes, as well as changes in their expression are among the molecular mechanisms involved in the neck squamous cell carcinoma development. They can be considered as prognostic and diagnostic markers for this pathology.

Adenoid hypertrophy (AH) is considered one of the most common diseases in the ear, nose and throat (ENT) practice. The cause of adenoid hypertrophy in children is still unknown. The main aim of the current study was to investigate IL-10 (interleukin 10) gene polymorphisms and human herpesviruses 6 (HHV6), cytomegalovirus (CMV), and Epstein–Barr virus (EBV) infections in children with AH. A total of 106 children with adenoid hypertrophy and 38 healthy children aged 2–11 years were included in this study. All children with adenoid hypertrophy were divided into three subgroups depending on the adenoid size. The viruses were determined via quantitative real-time polymerase chain reaction (PCR) using commercially available kits (QIAGEN, Germany). HHV6 was more frequently detected in patients with AH compared with CMV and EBV. Among the three subgroups of children with AH, HH6 and EBV were prevalent in the children with the largest adenoid size. The frequency of genotype GG tended to be higher in the control group of children. We found significantly higher frequencies of the G allele and GG and GA genotypes for IL-10 rs1800896 in the subgroup of children with the smallest size of adenoid compared with other subgroups. In conclusion, HHV6 and EBV infection could contribute to the adenoid size. The genotype GG for IL-10 rs1800896 could contribute to the resistance to adenoid hypertrophy and the spread of the adenoid tissue.

Genome stability of human embryonic stem cells (hESC) is an important issue because even minor genetic alterations can negatively impact cell functionality and safety. The incorrect repair of DNA double-stranded breaks (DSBs) is the ultimate cause of the formation of chromosomal aberrations. Using G2 radiosensitivity assay, we analyzed chromosomal aberrations in pluripotent stem cells and somatic cells. The chromatid exchange aberration rates in hESCs increased manifold 2 hours after irradiation as compared with their differentiated derivatives, but the frequency of radiation-induced chromatid breaks was similar. The rate of radiation-induced chromatid exchanges in hESCs and differentiated cells exhibited a quadratic dose response, revealing two-hit mechanism of exchange formation suggesting that a non-homologous end joining (NHEJ) repair may contribute to their formation. Inhibition of DNA-PK, a key NHEJ component, by NU7026 resulted in a significant decrease in radiation-induced chromatid exchanges in hESCs but not in somatic cells. In contrast, NU7026 treatment increased the frequency of radiation-induced breaks to a similar extent in pluripotent and somatic cells. Thus, DNA-PK dependent NHEJ efficiently participates in the elimination of radiation-induced chromatid breaks during the late G2 in both cell types and DNA-PK activity leads to a high level of misrejoining specifically in pluripotent cells.