[Identification of Functionally Significant Polymorphic Variants in miRNA Genes in Carotid Atherosclerosis].

miRNAs are vital molecules of gene expression. They are involved in the pathogenesis of various common diseases, including atherosclerosis, its risk factors, and its complications. A detailed characterization of the spectrum of functionally significant polymorphisms of miRNA genes in patients with advanced carotid atherosclerosis is an important research task. We analyzed miRNA expression and exome sequencing data of carotid atherosclerotic plaques of male patients (n = 8, 66-71 years of age, 67-90% degree of carotid artery stenosis). For further study and analysis of the association between the rs2910164 polymorphism of the MIR146A gene and advanced carotid atherosclerosis, we recruited 112 patients and 72 relatively healthy Slavic residents of Western Siberia. A total of 321 and 97 single nucleotide variants (SNVs) were detected in the nucleotide sequences of pre- and mature miRNAs in carotid atherosclerotic plaques. These variants were located in 206 and 76 miRNA genes, respectively. Integration of the data of exome sequencing and miRNA expression revealed 24 SNVs of 18 miRNA genes that were processed to mature form in carotid atherosclerotic plaques. SNVs with the greatest potential functional significance for miRNA expression predicted in silico were rs2910164:C>G (MIR146A), rs2682818:A>C (MIR618), rs3746444:A>G (MIR499A), rs776722712:C>T (MIR186), rs199822597:G>A (MIR363). The expression of miR-618 was lower in carotid atherosclerotic plaques of patients with the AC rs2682818 genotype of the MIR618 gene compared with the CC genotype (log2FC = 4.8; p = 0.012). We also found an association of rs2910164:C (MIR146A) with the risk of advanced carotid atherosclerosis (OR = 2.35; 95% CI: 1.43-3.85; p = 0.001). Integrative analysis of polymorphisms in miRNA genes and miRNA expression is informative for identifying functionally significant polymorphisms in miRNA genes. The rs2682818:A>C (MIR618) is a candidate for regulating miRNA expression in carotid atherosclerotic plaques. The rs2910164:C (MIR146A) is associated with the risk of advanced carotid atherosclerosis.

Changes in DNA methylation profile in liver tissue during progression of HCV-induced fibrosis to hepatocellular carcinoma.

In this study we compared methylation levels of 27,578 CpG sites between paired samples of the tumor and surrounding liver tissues with various degrees of damage (fibrosis, cirrhosis) in HCV-induced hepatocellular carcinoma (HCC) patients, as well as between tumor and normal tissue in non-viral HCC patients, using GSE73003 and GSE37988 data from GEODataSets (https://www.ncbi.nlm.nih.gov/). A significantly lower number of differentially methylated sites (DMS) were found between HCC of non-viral etiology and normal liver tissue, as well as between HCC and fibrosis (32 and 40), than between HCC and cirrhosis (2450 and 2304, respectively, according to GSE73003 and GSE37988 datasets). As the pathological changes in the tissue surrounding the tumor progress, the ratio of hyper-/hypomethylated DMSs in the tumor decreases. Thus, in tumor tissues compared with normal/fibrosis/cirrhosis of the liver, 75/62.5/47.7 % (GSE73003) and 16 % (GSE37988) of CpG sites are hypermethylated, respectively. Persistent hypermethylation of the ZNF154 and ZNF540 genes, as well as CCL20 hypomethylation, were registered in tumor tissue in relation to both liver fibrosis and liver cirrhosis. Protein products of the EDG4, CCL20, GPR109A, and GRM8 genes, whose CpG sites are characterized by changes in DNA methylation level in tumor tissue in the setting of cirrhosis and fibrosis, belong to "Signaling by G-protein-coupled receptors (GPCRs)" category. However, changes in the methylation level of the "driver" genes for oncopathology (АРС, CDKN2B, GSTP1, ELF4, TERT, WT1) are registered in tumor tissue in the setting of liver cirrhosis but not fibrosis. Among the genes hypermethylated in tumor tissue in the setting of liver cirrhosis, the most represented biological pathways are developmental processes, cell-cell signaling, transcription regulation, Wnt-protein binding. Genes hypomethylated in liver tumor tissue in the setting of liver cirrhosis are related to olfactory signal transduction, neuroactive ligand-receptor interaction, keratinization, immune response, inhibition of serine proteases, and zinc metabolism. The genes hypermethylated in the tumor are located at the 7p15.2 locus in the HOXA cluster region, and the hypomethylated CpG sites occupy extended regions of the genome in the gene clusters of olfactory receptors (11p15.4), keratin and keratin-associated proteins (12q13.13, 17q21.2, and 21q22.11), epidermal differentiation complex (1q21.3), and immune system function loci 9p21.3 (IFNA, IFNB1, IFNW1 cluster) and 19q13.41-19q13.42 (KLK, SIGLEC, LILR, KIR clusters). Among the genes of fibrogenesis or DNA repair, cg14143055 (ADAMDEC1) is located in the binding region of the HOX gene family transcription factors (TFs), while cg05921699 (CD79A), cg06196379 (TREM1) and cg10990993 (MLH1) are located in the binding region of the ZNF protein family transcription factor (TF). Thus, the DNA methylation profile in the liver in HCV-induced HCC is unique and differs depending on the degree of surrounding tissue lesion - liver fibrosis or liver cirrhosis.

[miRNA Regulome in Different Atherosclerosis Phenotypes].

Dysregulation of microRNA (miRNA) expression is associated with a susceptibility to many diseases, including atherosclerotic lesions of the coronary and carotid arteries and the development of clinical complications such as coronary heart disease, myocardial infarction, chronic cerebral ischemia, ischemic stroke. Recently, more and more studies analyze the miRNA regulome including a network of regulatory elements for the expression of miRNAs themselves and targets under their control. The review summarizes the data from articles concerned miRNA expression and changes in DNA methylation in the miRNA genes in human atherosclerotic arteries, as well as with the analysis of the association between single nucleotide polymorphisms and copy number variations in the miRNA genes with clinical complications of atherosclerosis.

[Comparative analysis of gene expression in vascular cells of patients with advanced atherosclerosis]. / Sravnitel'nyi analiz ékspressii genov v kletkakh sosudov u bol'nykh s klinicheski vyrazhennym aterosklerozom.

In this study we performed a comparative gene expression analysis of carotid arteries in the area of atherosclerotic plaques and healthy internal mammary arteries of patients with advanced atherosclerosis by using microarray HumanHT-12 BeadChip ("Illumina"). The most down-regulated genes were APOD, FABP4, CIDEC and FOSB, and up-regulated gene was SPP1 (|FC|>64; pFDR<0.05). The majority of differentially expressed genes were down-regulated in advanced atherosclerotic plaques. Unexpectedly, genes involved in immune and inflammatory responses were down-regulated in advanced atherosclerotic plaques to compare with the healthy arteries (arachidonic acid metabolism, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, Jak-STAT signaling pathway, TNF signaling pathway). "Cellular response to metal ion" (metallothioneins) and "Extracellular matrix organization" were the most significant Gene ontology terms among the down- and up-regulated genes, respectively.

Role of microRNA in Development of Instability of Atherosclerotic Plaques.

MicroRNAs are small noncoding single-stranded RNAs that regulate gene expression. Today, we see an increasing number of studies highlighting the important role of microRNAs in the development and progression of cardiovascular diseases caused by atherosclerotic lesions of arteries. We review the available scientific data on association of the expression of these biomolecules with instability of atherosclerotic plaques in animal models and humans. We made special emphasis on miR-21, -100, -127, -133, -143/145, -221/222, and -494 because they were analyzed in more than one study. We discuss the possibility of microRNAs using in the diagnosis and therapy of atherosclerosis and its complications.

Variability of Methylation Profiles of CpG Sites in microrNA Genes in Leukocytes and Vascular Tissues of Patients with Atherosclerosis.

In this study, we for the first time described the variability of methylation levels of 71 CpG sites in microRNA genes in leukocytes and blood vessels (coronary artery atherosclerotic plaques, intact internal thoracic arteries, and great saphenous veins) in patients with atherosclerosis using the Infinium HumanMethylation27 BeadChip microarray. Most of the analyzed CpG sites were characterized by the low variability, and most of these low-variable sites were hypomethylated in all tissue samples. CpG sites in coronary artery atherosclerotic plaques and leukocytes were similar in their methylation status. The highest variability of CpG methylation levels between different tissues was found for the CpG sites of the MIR10B gene; the methylation levels of these sites in leukocytes and atherosclerotic arteries were lower than in intact blood vessels. We also found that several cardiovascular disease risk factors, as well as medications, might affect methylation levels of CpG sites in microRNAs.

[Clinical and economic analysis of the feasibility of using Dicarbamine for the prevention of the toxic effects of antineoplastic chemotherapy].

The aim of the study was to conduct clinical and economic analysis of the feasibility of using Dicarbamine for the prevention of toxic effects of chemotherapy. There were compared the direct medical costs on prevention and treatment of febrile neutropenia in 2 groups of breast cancer patients: chemotherapy alone in TAC mode or chemotherapy in the same way against oral Dicarbamine. Total costs due to hematologic toxicity were 1003945 rubles in the control group (22817 rubles on average by 1 patient) and 658980 rubles in the group treated with Dicarbamine (14 644 rubles on average by 1 patient). Also, the study found that in the group treated by Dicarbamine there were lower rates of dose reduction and delay of the next course of chemotherapy, which might have an impact on other costs arising from cancer. The results of this study demonstrate the clinical and economic feasibility of using Dicarbamine for the prevention of hematotoxic complications of chemotherapy.

[Support of hematological homeostasis during chemotherapy with taxanes].

Study group consisted of 84 oncological patients with various tumor localization that received chemotherapy with taxanes. Medium follow up was 32.1 +/- 2.1 months. All patients had morphologic verification of the process. Distribution according to tumor localization was as follows: breast cancer--60 (71.4%), ovarian cancer--13 (15.5%), lung cancer--7 (8.3%), other localizations--4 (4.8%). Age varied from 22 to 73 years old. All patients had normal hematological status and survival expectation more than 3 months. Hematological complications were mentioned after the first cycle of chemotherapy in 70% cases.

[Cardiotoxicity in performing chemotherapy of breast cancer by the data of retrospective multicenter "case-control" investigation].

The authors describe results of 5 year observations of the state of the cardiovascular system in 1643 women who underwent nonajuvant and adjuvant polychemotherapy of breast cancer within the framework of retrospective multicenter case-control investigation. The total frequency of registration of acute cardiotoxicity was 39.3% at standard visits, and 75.2% at unplanned visits. The frequency of late toxicity was 34.5% according to clinical-echocardiography findings, and 100% according to the data of echocardiography of patients with risk factors and markers of cardiotoxicity. The necessity of joint management of such patients by oncologists and cardiologists is stressed.

[Assessment of gastrointestinal toxicity at patients with breast cancer receiving Taksans chemotherapy and doxorubicin].

UNLABELLED: The aim--assessment of gastrointestinal toxicity frequency of damaged mucosa of the colon. Type of study. A retrospective multicenter case-control study on the model of neoadjuvant and adjuvant chemotherapy for breast cancer. MATERIALS AND METHODS: Over the period 1993-2003 gg. were surveyed 1643 women (average age 52.3 +/- 2.8 years). RESULTS: It was revealed that the frequency of acute inflammatory and destructive changes in the mucous membrane of the colon in the course of chemotherapy was 13.6%. Frequency of sharp changes in the mucosa of the colon recording was increased almost in 10 times the rate of neoadjuvant to adjuvant that may be related to the cumulative effect of cytostatics. Revealed a higher incidence of toxicity in patients with a history of functional pathology of the intestine, which reached 22.7%. In these patients, the trigger mechanism of toxicity was the beginning of chemotherapy, and no increase in cumulative dose. All patients with inflammatory bowel disease had reported clinical signs of relapse during treatment. Noted a direct correlation between the severity of diarrhea and the severity of rectal (colitis). CONCLUSION: Damage to mucous membrane of the colon occurs often, growing over time (from course to course), to a greater extent in patients with diarrheal syndrome.

[Infantile spasms in children under 1-year-old]. / Infantil'nye spazmy u detei pervogo goda zhizni.

In the period of 1977 to 1982, 72 children suffering from infantile spasms and aged 10 days to 12 months were observed. Studies of the neurologic status over time were supplemented with echoencephalography, diaphanoscopy, cranial roentgenography and ophthalmoscopic examination. Furthermore, 58 children were subjected to electro-encephalographic investigations. The clinical findings and data provided by additional methods were evaluated over time, i.e., prior to, during and after the course of treatment. An analysis is presented of the results of corticosteroid therapy of two groups of patients: 1) "idiopathic"-where the medical history showed no previous nervous system impairments prior to the development of the spasms; 2) patients with a history of various damaging factors (pregnancy pathology in the mother, new-born asphyxia, intracranial birth injury, intrauterine infection, neuroinfection in the early postnatal period, etc.). The clinical picture of infantile spasms is extensively described. Before the initiation of hormonal therapy, the patients received anticonvulsive drugs for 1-10 months. The use of ACTH, synacthen and hydrocortisone proved to be fairly effective provided the treatment is instituted early. Possible mechanisms of the action of hormonal drugs are analyzed.