[Efficacy of Mexidol in the correction of postcovid syndrome in patients with chronic cerebrovascular diseases]. / Effektivnost' preparata Meksidol v korrektsii postkovidnogo sindroma u patsientov s khronicheskimi tserebrovaskulyarnymi zabolevaniyami.

OBJECTIVE: To evaluate the effectiveness of sequential therapy with Mexidol and Mexidol FORTE 250 in the correction of postcovoid syndrome (PKS) in patients with chronic cerebrovascular diseases (CVD). MATERIAL AND METHODS: The analysis of the results of examination and treatment of 110 patients with CVD who underwent COVID-19 was carried out. Patients of the main group (OH, n=55) received Mexidol (5 ml IV drip for 14 days, followed by the transition to the tablet form of Mexidol FORTE 250 1 table 3 times/day for 2 months); 55 patients of the comparison group (GS) did not receive antioxidants. All patients included in the study were conducted MRI examination and extensive neuropsychological testing. RESULTS: There was a significant improvement in the state of cognitive functions, regression of symptoms of asthenia, improvement of night sleep in patients with OG. The differences were statistically significant both in comparison with the baseline level and the HS. CONCLUSION: The administration of the drug does not require age-related dose adjustment and is well combined with basic therapy. The recommended regimen for the use of Mexidol: 14 days of 5 ml i/v or i/m, then taking the drug Mexidol FORTE 250 at a dose of 1 table 3 times/day for 2 months.

[Twin gestation with regressive partial hydatidiform mole and coexisting live fetus]. / Nerazvivayushchiisya chastichnyi puzyrnyi zanos v slitnoi dikhorial'noi platsente s normal'nym razvitiem vtorogo bliznetsa.

The case of dichorionic twin pregnancy is described, with a fused placenta, one part of which is represented by a tissue of partial hydatidiform mole (PHM) with signs of regression, the second part is a placenta of a common structure with a normal development of the second twin. The delivery took place at the term of 38 weeks with a live healthy girl weighing 3250 g. A single placental disc consisted of two fused placentas with a clear boundary between them. The placenta of a live-born girl was mature, with focal chorangiosis, the second part of the disc was represented by the PHM tissue with avascular giant bizarre villi, some of them with central cisterns, with stromal fibrosis, low proliferative activity of the villous trophoblast and a significant narrowing of the intervillous space. A genetic study was carried out on the material of paraffin blocks from two parts of the placental disc containing the tissue of the villous chorion, and the blood of the parents. Comparative analysis of DNA isolated from the paraffin block of PHM with the DNA of the parents revealed the presence of diandric dispermic triploidy. No chromosomal pathology was found in the placenta of a living girl. For hydatidiform mole in the case of multiple pregnancy, an increase in the volume of the affected placenta is characteristic compared to the normal placenta of the twin. In our observation, the presence in the placenta with PHM signs characteristic of placentas with antenatal fetal death, stromal fibrosis of the villi and low proliferative activity of the trophoblast suggests a regression of PHM.

Inactivation of Epigenetic Regulators due to Mutations in Solid Tumors.

Main factors involved in carcinogenesis are associated with somatic mutations in oncogenes and tumor suppressor genes representing changes in the DNA nucleotide sequence. Epigenetic changes, such as aberrant DNA methylation, modifications of histone proteins, and chromatin remodeling, are equally important in the development of human neoplasms. From this perspective, mutations in the genes encoding key participants of epigenetic regulation are of particular interest including enzymes that methylate/demethylate DNA, enzymes that covalently attach or remove regulatory signals from histones, components of nucleosome remodeling multiprotein complexes, auxiliary proteins and cofactors of the above-mentioned molecules. This review describes both germline and somatic mutations in the key epigenetic regulators with emphasis on the latter ones in the solid human tumors, as well as considers functional consequences of these mutations on the cellular level. In addition, clinical associations of the somatic mutations in epigenetic regulators are presented, as well as DNA diagnostics of hereditary cancer syndromes due to germline mutations in the SMARC proteins and chemotherapy drugs directly affecting the altered epigenetic mechanisms for treatment of patients with solid neoplasms. The review is intended for a wide range of molecular biologists, geneticists, oncologists, and associated specialists.

[Long Noncoding RNAs and Their Role in Oncogenesis].

The noncoding part of the human genome, which was previously considered nonfunctional or junk DNA, has been the subject of extensive research this decade. Nevertheless, long noncoding RNAs still represent one of the least investigated fields because of their complexity, multiplicity, and diversity. While some long noncoding RNAs have been characterized fairly well, the functions of many others remain poorly understood. Long noncoding RNAs play an essential role in the regulation of gene expression in all tissues and on all developmental stages. They are involved in a number of signaling pathways, and their aberrant functioning can be pathogenic. This review aims to summarize current state-of-the-art structures of these transcripts in this research field, their genomic localization, their functions, and underlying mechanisms. It also focuses on cancer-associated aberrations of long noncoding RNAs, as well as on prospects of their application in tumor diagnostics and therapy. Examples of decreasing the levels of oncogenic long noncoding RNAs via silencing with short interfering RNAs, antisense oligonucleotides, or low molecular-weight inhibitors are also described.

[Neuron specific enolase as a measure of the efficacy of mexidol in patients with neurologic complications of primary hypothyroidism]. / Neironspetsificheskaya enolaza v otsenke effektivnosti terapii meksidolom patsientov s nevrologicheskimi oslozhneniyami pervichnogo gipotireoza.

AIM: To evaluate the activity of neuron specific enolase (NSE) in patients with primary hypothyroidism (PGT) treated with mexidol. MATERIAL AND METHODS: Patients with PGT (n=110) were examined before and after treatment. Neuropsychological and neurological status of the patients was studied. To assess the status of the peripheral nervous system, electroneuromyography was performed and serum NSE level was determined. RESULTS AND CONCLUSION: The NSE activity depended on gender, age of the patient, duration of endocrinopathy and presence/absence of neurological symptoms. The clear positive dynamics of the majority of the parameters studied was noted during mexidol treatment. The efficacy of antioxidant therapy in these patients was confirmed.

[DNA methylation in the promoter regions of the laminin family genes in normal and breast carcinoma tissues].

Extracellular glycoproteins of the laminin family are essential components of basement membranes involved in a number of biological processes, including tissue differentiation, wound healing, and tumorigenesis. We present the first comprehensive study of promoter methylation status of the genes encoding laminin chains in normal tissues (peripheral blood leucocytes, buccal epithelial cells, autopsy breast tissue samples) and in breast carcinoma samples. Based on the results of this study, we divide laminin genes into three categories. Genes, constitutively methylated in breast tissues include LAMA3A, LAMB2, LAMB3, and LAMC2. Genes prone to abnormal methylation in breast carcinoma include LAMA1, LAMA2, LAMA3B, LAMA4, LAMB1, and LAMC3. Genes that are rarely if ever methylated in breast carcinoma include LAMA5 and LAMC1. The constitutively methylated group includes all of the genes that encode subunits of laminin-5 (the historical name of laminin 332), the promoters of which were previously considered unmethylated in normal tissues and prone to abnormal methylation in breast cancer.

[Reduced representation bisulfite sequencing design for assessing the methylation of human CpG islands in large samples].

The reduced representation bisulfite sequencing (RRBS) method has been developed for the high-throughput analysis of DNA methylation based on the sequencing of genomic libraries treated with sodium bisulfite by next-generation approaches. In contrast to whole-genome sequencing, the RRBS approach elaborates specific endonucleases to prepare libraries in order to produce pools of CpG-rich DNA fragments. The original RRBS technology based on the use of the MspI libraries allows one to increase the relative number of CpG islands in the pools of genomic fragments compared to whole-genome bisulfite sequencing. Nevertheless, this technology is rarely used due to the high cost compared with bisulfite methylation analysis with hybridization microarrays and significant residual amount of data represented by the sequences of genomic repeats that complicates the alignment and is not of particular interest for developing DNA methylation markers, which is often the main goal of biomedical research. We have developed an algorithm for estimating the likelihood that recognition sites of restriction endonucleases will be represented in CpG islands and present a method of reducing the effective size of the RRBS library without a significant loss of the CpG islands based on the use of the XmaI endonuclease for library preparation. In silico analysis demonstrates that the optimum range of the XmaI-RRBS fragment lengths is 110-200 base pairs. The sequencing of this library allows one to assess the methylation status of over 125000 CpG dinucleotides, of which over 90000 belong to CpG islands.

[Alexithymia in patients with left-hemispheric cerebral infarction in the late recovery period]. / Aleksitimiya u bol'nykh s infarktom golovnogo mozga levopolusharnoi lokalizatsii v pozdnem vosstanovitel'nom periode.

AIM: To study emotional status, including alexithymia, anxiety and depression, in patients with cerebral infarction in the area of the middle cerebral artery (on the left side) in the late recovery period and to develop a method for correction of the damage. MATERIAL AND METHODS: The study included 30 patients with cerebral infarction in the area of the middle cerebral artery (on the left side). A comparison group consisted of 10 patients with chronic brain ischemia. RESULTS AND CONCLUSION: The results have demonstrated the correlation between the level of alexithymia and the severity of neurological deficit, sex-related level of anxiety and depression. The cerebral infarction impacts on the level of alexithymia. Alexithymia in patients with cerebral infarction affects the adequate self-esteem of physical and mental condition that may complicate the rehabilitation of these patients and demands correction as a combination of pharmacotherapy and psychotherapeutic intervention.

[The possibility of treatment of cognitive impairment in the complex therapy of patients with the consequences of cerebral infarction].

AIM: To study neuropsychological status of inpatients with the consequences of cerebral infarction treated with cortexin and mexidol. MATERIAL AND METHODS: We carried out a neurological and neuropsychological examination of 62 patients with the consequences of cerebral infarction treated with cortexin in the dose of 10 mg and mexidol in the dose of 5 mL of 5% solution intravenously during 15 days. RESULTS AND CONCLUSION: It has been shown that the use of this drug combination decreasescomplaints and neurological symptoms and significantly improves cognitive and emotional status as well. The more positive changes are related to attention, speed of mental reactions, anxiety and verbal activity. The complex therapy with cortexin and mexidoldecreased neurological deficit and improve cognitive functioning and psychoemotional status thus increasing quality of life and rehabilitation potential of the patients.

[Efficiency of mexidol in patients with endocrine polyneuropathy].

OBJECTIVE: To evaluate the efficacy of mexidol and necessity of using it in patients with endocrine polyneuropathies caused by primary hypothyroidism (PPHT). MATERIALS AND METHODS; We have examined 51 patients with confirmed diagnosis of PPHT and assessed their neurological status and indicators of metabolic homeostasis before and after treatment. Electroneuromyography (ENMG) was performed to assess the status of the peripheral nervous system. RESULTS: The results indicate the presence of endocrine disorders of obligate metabolic homeostasis in patients with polyneuropathies. Antioxidants, in particular, mexidol, in a complex with other drugs can be used in the treatment of these disorders. Worsening of ENMG-parameters, demonstrating a trend towards the normalization in response to treatment antioxidants, are characteristics of this pathology. CONCLUSION: The efficacy of mexidol in patients with PPHT has been confirmed.

[Polymorphism among RFL-PPR homologs in sunflower (Helianthus annuus L.) lines with varying ability for the suppression of the cytoplasmic male sterility phenotype].

A complex comparative genetic approach was used for the investigation of the structural and functional diversity of genes for the restoration of sunflower pollen fertility. It includes (i) hybridological analysis; (ii) analysis of polymorphism among EST fragments.homologous to the known Rf genes that contain repeated motives of 35 amino acids (RFL-PPR); (iii) the development of molecular markers. Monogenic segregation in three interline cross combinations and the results of molecular marker analysis confirmed the allelic differences of parental lines in the Mendelian locus for CMS PET1 pollen fertility restoration. Introns were found in two RFL-PPR fragments. Two allelic variants of the QHL12D20 fragment were detected among the sixty lines of the sunflower genetic collection. An intron of QHL12D20 fragment was homologous to an intron of the AHBP-1B gene; the product of this gene-has a similarity with the transcription factor of the bZIP-family of Arabidopsis. A relationship between the QHL12D20 polymorphism and the functional state of the Rfl locus was revealed.

[Structural and functional analysis of tumor genomes and the development of test systems for early diagnosis, prognosis and cancer therapy optimization].

The article discusses results of the structural and functional analysis of molecular genetic abnormalities in various malignant tumors. Investigations have discovered more than 20 new markers for sporadic breast cancer. Several of them formed the test system, allowing the diagnosis with a specificity of 100%. Appearance of TMPRSS2/ERG4 chimeric gene is a frequent tumor-specific event, its expression is correlated with more aggressive forms of prostate cancer, may serve as a molecular marker for tumor cells and androgen assessment of tumor response to hormonal therapy. The effective systems for the early diagnosis of cervix and endometrium cancer were developed as well. Mutations in the VHL, deletions of chromosome 3 and methylation of several genes can predict the course and selection of effective therapy of clear cell kidney cancer, a number of molecular markers were identified for early diagnosis and prognosis of recurrence of bladder cancer. For diagnosis, prognosis and treatment of brain tumors we developed an effective complex system of markers. Protocol of molecular genetics investigation reveals the cause of the disease by more than 90% of patients with retinoblastoma. In order to study abnormal methylation in tumor genomes an innovative technology AFLOAT has been developed that allows to efficiently identify new markers with diagnostic value. Test systems of molecular genetic and epigenetic markers for early diagnosis and prognosis as well as for cancer therapy optimization have shown to be effective, have been approved for use in clinical practice and are being introduced into practical healthcare.

[Amplification of intermethylated sites experimental design and results analysis with aims in silico computer software].

Amplification of intermethylated sites (AIMS) is a powerful tool for differential methylation screening of genomes. Its applications have nevertheless been limited until recently for the absence of systemic approach to AIMS experimental design and of appropriate computer software for the analysis of AIMS results. We have developed AIMS in silico computer suggestion tool capable of predicting possible experimental outcomes, which assists in designing AIMS experiments depending on the research aims and available instrumentation, and in analyzing experimental results from the point of view of genomic locations of the DNA fragments under study. With AIMS in silico we have characterized qualitatively and quantitatively AIMS products obtainable under different conditions; to ease experimental design we demonstrate AIMS products hierarchical structure. We discuss examples of designing AIMS experiments and results analysis as well as possible relative to AIMS alternative approaches to differential methylation screening. AIMS in silico computer software is intended to standardize AIMS applications and to turn it into one of the principal approaches towards cancer epigenomes studies as well as towards diagnostics in oncology, including early screening.

[The enhancement of prevention and treatment of the patients with the stroke in Saint-Petersburg].

The clinical epidemiological and medical organizational characteristics of strokes in 621 patients resident of Puschkinsky district of the City of Saint-Petersburg is presented. In the district, the corresponding morbidity and mortality rate is higher as compared with similar indicators in the Russian Federation and the international community. The comprehensive program of target actions on the prevention and treatment of the patients with the stroke is proposed both during acute and rehabilitation period.

[Novel methylation and expression markers associated with breast cancer].

We have developed a modification of methylation sensitive arbitrarily primed PCR, one of the methods of differentially methylated CpG islands in cancer cells genomes screening. Seven genes undergoing abnormal epigenetic regulation in breast cancer, SEMA6B, BIN1, VCPIP1, LAMC3, KCNH2, CACNG4 and PSMF1, have been identified by this method. Methylation and loss of expression frequencies were evaluated for each of the identified genes on 100 paired (cancer/morphologically intact control) breast tissue samples. Significant frequencies of abnormal methylation were detected for SEMA6B, BIN1, and LAMC3 (38%, 18%, and 8% correspondingly). Methylation of the above genes was not characteristic for morphologically intact breast tissues. Downregulation of SEMA6B, BIN1, VCPIP1, LAMC3, KCNH2, CACNG4 and PSMF1 in breast cancer was as frequent as 44-94% by real-time PCR expression assay. The most pronounced functional alterations were demonstrated for SEMA6B and LAMC3 genes, which allows recommending their inclusion into the panels of carcinogenesis diagnostic panels. Fine methylation mapping was performed for the genes most frequently methylated in breast cancer (SEMA6B, BIN1, LAMC3), providing a fundamental basis for the development of effective methylation tests for these genes.

TNR/11q#1 trinucleotide (GCC)n repeat alleles and predisposition to acute and chronic leukemia.

TNR/11q#1 is a polymorphic trinucleotide (GCC)n repeat located within the minimal region of the 11q deletion in chronic lymphocytic leukemia (CLL). It was recently shown that certain alleles of this repeat are associated with a worse prognosis in CLL patients. To investigate the role of TNR/11q#1 variants as risk-modifying factors in leukemogenesis, we conducted a case-control study on 113 acute lymphotic leukemia (ALL) patients, 82 CLL patients and 146 healthy controls of Russian origin. Comparison of allele and genotype distributions in the control, ALL and CLL groups, performed by Fisher's exact test with two-sized P-value, showed significant decrease in the presence of the GCC(6) allele in the ALL and CLL groups compared to controls. Moreover, 'rare' alleles GCC(7-8) and GCC(13-14) were significantly overrepresented in the ALL group versus controls. We found that CLL risk genotypes were those with both alleles containing more than 6 GCC repeats (P = 0,0212, odds ratio = 1,68 (95% CI, 1,121...2,531)). ALL risk genotypes include three allele combination variants: 1) both alleles containing more than 6 GCC repeats (P = 0,0019, odds ratio = 1,756 (95% CI 1,223...2,502)); 2) one of the alleles containing 7 or 8 repeats (P = 0,0155, odds ratio = 18,22 (95% CI 1,93...136.37)); 3) one of the alleles containing more than 12 repeats (P = 0,0209, Odds ratio = 2,599 (95% CI 1,161...5,815)). Association of certain alleles and genotypes of the TNR/11q#1 repeat with both acute and chronic lymphocytic leukemia suggests the presence of a cancer related gene, involved in a wide spectrum of neoplasia, in the vicinity of this repeat.