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OBJECTIVE: To study the relationship of the parameters of immunity and systemic inflammation with the structural magnetic resonance imaging (MRI) parameters in patients with mild cognitive impairment (MCI) and pre-MCI undergoing neurocognitive rehabilitation to search for candidate markers of its effectiveness. MATERIAL AND METHODS: The main group included 49 patients, aged ≥60 years, with MCI and pre-MCI with memory impairment, who underwent a course of neurorehabilitation for 5 weeks. The control group included 19 volunteers of similar age with a total MoCA score of ≥25, who did not have cognitive impairment and immuno-inflammatory disorders. The parameters of cellular and humoral immunity and markers of inflammation were studied, and structural MRI was performed. RESULTS: The content of activated natural killer cells (NK-cells) was increased in MCI and pre-MCI (0.63±0.12% vs. 0.22±0.07% in the control group, p=2.2·10-7). The level of immunoglobulin G (IgG) <12.5 g/l in patients with MCI and pre-MCI with the Montreal Cognitive Assessment Scale (MoCA) score <22 was associated with a decrease in the volume of the right nucleus accumbens (376±35 mm3 in patients with IgG <12.5 g/l (p=0.0013) and 480±44 mm3 at IgG <12.5 g/l, 480±44 mm3 in the control group), as well as with a decrease of the thickness and volume of a number of other cortical zones. A logistic regression model including the level of immunoglobulin G, NK cells, CD8+ NK cells and right amygdala volume was constructed to predict the number of MoCA scores 6 months after the course of rehabilitation (R2=0.57; p<1·10-5; standard error of estimate: 2.93). CONCLUSION: As a result of this work, the perspectives of assessing the immunological parameters in combination with socio-demographic data and morphometric changes of the brain as potential prognostic markers of the dynamics of cognitive impairment in patients with MCI and pre-MCI after neurorehabilitation has been shown.

Asunto(s)

Biomarcadores , Disfunción Cognitiva , Células Asesinas Naturales , Imagen por Resonancia Magnética , Humanos , Disfunción Cognitiva/inmunología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Células Asesinas Naturales/inmunología , Inmunoglobulina G/sangre , Inflamación/inmunología

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Summary: Anaphylaxis is a severe, rapidly developing, and life-threatening systemic hypersensitivity reaction. The diagnosis of anaphylaxis is primarily clinical. Numerous studies on the mechanisms and the biomarkers of the disease are initiated every year. The biomarkers of anaphylaxis may become an important tool for the diagnosis, prevention, repeated risk assessment, severity stratification, and new therapeutic strategies for treatment of the disease. Various immune and non-immune mediators produced and released by effector cell populations are currently considered as biomarkers of anaphylaxis. Here, we review the current data on potential biomarkers of anaphylaxis and the possibilities and perspectives for their use in future clinical practice.

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Breast cancer is the most common type of cancer among women. The study of the mechanisms of metastasis, the main cause of death from breast cancer, as well as the search for new markers for early diagnosis and prognosis of breast cancer, is an extremely topical issue. New perspectives in the diagnosis and treatment of breast cancer are opened by the mechanisms of gene regulation involving non-coding RNAs, in particular, long non-coding RNAs (lncRNAs). In this work, we analyzed the methylation levels of seven lncRNA genes (MEG3, SEMA3B-AS1, HAND2-AS1, KCNK15-AS1, ZNF667-AS1, MAGI2-AS3, and PLUT) by quantitative methyl-specific PCR on a set of 79 paired (tumor/normal) samples of breast cancer. Hypermethylation of all seven lncRNA genes was revealed, and hypermethylation of HAND2-AS1, KCNK15-AS1, MAGI2-AS3, and PLUT was detected in breast cancer for the first time. It was found that the level of meth ylation of the studied lncRNA genes correlated statistically significantly with the stage of the tumor process, the size of the tumor, and the presence of metastases in the lymph nodes. Thus, methylation of the seven studied lncRNA genes is associated with the development and progression of breast cancer, and these genes can be useful as potential markers in the diagnosis and prognosis of breast cancer.

Asunto(s)

Neoplasias de la Mama , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Progresión de la Enfermedad , Adulto , Anciano

RESUMEN

BACKGROUND: Bowel ultrasound (US) is one of the methods used to enhance diagnostic accuracy of necrotizing enterocolitis (NEC) and its associated complications in premature newborns. AIM: To explore the diagnostic accuracy of bowel US in extremely low birth weight (ELBW) infants with NEC. METHODS: A single-center retrospective case-control study included 84 extremely low birth weight (ELBW) infants. The infants were divided into three groups: Group 1 -infants with NEC (n = 26); Group 2 -infants with feeding problems (n = 28); Group 3 -control group (n = 30). RESULTS: The specific bowel US findings in premature newborns with NEC (stage 3) included bowel wall thinning, complex (echogenic) ascites, and pneumoperitoneum, p < 0.05. The diagnostic effectiveness of these sonographic signs was 96.8% (sensitivity 75.0% and specificity 97.6%), p < 0.05. These findings with high specificity were associated with the need for surgical intervention, poor outcomes, or increased mortality. Stage 2 NEC which did not require surgery showed impaired differentiation of the bowel wall layers, absent or decreased bowel peristalsis, pneumatosis intestinalis, portal venous gas, or simple ascites, with a diagnostic accuracy of 82.9% (sensitivity 55.6%, specificity 91.4%, p < 0.05). CONCLUSIONS: Bowel US can be used as an adjunct to abdominal radiography to aid in the diagnosis of infants with suspected NEC by providing more detailed evaluation of the intestine.

Asunto(s)

Enterocolitis Necrotizante , Recien Nacido con Peso al Nacer Extremadamente Bajo , Ultrasonografía , Humanos , Enterocolitis Necrotizante/diagnóstico por imagen , Recién Nacido , Estudios Retrospectivos , Ultrasonografía/métodos , Masculino , Femenino , Estudios de Casos y Controles , Sensibilidad y Especificidad , Intestinos/diagnóstico por imagen , Neumoperitoneo/diagnóstico por imagen , Ascitis/diagnóstico por imagen , Ascitis/etiología , Enfermedades del Prematuro/diagnóstico por imagen , Enfermedades del Prematuro/diagnóstico , Recien Nacido Prematuro

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There are three types of metastases in ovarian cancer: lymphogenous, hematogenous, and peritoneal. Dissemination of the tumor in the peritoneum is directly related with the development of ascites and a poor prognosis. The purpose of this study is to determine changes in the methylation level of a group of long non-coding RNA (lncRNA) genes at different stages of ovarian cancer progression. The methylation level of 7 lncRNA genes (LINC00472, LINC00886, MAFG-DT, SNHG1, SNHG6, TP53TG1, and TUG1) was studied by quantitative methyl-specific PCR in 93 samples of ovarian tumors and 75 paired samples of histologically normal tissue, as well as in 29 peritoneal macroscopic metastases. Using the nonparametric Mann-Whitney test, a significant (p<0.001) increase in the level of methylation of the LINC00886, SNHG1, SNHG6, and TUG1 genes in the tumor tissue was shown. For the LINC00472, LINC00886, and SNHG6 genes, a significant relationship was found with the clinical stage (p≤0.001), as well as with the appearance of metastases for the LINC00472 (p<0.001) and SNHG6 (p=0.005) genes. There was a significant increase in the level of methylation of MAFG-DT and TP53TG1 (p<0.001) genes, as well as a decrease in LINC00886 (p=0.003) in peritoneal metastases relative to the primary focus. Methylation of the LINC00472 and SNHG6 genes can be considered as a factor in initiating ovarian cancer metastasis, and methylation of the LINC00886, MAFG-DT, and TP53TG1 genes as a colonization factor for metastases in the peritoneum. Thus, a relationship between methylation of a group of lncRNA genes at different stages of ovarian cancer dissemination was shown, which is important for understanding the mechanisms of these processes and for developing innovative approaches to ovarian cancer therapy.

Asunto(s)

Neoplasias Ováricas , ARN Largo no Codificante , Humanos , Femenino , Metilación de ADN/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Proliferación Celular/genética

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AIM: To perform language and cultural adaptation and validation of the OABSS (Overactive Bladder Symptom Score) questionnaire among patients with overactive bladder (OAB), proposed as an effective tool for assessing the severity of symptoms and the efficiency of treatment in clinics of the Russian Federation. MATERIALS AND METHODS: In accordance with the protocols for carrying out such studies, the procedure of standardized forward-backward translation of the OABSS questionnaire was performed. Further, the intermediate Russian-language version was applied to 15 patients with subsequent correction of deficiencies and approval of the final Russian-language version of the questionnaire. In total, the study group included 176 patients of both sexes with OAB symptoms who filled out the questionnaire twice (test-retest) with an interval of 10-14 days. RESULTS: Based on the statistical analysis (Cronbach's alpha = 0.961), there was a significant degree of internal consistency of the sample. This fact is also supported by the very high retest reliability of the questionnaire (ICC >0.9). CONCLUSION: Our data showed that the Russian version of the OABSS questionnaire is a reliable and valid tool for subjective assessment of the severity of OAB symptoms.

Asunto(s)

Vejiga Urinaria Hiperactiva , Masculino , Femenino , Humanos , Vejiga Urinaria Hiperactiva/diagnóstico , Reproducibilidad de los Resultados , Lenguaje , Encuestas y Cuestionarios , Federación de Rusia

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The role of methylation of 9 miRNA genes in the pathogenesis of metastatic clear cell renal cell carcinoma was determined by quantitative methylation-specific PCR (MS-PCR). For 5 genes (MIR125B-1, MIR137, MIR193A, MIR34B/C, and MIR375), a significant correlation of high methylation level with late (III-IV) stages, large size (T3+T4) of the tumor, and metastasis to lymph nodes and/or distant organs was revealed. For another group of genes (MIR125B-1, MIR1258, MIR193A, MIR34B/C, and MIR375), a statistically significant correlation of high methylation level with loss of differentiation in the tumor (G3-G4) was found, and the opposite pattern was found for MIR203A. A total of 7 microRNA genes (MIR125B-1, MIR1258, MIR137, MIR193A, MIR203A, MIR34B/C, and MIR375) were identified, the methylation of which is associated with the progression of metastatic clear cell renal cell carcinoma. For 6 of them (except MIR34B/C) these data were obtained for the first time. Thus, new factors of the development and progression of clear cell renal cell carcinoma were identified as potential biomarkers for the early diagnosis and prognosis of metastatic clear cell renal cell carcinoma.

Asunto(s)

Carcinoma de Células Renales , Neoplasias Renales , MicroARNs , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Metilación de ADN/genética , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética

RESUMEN

The toxicity and antiviral activity of extracts obtained by the methods of aqueous and ethanol extraction of bioactive substances from Cetraria islandica lichen as a raw material were studied. Aqueous and ethanol extracts of lichen were characterized by low toxicity with respect to the passaged MDCK cell culture and exhibited antiviral activity. The ethanol extract showed more potent in vitro antiviral activity against human A/H3N2 and avian A/H5N1 influenza viruses: in a concentration of 50 µg/ml, it suppressed replication of these viruses by 3.5 and 4 log10, respectively, while the aqueous extract inhibited replication of viruses by 2 and 6 log10, respectively, when taken in a concentration of 500 µg/ml that was 10-fold higher than the concentration of the ethanol extract.

Asunto(s)

Subtipo H5N1 del Virus de la Influenza A , Gripe Humana , Líquenes , Parmeliaceae , Humanos , Subtipo H3N2 del Virus de la Influenza A , Antivirales/farmacología , Antivirales/uso terapéutico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico

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The search for interacting long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs of protein-coding genes through the mechanism of competing endogenous RNAs in tumors of ovarian cancer patients was carried out. The levels of expression of 24 lncRNAs, 20 miRNAs, and 28 mRNAs of protein-coding genes involved in oncogenesis were determined by real-time PCR on a set of representative samples. Correlations between lncRNAs/miRNA and miRNA/mRNA levels in ovarian cancer samples were analyzed. We identified 8 pairs of lncRNAs/miRNA and 17 pairs of miRNA/mRNA, the expression levels of which have a negative correlation. Five triplets of potentially interacting lncRNAs/miRNA/mRNA have been identified, among which the most significant triplet is the OIP5-AS1/miR-203a-3p/ZEB1. The data obtained determine new epigenetic profiles, as well as new potential biomarkers and targets for targeted therapy of ovarian cancer patients.

Asunto(s)

MicroARNs , Neoplasias Ováricas , ARN Largo no Codificante , Humanos , Femenino , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Redes Reguladoras de Genes , Neoplasias Ováricas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación Neoplásica de la Expresión Génica/genética

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We analyzed changes in the level of methylation of CpG islands in four long non-coding RNA (lncRNA) genes MEG3, ZNF667-AS1, GAS5, and SEMA3B-AS1 as promising markers of breast cancer. Methylation analysis was performed by quantitative methylation-specific PCR on a set of 38 paired (tumor/normal) breast cancer samples. Significantly (p<0.001) increased methylation was shown for three of the four lncRNA genes: MEG3, ZNF667-AS1, and SEMA3B-AS1. We found significant correlations of the methylation level of all the studied lncRNA genes with the stage of cancer and with lymphogenic metastasis, and for MEG3 and ZNF667-AS1 also with the tumor size. Methylation of ZNF667-AS1, and SEMA3B-AS1 genes in breast cancer was detected for the first time. Based on these findings, new potential markers for the diagnosis and prognosis of breast cancer can be proposed.

Asunto(s)

Neoplasias de la Mama , ARN Largo no Codificante , Humanos , Femenino , ARN Largo no Codificante/genética , Neoplasias de la Mama/genética , Metilación de ADN/genética , Islas de CpG/genética , Regulación Neoplásica de la Expresión Génica/genética , Línea Celular Tumoral , Proliferación Celular/genética

RESUMEN

This article describes the experience of application of multipotent mesenchymal stromal cells in the complex therapy of severe recurrent cholangitis in 2 children with biliary atresia after Kasai surgery. In both children, hepatic cellular insufficiency and portal hypertension developed against the background of long-term inflammatory process poorly controlled by standard therapy, which was the indication for liver transplantation. During the course of mesenchymal stromal cells therapy, the relief of the inflammatory process and functional recovery of the liver were achieved. At the time of preparing the article, the follow-up of two children since the start of multipotent mesenchymal stromal cell therapy was 3 years 9 months and 2 years 6 months. No recurrence of cholangitis was observed in the patients during the follow-up period, the liver function was preserved. There are no indications for liver transplantation at this moment. Thus, despite the fact that the mechanisms of therapeutic action of multipotent mesenchymal stromal cells in biliary atresia require further investigation, we obtained promising results suggesting the possibility of using mesenchymal stromal cells in the treatment of postoperative complications in children with biliary atresia.

Asunto(s)

Atresia Biliar , Células Madre Mesenquimatosas , Niño , Humanos , Atresia Biliar/cirugía

RESUMEN

We studied the correlations between the levels of methylation of a group of 21 microRNA genes in 99 primary tumors and 29 macroscopic peritoneal metastases of ovarian cancer. Analysis of the level of methylation by quantitative methylation-specific PCR showed that co-methylation was detected for 13 pairs of microRNA genes in primary tumors and for 22 pairs in metastases. Pairs of microRNA genes that have shown significant co-methylation can be involved in common processes and pathways of gene regulation and interaction and can have common target genes. The results are highly significant and pairs of microRNA genes can be proposed as new potential markers for the diagnosis and prognosis of ovarian cancer metastasis.

Asunto(s)

MicroARNs , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/genética , Metilación de ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Ováricas/patología

RESUMEN

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.

Asunto(s)

MicroARNs , Neoplasias Ováricas , ARN Largo no Codificante , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/metabolismo , Proliferación Celular/genética , Femenino , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética

RESUMEN

Changes in the methylation levels of 21 microRNA genes in 91 breast cancer samples in comparison with paired samples of histologically unchanged tissue were studied by quantitative methylation-specific PCR. For 19 microRNA genes, a significant increase in the methylation level in tumors in comparison with normal tissues was shown (Mann-Whitney test). When considering the data for breast cancer samples only from patients with clinical stages I and II (59samples), 17 genes with a significantly increased level of methylation were identified. Increased methylation level for 11 genes (MIR124-1, MIR124-3, MIR125B-1, MIR127, MIR129-2, MIR132, MIR137, MIR193a, MIR34B/C, MIR375, and MIR9-1) compared to the paired norm was highly significant (p<0.001, FDR=0.01). The ROC analysis was used to optimize a set of markers for diagnosing breast cancer at the early stages consisting of 4 microRNA genes: MIR125B1, MIR127, MIR1258, and MIR132; the system is characterized by 100% specificity, 85% sensitivity, and AUC=0.924. Importantly, 100% specificity eliminates false positive results. Detection of methylation of at least one of the 4 genes of this set is sufficient to classify the patient's sample as breast cancer.

Asunto(s)

Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Metilación de ADN/genética , Detección Precoz del Cáncer/métodos , MicroARNs/genética , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estadificación de Neoplasias

RESUMEN

Systemic analysis of the relationship between the levels of methylation of 21 microRNA genes and the parameters of breast cancer progression was performed on a representative sample of 91 paired specimens of breast cancer and histologically normal tissues and a system of markers for prediction of metastasis was proposed. A significant association of hypermethylation of 11 genes with late (III-IV) clinical stages was found, and for 6 genes (MIR124-1, MIR127, MIR34B/C, MIR9-3, MIR1258, and MIR339) this association was highly significant (p≤0.001, FDR=0.01). For MIR9-3 and MIR339, an association with tumor size was demonstrated (p<0.001, FDR=0.01). No association of the levels of methylation of the analyzed microRNA genes with the degree of differentiation were found. An association with lymph node metastasis was established for 9 microRNA genes; the most significant association was shown for 6 genes MIR125B-1, MIR127, MIR9-3, MIR339, MIR124-3, and MIR1258 (p<0.005, FDR=0.05). Based on these 6 genes, a marker system for predicting breast cancer metastasis was developed by ROC analysis. This system is characterized by 87% sensitivity and 77% specificity (AUC=0.894). The proposed system may have clinical application in the personalized treatment of breast cancer patients.

Asunto(s)

Neoplasias de la Mama/genética , Metilación de ADN/genética , Metástasis Linfática/genética , MicroARNs/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Islas de CpG/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Metástasis Linfática/diagnóstico , Estadificación de Neoplasias , Pronóstico , Regiones Promotoras Genéticas/genética

RESUMEN

We studied the relationship of the levels of microRNA group expression and methylation with clinical and pathomorphological parameters of breast cancer and its immunohistochemical status. Quantitative methylation specific PCR analysis showed a significant (p<0.001) increase in the methylation level of 4 microRNA genes (MIR127, MIR129-2, MIR132, and MIR148A) and a significant (p<0.001) decrease for gene MIR375 relative to paired histologically normal tissue. Real-time PCR analysis revealed a significant (p≤0.001) decrease in the expression of 4 microRNAs (miR-127-5p, miR-129-5p, miR-132-3p, and miR-148a-3p) and a significant (p≤0.001) increase in the expression of miR-375-3p. A significant (rs=-0.6--0.7, p≤0.001) relationship between changes in the expression level of miR-129-5p, miR-132-3p, miR-148a-3p, and miR-375-3p and the levels of methylation of the corresponding genes in breast cancer was showed by using Spearman's rank correlation test. Analysis of the samples with consideration of the pathophysiological characteristics of the tumor revealed two significant markers of tumor progression: MIR129-2/miR-129-5p and MIR375/miR-375-3p. Both factors, the increase in the level of MIR129-2 methylation (p<0.001) and a decrease in the expression level of miR-129-5p (p<0.001), are significantly associated (p<0.001) with stage III/IV and the absence of HER2 expression. For MIR375/miR-375-3p, on the contrary, an association of low methylation level and enhanced expression with increased Ki-67 level (>30%, p<0.05) was revealed. These findings are of interest for understanding the mechanisms of breast cancer development and can provide the basis for the diagnosis and prognosis of the course of this disease. Moreover, the revealed features can be useful for adjusting the course of treatment with consideration of the pathophysiological characteristics of the tumor.

Asunto(s)

Neoplasias de la Mama/genética , MicroARNs/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Metilación , MicroARNs/metabolismo , Estadificación de Neoplasias , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo

RESUMEN

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.

Asunto(s)

Glicoproteínas de Membrana/genética , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genética , ARN Largo no Codificante/genética , Semaforinas/genética , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/secundario , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/secundario , Metilación de ADN , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Glicoproteínas de Membrana/metabolismo , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Peritoneales/diagnóstico , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/secundario , ARN Largo no Codificante/metabolismo , Semaforinas/metabolismo

RESUMEN

Ovarian cancer (OC) is mostly detected at late stages weighed down with metastasis, and the five-year survival rate of patients is only 30%, which dictates the necessity to develop gentler and more selectively targeted drugs that current chemotherapeutic agents. The search for factors that can influence on the activity of the PD-1/PD-L1 immune checkpoint signaling pathway in tumors is relevant, and micro RNAs (miRNAs) play an important role in it. Over the past 5 years, only a few miRNAs (miR-34a, miR-145, and miR-424), which have a regulatory effect on the PD-1/PD-L1 system in OC patients, have been discovered. In present work, the methylation levels of 13 miRNA genes in 26 primary tumors and 19 peritoneal metastases of OC patients were determined and compared with the level of the soluble form of PD-L1 (sPD-L1) in the blood plasma of the same patients. It was shown that the methylation levels of five miRNA genes (MIR124-2, MIR34B/C, MIR9-1, MIR9-3, and MIR339) in tumors are in direct correlation with the sPD-L1 level in the blood plasma. In addition, when analyzing these five genes, a significant association of the methylation level of the MIR9-1 gene with a decrease in the three-year relapse-free survival, and a trend for decrease in the three-year survival rate with the methylation level of the MIR124-2 gene of OC patients were determined. Thus, the first data suggesting the role of inhibitors of the sPD-L1 immune checkpoint for five miRNAs (miR-124, miR-34b, miR-34c, miR-9, miR-339) and the possibility of using hypermethylated MIR9-1 and, presumably, MIR124-2 genes as independent prognostic markers of poor disease-free survival in OC patients were obtained.

Asunto(s)

Antígeno B7-H1/genética , MicroARNs/genética , Neoplasias Ováricas , Receptor de Muerte Celular Programada 1/genética , Femenino , Humanos , Metilación , Neoplasias Ováricas/genética , Pronóstico

RESUMEN

The morphological and physiological characteristics of Bacillus thuringiensis strains were analyzed and conditions for obtaining culture fluid with maximum yield of secreted RNases were determined. Zymographic analysis showed that culture fluid of B. thuringiensis strains along with low-molecular-weight (15-20 kDa) RNases contained enzymes with a molecular weight ~55 kDa and their content depended on the duration and conditions of culturing. Preparations based on B. thuringiensis culture fluid were effective against human influenza virus A/Aichi/2/68 (H3N2). In experiments on mice infected with 10 LD50 influenza virus strain A/Aichi/2/68 (H3N2), we selected effective variants of preparations based on culture fluid of B. thuringiensi strains for preventive administration that provided reliable protection of infected animals (protection coefficient 50%), close to that of the reference drug Tamiflu.

Asunto(s)

Antivirales/farmacología , Bacillus thuringiensis/efectos de los fármacos , Bacillus thuringiensis/virología , Subtipo H3N2 del Virus de la Influenza A/patogenicidad , Virus de la Influenza A/patogenicidad , Kobuvirus/patogenicidad , Oseltamivir/farmacología , Humanos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/microbiología , Kobuvirus/efectos de los fármacos

RESUMEN

It was found that the proportion of microRNA genes inactivated by methylation of regulatory CpG islands is several times higher than the genes encoding proteins, which increases their attractiveness as promising markers of cancer. The aim of this work is to evaluate the clinical significance of methylation of 13 tumor-associated microRNA genes (MIR-124a-2, MIR-124a-3, MIR-125-B1, MIR-127, MIR-129-2, MIR-132, MIR-137, MIR-203a, MIR-34b/c, MIR-375, MIR-9-1, MIR-9-3, MIR-339) in 26 patients with ovarian cancer. Methylation level was evaluated by the method of methylation-specific PCR in real time. The data obtained in primary tumors (26), histologically unchanged ovarian tissues (15) and peritoneal metastases (19) were compared using a number of statistical programs. For all 13 genes, an increase in the level of methylation was revealed during the transition from unchanged tissue to primary tumors and further from primary tumors to peritoneal metastases; moreover, in the genes MIR-203a, MIR-375 and MIR-339, the level of methylation in metastases increased most significantly (in 2 and more times). A correlation was observed for the first time, showing a consistency between the increase in methylation level in some miRNA pairs, for example, MIR-129-2/MIR-132 (rs> 0,7; p<0,0001), both in primary tumors and in metastases. An analysis of microRNA gene methylation in clinical samples of ovarian cancer showed a correlation between the observed molecular changes both with the initial stages of tumor formation and with the progression and dissemination of ovarian cancer, with the presence of metastases in a large omentum and with the appearance of ascites. The revealed dependencies deepen the understanding of the mechanism of peritoneal metastasis and can be used to select new diagnostic and prognostic markers of ovarian cancer.

Asunto(s)

Metilación de ADN , MicroARNs/genética , Neoplasias Ováricas/genética , Islas de CpG , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos