The tumor suppressor PTEN controls multiple cellular functions, including cell cycle, apoptosis, senescence, transcription, and mRNA translation of numerous genes. In tumor cells, PTEN is frequently inactivated by genetic mutations and epimutations. The aim of this study was to investigate the methylation patterns of the PTEN gene and its pseudogene PTENP1 as potential genetic markers of endometrial hyperplasia (EH) and endometrial carcinoma (EC). Methylation of the 5-terminal regions of the PTEN and PTENP1 sequences was studied using methyl-sensitive PCR of genomic DNA isolated from 57 cancer, 43 endometrial hyperplasia, and normal tissue samples of 24 females aged 17-34 years and 19 females aged 45-65 years, as well as 20 peripheral venous blood samples of EC patients. None of the analyzed DNA samples carried a methylated PTEN gene. On the contrary, the PTENP1 pseudogene was methylated in all analyzed tissues, except for the peripheral blood. Comparison of PTENP1 methylation rates revealed no differences between the EC and EH groups (0.80 p 0.50). In all these groups, the methylation level was high (71-77% in patients vs. 58% in controls). Differences in PTENP1 methylation rates between normal endometrium in young (4%) and middle-aged and elderly (58%) females were significant (p 0.001). These findings suggest that PTENP1 pseudogene methylation may reflect age-related changes in the body and is not directly related to the endometrium pathology under study. It is assumed that, depending on the influence of a methylated PTENP1 pseudogene on PTEN gene expression, the pseudogene methylation may protect against the development of EC and/or serve as a marker of a precancerous condition of endometrial cells.

The processed pseudogene PTENP1 is involved in the regulation of the expression of the PTEN and acts as a tumor suppressor in many types of malignances. In our previous study we showed that PTENP1 methylation is present not only in tumor, but also in normal endometrium tissues of women over 45 years old. Here we used methylation-specific PCR to analyze methylation status of CpG island located near promoter region of PTENP1 in malignant and non-malignant endometrium tissues collected from 236 women of different age groups. To confirm our results, we also analyzed RNA sequencing and microarray data from 431 women with endometrial cancer from TCGA database. We demonstrated that methylation of PTENP1 is significantly increased in older patients. We also found an age-dependent increase in the level of PTENP1 expression in endometrial tissue. According to our data, PTENP1 methylation elevates the level of the pseudogene sense transcript. In turn, a high level of this transcript correlates with a more favorable prognosis in endometrial cancer. The data obtained suggested that PTENP1 methylation is associated with age-related changes in normal and hyperplastic endometrial tissues. We assumed that age-related increase in PTENP1 methylation and subsequent elevation of its expression may serve as a protective mechanism aimed to prevent malignant transformation of endometrial tissue in women during the perimenopause, menopause, and postmenopause periods.

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Introduction. Recurrent pregnancy loss is a pathological condition characterized by inevitable miscarriage before 22 weeks of pregnancy or at birth of a fetus below 500 g of weight. The causes of miscarriage are quite diverse, and viral infections, including herpesvirus infection (HVI), is one of the important etiological factors for the development of this pathology. Activation of herpesvirus infection (HVI) has an extremely adverse effect on the course of pregnancy. The issue of the mechanism of reactivation of herpes viruses (HS) and the role of toll-like receptors (TLR) in predicting the activation of latent HVI during pregnancy has been insufficiently studied until the present. The study is aimed at evaluating the possibilities of predicting the activation of latent herpesvirus infection during pregnancy.Materials and methods. A total of 110 pregnant women with different courses of HVI were examined. The examination included the study of the TLR expression level and measurement of the pro- and anti-inflammatory cytokine levels.Results and discussion. Given the high specificity of TLR8 and the interferon system (IFN) against viral antigens, it can be assumed that the activation of TLR and the development of early cytokine reactions prior to the detection of specific antibodies in patients with latent HVI are predictors of advanced herpes infection. The levels of TLR8 expression and concentration of IFN-γ and IL-10 at the local level in patients with latent BBVI can be regarded as predictors of the transition of HBV from the latent phase of the life cycle to the lytic phase.Conclusion. If HVI develops actively during pregnancy, the antiviral immune response cascade that underlie the natural immune response starts at the local level, regardless of the localization of the antigen, and only a breakdown of the compensatory and adaptive mechanisms leads to the implementation of a systemic antiviral immune response. This suggests the important role of HVI, especially of its active forms, in the suppression of immunity during pregnancy.

INTRODUCTION: Iron deficiency (ID) occurring latently or as iron deficiency anemia (IDA) is common in gynecology, particularly in patients with abnormal uterine bleeding (AUB). AIM: We aimed at exploring the efficiency of a medication containing ferrous sulfate and multivitamins for the correction of latent ID and treatment of mild IDA in AUB patients. MATERIALS AND METHODS: We performed a comprehensive clinical, laboratory, and instrumental examination of 60 women aged 35 to 50 years with AUB, revealing many gynecological pathologies (endometrial polyps or hyperplasia, ade nomyosis, and uterine myoma). The examined patients with AUB were divided into two groups: women with latent ID (group 1, n=38) and women with IDA (group 2, n=22). Moreover, all the patients had extragenital pathology in addition to gynecological diseases. As a treatment, ferrous sulfate with multivitamins was prescribed for 13 months. RESULTS: Before treatment, the hemoglobin level in the examined patients ranged from 95 to 130 g/L, with an average of 127.11.8 g/L in group 1 and 100.32.1 g/L in group 2. Serum iron concentrations in the examined groups were 9.80.2 and 6.91.3 mol/L, respectively. After treatment, the average levels of hemoglobin and serum iron increased significantly and reached normal levels in all those examined. Hemoglobin was 143.31.8 g/L in group 1 and 122.51.5 g/L in group 2, whereas serum iron was 14.90.2 mol/L in group 1 and 13.51.0 mol/L in group 2. Furthermore, a significant increase to normal values was observed in other indicators of complete blood count and biochemical analysis. CONCLUSIONS: The results of the study reveal a high clinical efficiency of ferrous sulfate and multivitamins in the treatment of ID in patients with AUB.

Mutational changes in the promoter regions of MTHFR genes from patients with hyperhomocysteinemia and PTEN genes from patients with endometrial and ovarian tumors were studied. An increased level of homocysteine was found in a part of the patients with a heterozygous C677T mutation in the MTHFR gene, although a moderate hyperhomocysteinemia is usually associated with homozygous mutation. We hypothesized that, in this case, the allele lacking the C677T mutation may be inactivated by the promoter mutation. The sequencing of both DNA strands of the minimal promoter region of the MTHFR gene in ten patients did not reveal any mutation, which implied another mechanism of the development of hyperhomocysteinemia in these patients. A PCR analysis of the minimal promoter region of the tumor suppressor PTEN in the presence of 2-pyrrolidone in 101 patients from Moscow clinics revealed changes in it in patients with endometrial (56%) or ovarian (29%) cancer, as well as in patients with endometrial hyperplasia and benign ovarian tumors (34.6 and 29%, respectively). It was presumed that the found PTEN gene promoters may arise from epigenetic alterations (erroneous methylation) or may (more rarely) be induced by mutations. As a result of the studies, new molecular markers associated with endometrial and ovarian tumors were revealed and a simple and effective method of detection of these markers was developed.