The Role of Long Non-Coding RNA CCAT1 and SNHG14 in Activation of Some Protein-Coding Genes Associated with the Development of Ovarian Cancer.

Late diagnosis of ovarian cancer is one of the most important problems in its treatment. Long non-coding RNA (lncRNA) are a poorly studied, but promising type of diagnostic biomarkers. We studied the lncRNA interactome to identify biomarkers with potential significance for molecular diagnostics of ovarian cancer. By screening the TCGA database, we identified differentially expressed lncRNA CCAT1 and SNHG14. Based on the indices of complementarity of CCAT1 and SNHG14 to the mRNA sequences, we selected 5 protein-coding genes MAPK1, c-MET, TGFB2, SNAIL1, and WNT4 associated with the epithelial-mesenchymal transition. Real-time PCR on 54 ovarian cancer samples confirmed the high expression levels of CCAT1 and SNHG14 (logFC>1.5, p<0.05). A positive correlation between the expression levels of two lncRNA and mRNA of 5 genes in 6 pairs was established. The activating effect of CCAT1 and SNHG14 on the expression of these genes can be mediated by miR-203 and miR-124.

[Identification of Novel Differentially Expressing Long Non- Coding RNAs with Oncogenic Potential].

Recently, a wealth of data have been accumulating on the role of long non-coding RNAs (lncRNAs) in the fine-tuning of mRNA expression. Four new lncRNAs, namely, TMEM92-AS1, FAM222A-AS, TXLNB, and lnc-CCL28, were identified as differentially expressed in ovarian tumors using deep machine learning. The levels of lnc-CCL28 transcripts in both tumors and normal tissue samples were sufficient for further analysis by RT-PCR. In addition, the promising ovarian cancer biomarkers, lncRNAs LINC00152, NEAT 1 and SNHG17 were added to RT-PCR analysis. For the first time, an increase in the level of lnc-CCL28 and SNHG 17 lncRNAs was found in ovarian tumors, and the overexpression of LINC00152 and NEAT1 was confirmed. It seems that lnc-CCL28 is involved in carcinogenesis and, in particular, in ovarian cancer progression. Overexpression of LINC00152 and lnc-CCL28 was significantly associated with the later stages and metastasis.

Hypermethylation of Genes in New Long Noncoding RNA in Ovarian Tumors and Metastases: A Dual Effect.

The role of methylation in the regulation of genes of long noncoding RNA (lncRNA) is still poorly understood. We revealed new hypermethylated lncRNA genes in ovarian tumors and their effect on metastasis of ovarian cancer. A multiple and significant (p<0.001) increase in methylation of a group of lncRNA genes (MEG3, SEMA3B-AS1, ZNF667-AS1, and TINCR) was shown by quantitative methylation-specific PCR using the non-parametric Mann-Whitney test. Moreover, methylation of SEMA3B-AS1, ZNF667-AS1, and TINCR genes in ovarian cancer tumors was detected for the first time. Comparative analysis of 19 samples of peritoneal metastases and paired primary tumors showed a significant decrease in the methylation level of the same 4 genes: MEG3 (p=0.004), SEMA3B-AS1 (p=0.002), TINCR (p=0.002), and ZNF667-AS1 (p<0.001). Reduced methylation of suppressor lncRNA genes in peritoneal metastases is probably associated with the involvement of these lncRNA in the regulation of plastic reversion of the epithelial-mesenchymal transition to the mesenchymal-epithelial transition. Thus, the effect of lncRNA and their methylation on the development of tumors and metastases of ovarian cancer was demonstrated, which is important for understanding of the pathogenesis and mechanisms of metastasis of ovarian cancer. New properties of lncRNA can find application in the development of new approaches in the therapy of ovarian cancer.

[Long Non-Coding RNAs as Competitive Endogenous RNAs in Osteosarcoma].

It was more than twenty years ago that miRNAs were recognized as a new class of RNA, but the understanding of their regulatory role is just beginning to emerge. Furthermore, it was found that the function of miRNAs as "master regulators" can be controlled by other non-coding RNAs (ncRNAs), in particular, long ncRNAs (lncRNAs). The regulatory functions of lncRNAs have been indicated in tumors in various locations and, in particular, in osteosarcoma, the most common and most aggressive malignant bone disease in children during puberty. This review discusses studies about the role of lncRNAs in the regulation of gene expression by the competitive endogenous RNAs (ceRNAs) mechanism. Data from these publications confirm the involvement of lncRNAs in the major signaling pathways, such as Notch, PI3K/AKT, Wnt/ß-catenin, JNK, and HIV/VEGF. For example, seven members of the SNHG family (small nucleolar RNA host gene) were shown to participate in the Notch and PI3K/AKT signaling pathways; moreover, several lncRNA/miRNA/mRNA regulatory axes were identified for nearly all members of this family. The functions of other multifunctional oncogenic lncRNAs are also discussed; in particular, six to ten such axes have been determined for TUG1, MALAT1, and XIST. Using the Gene Cards, KEGG, and Panther databases, the key signaling pathways were identified for the targets of these three multifunctional lncRNAs. Investigation of lncRNA function contributes to the development of new diagnostic and prognostic markers for the treatment of patients with osteosarcoma. According to the available data, interactions between ceRNAs, that is, miRNAs, mRNAs, and lncRNAs, represent a new form of gene expression regulation that is involved in various pathophysiological processes, including bone oncogenesis.

System of Markers Based on the Methylation of a Group of Proapoptotic Genes in Combination with MicroRNA in the Diagnosis of Breast Cancer.

Systems of markers for the diagnosis of breast cancer based on DNA methylation of a group of suppressor protein-coding genes, hypermethylated microRNA genes, and their combinations were compiled. On a representative sample of 70 paired breast cancer specimens (tumor/normal), MS-PCR analysis revealed a significant increase in the methylation frequency of 5 protein-coding genes: RASSF1A suppressor and apoptosis genes APAF1, BAX, BIM/BCL2L11, and DAPK1 (34-61% vs. 4-24%) and 6 microRNA genes: MIRG124G1, MIRG125bG1, MIRG129G2, MIRG148a, MIRG34b/c, and MIRG9G3 (36-76% vs. 6-27%). ROC-analysis showed that a combination of 4 genes (APAF1, BAX, BIM/BCL2L11, and DAPK1) and MIRG125bG1 gene constitute a highly efficient 5-marker system with 100% specificity and sensitivity of 94-96% at AUC=0.98-0.97, suitable also for patients with stage I and II breast cancer. Detection of methylation of at least one gene in this system in biopsy or postoperative material is sufficient to refer the sample to breast cancer.

Marker Systems Based on MicroRNA Gene Methylation for the Diagnosis of Stage I-II Breast Cancer.

Groups of microRNA genes, methylation of which is associated with the initial (I-II) stages of breast cancer, are determined, and new markers and marker systems for the disease diagnosis were created on the basis of these data. A total of 14 genes in which methylation was associated with breast cancer were identified with the use of methyl-specific PCR on a representative sample of 70 tumor specimens. Analysis of 46 specimens from patients with clinical stages I and II detected 9 genes (MIR-124-1, MIR-124-3, MIR-125b-1, MIR-129-2, MIR-132, MIR-148a, MIR-193a, MIR-34b/c, and MIR-9-3), in which methylation was associated with the initial stages of the disease. Using ROC analysis, we formed two systems including 6 markers each and detecting breast cancer at stages I-II with high sensitivity (89 and 91%) and specificity (88%) at AUC=0.92-0.93. These sets were validated on the total sample of 70 specimens including all disease stages; they showed 93 and 94% sensitivities, 88% specificity, and AUC=0.95. Highly sensitive systems of markers, based on microRNA gene methylation, were created for the diagnosis of breast cancer at stages I-II.

Hypermethylated Genes of MicroRNA in Ovarian Carcinoma: Metastasis Prediction Marker Systems.

We identified a group of miRNA genes whose methylation is associated with ovarian cancer metastasis. Based on these data, new markers and the systems of markers predicting tumor dissemination were selected. Using methylation-specific PCR and a representative set of 54 ovarian cancer samples, we identified 10 microRNA genes (MIR-124a-2, MIR-127, MIR-125b-1, MIR-129-2, MIR-137, MIR-193a, MIR-203a, MIR-34b/c, MIR-130b, and MIR-1258) whose methylation is associated with tumor metastasis. The greatest association was established for 4 genes: MIR-137, MIR-193a, MIR-34b/c, and MIR-130b (p<0.01). ROC analysis revealed 3 most optimal marker systems including 4-5 miRNA genes and characterized by high sensitivity (82-94%) and specificity (76-86%) at AUC=0.89-0.92. Methylation of any three genes from these systems is sufficient to predict metastasis with the specified accuracy. Detection of the group of hypermethylated miRNA genes with predictive value for ovarian cancer metastasis is of great importance for personalized treatment of the patients.

Molecular Mechanisms of Ovarian Carcinoma Metastasis: Key Genes and Regulatory MicroRNAs.

Metastasis of primary tumors progresses stepwise - from change in biochemistry, morphology, and migratory patterns of tumor cells to the emergence of receptors on their surface that facilitate directional migration to target organs followed by the formation of a specific microenvironment in a target organ that helps attachment and survival of metastatic cells. A set of specific genes and signaling pathways mediate this process under control of microRNA. The molecular mechanisms underlying biological processes associated with tumor metastasis are reviewed in this publication using ovarian cancer, which exhibits high metastatic potential, as an example. Information and data on the genes and regulatory microRNAs involved in the formation of cancer stem cells, epithelial-mesenchymal transition, reducing focal adhesion, degradation of extracellular matrix, increasing migration activity of cancer cells, formation of spheroids, apoptosis, autophagy, angiogenesis, formation of metastases, and development of ascites are presented. Clusters of microRNAs (miR-145, miR-31, miR-506, miR-101) most essential for metastasis of ovarian cancer including the families of microRNAs (miR-200, miR-214, miR-25) with dual role, which is different in different histological types of ovarian cancer, are discussed in detail in a section of the review.

[Methylation of the genes for the microRNAs miR-129-2 and miR-9-1, changes in their expression, and activation of their potential target genes in clear cell renal cell carcinoma].

Methylation of promoter CpG islands and microRNA (miRNA) interactions with mRNAs of target genes are epigenetic mechanisms that play a crucial role in deregulation of gene expression and signaling pathways in tumors. Altered expression of six chromosome 3p genes (RARB(2), SEMA3B, RHOA, GPX1, NKIRAS1, and CHL1) and two miRNA genes (MIR-129-2 and MIR-9-1) was observed in primary clear cell renal cell carcinomas (ccRCCs, 31-48 samples) by RT-PCR and qPCR. Significant downregulation (p < 0.05, Fisher's exact test) was observed for SEMA3B, NKIRAS1, and CHL1; and differential expression, for the other chromosome 3p and miRNA genes. Methylation-specific PCR with primers to RARB(2), SEMA3B, MIR-129-2, and MIR-9-1 showed that their methylation frequency was significantly (p < 0.05, Fisher's exact test) elevated in the ccRCC samples. Significant correlations between promoter methylation and expression were confirmed for SEMA3B and observed for the first time for RARB(2), GPX1, and MIR-129-2 in ccRCC (Spearman's correlation coefficient rs ranging 0.31-0.60, p < 0.05). The MIR-129-2 and RARB(2) methylation frequencies significantly correlated with ccRCC progression. MIR-129-2 methylation correlated with upregulation of RARB(2), RHOA, NKIRAS1, and CHL1 (rs ranging 0.35-0.53, p < 0.05). The findings implicate methylation in regulating RARB(2), SEMA3B, GPX1, and MIR-129-2 and indicate that miR-129-2 and methylation of its gene affect RARB(2), RHOA, NKIRAS1, and CHL1 expression.

Synthesis and evaluation of membrane permeabilizing properties of cationic amphiphiles derived from the disaccharide trehalose.

Cationic amphiphiles derived from trehalose have been synthesized; trehalose analogues substituted with n-pentyl or n-hexyl ethers exhibited membrane disrupting activities against clinically important Gram positive and Gram negative bacteria and fungi. Our results demonstrate that trehalose is a useful disaccharide scaffold for the development of broad-spectrum antimicrobial and antifungal agents.

Molecular Mechanisms and microRNAs in Osteosarcoma Pathogenesis.

This review summarizes data on microRNA (miRNA) genomic organization, biogenesis, and functions in carcinogenesis. The roles of key genes and regulatory miRNAs in molecular mechanisms and signaling pathways involved in the development of osteosarcoma, the most aggressive type of bone tumor striking mainly in adolescence and early adulthood, are discussed in detail. The most critical pathways in osteosarcoma pathogenesis are the Notch, Wnt, NF-κB, p53, PI3K/Akt, and MAPK pathways. The balance between cell survival and apoptosis is determined by the Wnt and NF-κB pathways, as well as by the ratio between the activities of the MAPK and PI3K/Akt pathways. Several miRNAs (miR-21, -34a, -143, -148a, -195a, -199a-3p, -382) regulate multiple target genes, pathways, and processes essential for osteosarcoma pathogenesis. Data on the key genes and regulatory miRNAs involved in metastasis and tumor cell response to drug treatment are presented. Possible applications of miRNA in osteosarcoma diagnostics and treatment are discussed.

Morphological evaluation of the effectiveness of bipolar radiofrequency ablation for thyroid nodules.

Recently, radiofrequency ablation has been increasingly used for the treatment of thyroid nodules. The widespread introduction of this method, however, hampered by the lack of data on efficacy and safety of different devices that are currently on the market, the selection of the optimal mode of procedure also remains to be elucidated. Experimental data obtained during the application of the original patented device is presented. The results make it possible to move from ex vivo experiments to clinical practice.

A meta-analysis of the prevalence of attention deficit hyperactivity disorder in incarcerated populations.

BACKGROUND: Studies report the variable prevalence of attention deficit hyperactivity disorder (ADHD) in incarcerated populations. The aim of this meta-analysis was to determine the prevalence of ADHD in these populations. METHOD: Primary research studies reporting the prevalence (lifetime/current) of ADHD in incarcerated populations were identified. The meta-analysis used a mixed log-binomial model, including fixed effects for each covariate and a random study effect, to estimate the significance of various risk factors. RESULTS: Forty-two studies were included in the analysis. ADHD prevalence was higher with screening diagnoses versus diagnostic interview (and with retrospective youth diagnoses versus current diagnoses). Using diagnostic interview data, the estimated prevalence was 25.5% and there were no significant differences for gender and age. Significant country differences were noted. CONCLUSIONS: Compared with published general population prevalence, there is a fivefold increase in prevalence of ADHD in youth prison populations (30.1%) and a 10-fold increase in adult prison populations (26.2%).

Co-morbid psychiatric disorders among incarcerated ADHD populations: a meta-analysis.

BACKGROUND: Rates of psychiatric disorders are highly prevalent among prison inmates, and recent evidence confirms over-representation of youths and adults with attention deficit hyperactivity disorder (ADHD). The risk for psychiatric co-morbidity may be greater among offenders with ADHD. We undertook a systematic review and meta-analysis of reported rates of co-existing psychiatric morbidity with ADHD in prison samples. METHOD: Studies published from 1980 to 2015 were identified using five bibliographic indexes, review articles and reference lists. Included studies had a defined ADHD group and provided additional prevalence on at least one of the following: conduct disorder, substance use disorder, mood disorder, anxiety disorder, or personality disorder. We performed meta-analytical estimates of the prevalence of each co-morbid disorder within ADHD, and estimated the risk for co-existing disorders among prisoners with ADHD by pooling odds ratios (OR) with 95% confidence intervals. RESULTS: Eighteen studies with data for 1615 with ADHD and 3128 without ADHD were included. The risk (OR) of all psychiatric morbidity is increased among adult inmates with ADHD. Associations in youths with ADHD were restricted to mood disorder (OR 1.89, 95% confidence interval 1.09-3.28). CONCLUSIONS: This study quantifies the extent of co-morbidity presented by offenders with ADHD, especially adults. The differences between risk estimates for youths and adults indicate an incremental effect in both frequency and severity for the development of further co-morbid pathology through adulthood. The findings have implications for clinical intervention and for criminal justice policy.

Methylation of miRNA genes and oncogenesis.

Interaction between microRNA (miRNA) and messenger RNA of target genes at the posttranscriptional level provides fine-tuned dynamic regulation of cell signaling pathways. Each miRNA can be involved in regulating hundreds of protein-coding genes, and, conversely, a number of different miRNAs usually target a structural gene. Epigenetic gene inactivation associated with methylation of promoter CpG-islands is common to both protein-coding genes and miRNA genes. Here, data on functions of miRNAs in development of tumor-cell phenotype are reviewed. Genomic organization of promoter CpG-islands of the miRNA genes located in inter- and intragenic areas is discussed. The literature and our own results on frequency of CpG-island methylation in miRNA genes from tumors are summarized, and data regarding a link between such modification and changed activity of miRNA genes and, consequently, protein-coding target genes are presented. Moreover, the impact of miRNA gene methylation on key oncogenetic processes as well as affected signaling pathways is discussed.

[Laparoscopic surgery in treatment for colon cancer].

There are presented results of treatment of 347 patients with colorectal cancer. Laparoscopic surgery had been planned for 92 (26.5%) patients (study group). In 79 (85.9%) patients surgery was performed completely by laparoscopy, 13 (14.1%) patients underwent conversion. In 255 (73.5%) patients surgery was carried out from an open access (control group). The authors showed the effectiveness of the use of minimally invasive techniques in treatment for colorectal cancer.

[Comparative clinical and morphological analysis of technogenic and cryptogenic papillary thyroid carcinoma in children and adolescents].

OBJECTIVE: To make a comparative retrospective clinical and morphological analysis of cases of post-Chernobyl (technogenic) and sporadic (cryptogenic) papillary thyroid carcinoma (PTC) in children and adolescents in the Republic of Belarus. MATERIAL AND METHODS: Nine hundred and thirty-six patients aged less than 19 years, operated on in 1990-2005, when cancer incidence in this age group was directly related to the consequences of the Chernobyl accident (technogenic carcinoma) were examined. A comparison group included their 140 peers who were born after March 1987 and treated in 2005-2010 for PTC (cryptogenic carcinoma). The Kruskal-Wallis test was used to compare quantitative variables; the Fisher, Pearson, and Fisher-Freeman-Halton tests were employed to compare categorical variables. All calculations were made using the R package version 2.15.0. The results were considered to be statistically significant at p<0.05. RESULTS: Comparison of cases of cryptogenic carcinoma and those of technogenic carcinomas diagnosed in 1990-1995 and 1996-2001 revealed substantial differences in the clinical and morphological patterns of the disease. In both mentioned periods, the patients with technogenic PTC were younger than those with cryptogenic PTC (p<0.0001 and p=0.0014, respectively). The proportion of male patients in the technogenic carcinoma group was much higher than that in the cryptogenic carcinoma one (p=0.0006 and p=0.0031). The patients with technogenic carcinoma were also more frequently observed to have infiltrative tumor growth (p=0.0003 and p=0.0169) and lung metastastic involvement (p=0.0001 and p=0.0008). What is more, the architectonics of technogenic versus cryptogenic carcinoma more often contained a solid component (p<0.0001 and p<0.0001), marked intratumoral fibrosis (p=0.0008 and p=0.0266), mononuclear infiltration (p<0.0001 and p<0.0001), and no baseline abnormality (p<0.0001 and p<0.0001). CONCLUSION: In spite of its age similarity, technogenic carcinoma proved to be more clinically aggressive than cryptogenic carcinoma: the extent of organ invasion and the infiltrative growth of carcinoma were more frequently observed.

[Clinical and morphological features of papillary thyroid cancer in children and adolescents in the Republic of Belarus: analysis of 936 post-Chernobyl carcinomas].

There is presented clinical and morphological characteristics of post-Chernobyl papillary thyroid cancer in 936 children and adolescents. In general, carcinoma of these patients featured by locally advanced growth - 57.4% (387 of 674 patients with this sign could be assessed), metastases in regional lymph nodes - 73,7% (N1b in 40.7%) and internal organs - 11.1%. The mean duration of follow-up was 12,4 +/- 3,5 years (range 4.3 to 19.6 years) including children 14,6 +/- 2,7 years (range 8.8 to 19.6 years) and adolescents - 10,1 +/- 3,1 years (range 4.3 to 18.8 years). Overall survival for the 20-year period was 96,6% +/- 1,2%. The causes of death were suicide (7), injuries and accidents (5), secondary malignancies (1), somatic diseases (2). Only in two patients the death was related to the main disease - lung metastases. Free-recurrence survival for the cohort of post-Chernobyl carcinomas was 92,7% +/- 1,0%.

[Influence of nutritive support on surgery outcomes in elderly patients with colon cancer].

The article presents the results of surgery outcomes in 127 elderly patients with colon cancer. The patients were divided into two groups: the main group (prospective, n = 52) and control group (retrospective, n = 75). The combined preoperative nutritive status assessment by BMI and a prognostic hypotrophy index were used. It included the optimization of nutritive support on all stages and an early tube removal, an enteral feeding during postoperative period. It was stated, that it significantly reduced the level of complications, period of intensive care unit stay on 2 days and a hospital stay on 4 days in main group. All the patients of the main group improved the quality of life during 7 days (EORTC QIQ CR29). Proposed nutritive support program allowed improvement of the quality of life and positive treatment outcomes in elderly patients with colon cancer.

[Clinical recommendations on treatment of the elderly colorectal cancer patients].

Colorectal cancer (CRC) is one of the commonest malignancies of Western countries, with approximately half the incidence occurring in patients > 70 years of age. Elderly CRC patients, however, are insufficient to fully examined, therefore, they receive inadequate treatment and underrepresented in clinical trials. The International Society of Geriatric Oncology created a task force with a view to assessing potential for developing guidelines for the treatment of elderly (geriatric) patients. A review of the evidence presented by the task force members confirmed the paucity of clinical trial data in elderly people and the lack of evidence-based guidelines. However, recommendations have been proposed on the basis of the available data and on the emerging evidence that treatment outcomes for fit, elderly CRC patients can be similar to those of younger patients. This gives hoped that such efforts will pave the way for formal treatment guidelines based upon solid scientific evidence in the future.