Crosstalk between the estrogen receptors and the receptor tyrosine kinases, including vascular endothelial growth factor receptor type II (VEGFR2), is a key mechanism in breast cancer resistance to antiestrogen therapy with tamoxifen. A high level of VEGFR2 expression in a tumor serves as a marker of tamoxifen resistance. The tamoxifen efficacy prognostic value of functional polymorphisms in the VEGFR2/KDR gene has not been established. Using qRT-PCR, we detected the rs2071559 and the rs2305948 variants and the levels of KDR gene expression in 122 breast tumor tissue samples from cohorts of patients with progression (distant metastases or relapse) and patients with no progression during tamoxifen therapy. The expression levels of VEGFR2 protein were analyzed by immunohistochemistry. The frequency of heterozygous and mutant genotypes of the rs2305948 SNP was significantly higher in patients without progression than in the cohort with progression. KDR rs2305948 was associated with high survival rates in breast cancer patients. A correlation between the mRNA of the ESR1 and KDR genes in patients without progression was detected. The results indicate the prognostic value of rs2305948 and its potential contribution to the tumor phenotype sensitive to tamoxifen.

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family, primarily known as a mediator of the humoral immune response. It provides protection of barrier tissues and participates in the development of a range of diseases. This cytokine promotes carcinogenesis by induction of proliferation and survival of cancer cells, remodeling of the tumor microenvironment, and promoting immunosuppressive conditions. Elevated levels of IL-33 were observed in many types of cancers. This elevation correlates with a poor prognosis, making IL33 a promising target for cancer immunotherapy. The mechanisms of IL-33 expression regulation in human tumor cells are not well understood. Here, we show that that expression of IL-33 in breast and lung cancer cell lines depends, at least in part, on the activity of the SP1 and FOXA1 transcription factors. Increases in the activity of these transcription factors may be responsible for elevated levels of IL-33 and subsequent tumor progression.

Medicines from the group of interferon inducers (IFNs) "swith on" the synthesis of type 1 interferons (IFN-I) and induce the expression of IFN-stimulated genes (ISGs) that regulate innate immunity reactions and protect the host from infectious agents and the tumour pathology.The purpose of the study was to determine the role of the drug celagrip (CA) in the activation of innate immunity genes and the effect on the production of reactive oxygen species (ROS) in patients with follicular lymphoma (FL).

Primary myelofibrosis is a common disease from the group of Ph-negative myeloproliferative diseases. The article presents modern data on the pathogenesis of Ph-negative myeloproliferative diseases, as well as diagnostic criteria, treatment tactics and prognosis factors for primary myelofibrosis. A clinical case of transformation of primary myelofibrosis into acute myeloid leukemia is described. Purpose of the study - to present up-to-date information on the pathogenesis, diagnostic criteria, principles of treatment and prognostic factors of primary myelofibrosis, as well as to present a clinical case of transformation of primary myelofibrosis into acute myeloblastic leukemia. According to modern concepts, for the early diagnosis of primary myelofibrosis, along with the clinical and morphological methods of examining patients, molecular genetic verification of the disease is extremely important. To improve the survival rate of patients with primary myelofibrosis, molecular genetic verification of the disease and stratification for the choice of treatment tactics are necessary.

Seromucinous tumors belong to a group of ovarian epithelial tumors. They were originally described as tumors characterized by Müllerian endocervical differentiation. Molecular genetic studies have indicated these tumors as endometriosis-associated tumors due to the presence of ARID1 gene mutations. However, the histogenesis of these neoplasms is still unstudied.

To investigate the expression of microsatellite instability (MSI) markers, which is detected by an immunohistochemical technique, and to compare the expression with the PD-L1 status in luminal B, HER2-negative and triple-negative breast cancer.

Changes in the expression of non-coding ribonucleic acids (ncRNAs) take part in the formation of various tumors. Multiple endocrine neoplasia syndrome type 1 (MEN1) is a rare autosomal dominant disease caused by mutations of the MEN1 gene encoding the menin protein. This syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, pituitary adenomas, as well as other endocrine and non-endocrine tumors. The pathogenesis of MEN-1 associated tumors due to MEN1 mutations remains unclear. In the absence of mutations of the MEN1 gene in patients with phenotypically similar features, this condition is regarded as a phenocopy of this syndrome. The cause of the combination of several MEN-1-related tumors in these patients remains unknown. The possible cause is that changes in the expression of ncRNAs affect the regulation of signaling pathways in which menin participates and may contribute to the development of MEN-1-related tumors. The identification of even a small number of agents interacting with menin makes a significant contribution to the improvement of knowledge about its pathophysiological influence and ways of developing tumors within the MEN-1 syndrome and its phenocopies.

To study the peculiarities of carrying clinically significant allelic variants of TPMT and DPYD genes associated with the response to drug therapy in cancer practice among 9 ethnic groups of the Russian Federation.

In this study, we explored the effects of treating human endometrial cancer cells with γ-synuclein-specific short hairpin RNA (shRNA) and elucidated the associated mechanisms in vitro and in vivo through the p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) signaling pathways. Cell proliferation and migration were assessed using CCK8, Transwell, and scratch wound healing assays. Flow cytometry and laser scanning confocal microscopy were used to detect cell cycle changes. Relative levels of phosphorylated and non-phosphorylated (p) p38, ERK1/2 and JNK1/2/3 were determined in vitro and in vivo using simple western blotting assays. Cell proliferation in the experimental group decreased significantly and cells transfected with shRNA showed reduced migration rates (P < 0.05). p-p38, p-ERK1/2, and p-JNK1/2/3 levels were downregulated in the experimental group in vitro and in vivo. Tumor volumes and weights in the experimental group were significantly lower (P < 0.05). Tumor formation time in the negative control group was significantly shorter (P < 0.05). Flow cytometry showed that the number of cells in the G1 and mitotic phases increased and that in the S phase decreased after SNCG silencing (P < 0.05). Confocal microscopy showed that the percentage of cells in the mitotic phase increased after SNCG gene silencing (P < 0.05). We conclude that shRNA-mediated suppression of γ-synuclein decreased the proliferation, migration, and tumorigenicity of endometrial cancer cells via downregulation of p38, ERK, and JNK phosphorylation. High SNCG expression is closely related to the growth cycle of endometrial cancer cells.

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.

The somatic isoform of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC1.2.1.12) is involved in such crucial for cancer cells development pathways as induction of apoptosis and glycolytic regulation. At the same time, sperm-specific isoform (GAPDHS) does not exhibit all the same functions as somatic enzyme. The expression of sperm-specific GAPDH without N-terminal domain in some melanoma cells along with somatic isoenzyme, shown in our previous work, has led to the proposal of this unusual enzyme's possible role in regulation of cancer cells glycolysis. In the presented work we have tested production of GAPDHS in 13 additional melanoma cell lines by immunoblotting. We have also gathered data on energy metabolism in 5 selected cell lines by evaluation of glucose uptake and lactate production in differing conditions. We have demonstrated that in standard cultivation media glucose uptake by MelP cells, producing substantial amounts of GAPDHS protein was higher than in MelKor cells, producing lesser amounts of GAPDHS. All other analyzed cell lines that do not produce GAPDHS (MelMS, MelSi and Malme3M) had even a lower glucose uptake rate.

Lung cancer is one of the main causes of cancer death. It is a heterogeneous group of malignant neoplasms, the treatment tactics for which directly depends on tumor morphology and genetic characteristics. However, the pathomorphological differential diagnosis of adenocarcinoma and squamous cell cancer of the lung is difficult in some cases and an immunohistochemical (IHC) study is needed to verify these tumors; moreover, the IHC panel should include both squamous cell and pneumocyte markers. Fifty surgical and biopsy specimens underwent morphological and IHC studies using antibodies against p40, p63, CK5/6, CK7, and TTF1. In this investigation, p40 showed a higher specificity than another squamous cell differentiation marker, such as p63; this confirms the data that it is advisable to use the marker p40 to verify squamous cell lung carcinoma. If there is a small amount of material for an IHC study in the differential diagnosis of adenocarcinoma from squamous cell cancer of the lung, the optimal solution is to limit the IHC panel to two markers, such as p40 and TTF1.

To determine the prognostic value of the expression of Ki-67, p53, and Notch1 in the diagnosis of prostate cancer.

Rhabdomyosarcoma (RMS) is a malignant soft tissue tumor originating from primitive mesenchymal cells, which is most common in children.

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/β-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.

Classical views of hereditary mechanisms consider linear nucleic acids, DNA and RNA, as template molecules wherein genetic information is encoded by the sequence of nitrogenous bases. The template principle embodied in the central dogma of molecular biology describes the allowed paths of genetic information transfer from nucleic acids to proteins. The discovery of prions revealed an additional hereditary mechanism whereby the spatial structure is transmitted from one protein molecule to another independently of the sequence of nitrogenous bases in their structural genes. The simultaneous existence of linear (type I) and conformational (type II) templates in one cell inevitably implies their interaction. The review analyzes the current data confirming the idea that protein amyloid transformation may influence the genome stability and considers potential mechanisms of interactions between type I and type II template processes. Special attention is paid to the joint contribution of the two process to tumor "evolution" and the mechanisms of genome destabilization due to amyloid transformation of proteins in Alzheimer's and Parkinson's diseases and Down syndrome.

A majority of BRCA1/2 (BRCA) pathogenic variants (PVs) are single nucleotide substitutions or small insertions/deletions. Copy number variations (CNVs), also known as large genomic rearrangements (LGRs), have been identified in BRCA genes. LGRs detection is a mandatory analysis in hereditary breast and ovarian cancer families, if no predisposing PVs are found by sequencing. Next generation sequencing (NGS) may be used to detect structural variation, since quantitative analysis of sequencing reads, when coupled with appropriate bioinformatics tools, is capable of estimating and predicting germline LGRs (gLGRs). However, applying this approach to tumor tissue is challenging, and the pipelines for determination of CNV are yet to be optimized. The aim of this study was to validate the Next Generation Tumor Sequencing (NGTS) technology to detect various gLGRs of BRCA1 locus in surgical tumor tissue samples. In this study, seven different BRCA1 gLGRs, previously found in high-grade serous ovarian cancers (HGSOC) patients, were detected in tumor samples collected from the patients at a time of HGSOC surgery. This study demonstrated that NGS can accurately detect BRCA1 gLGRs in primary tumors, suggesting that gLGR evaluation in BRCA1 locus should be performed in cases when the screening for BRCA alterations starts from tumor instead of blood. NGS sequencing of tumor samples may become the preferred method to detect both somatic and germline gLGRs in BRCA-encoding loci.

Chronic myeloid leukemia is a clonal hematopoietic stem cell disease characterized by myeloid expansion. The hallmark of the disease is the Philadelphia chromosome, which results in the formation of the BCR-ABL oncogene, a tyrosine kinase that is involved in many signaling pathways including Wnt signaling. The latter has a unique role in chronic myeloid leukemia progression; activated signaling leads to the establishment of an additional leukemic stem cell population derived from granulocyte-macrophage progenitors. sFRP1 is an inhibitor of Wnt signaling and its expression is important for differentiation and maintenance of hematopoietic stem cells. In this study, we aimed to investigate miRNAs that target Wnt signaling by being co-induced along with the expression of sFRP1 in K562 cells. We present a detailed analysis of hsa-mir-221 -3p, hsa-mir-222-3p, hsa-mir-106b-5p, hsa-let-7f-5p, hsa-mir-182-5p, hsa-mir-191-5p, and hsa-mir-183-5p and their target genes and their involvement in Wnt signaling.

The transcriptional activity of genes encoding cancer/testis antigens (CTA) and its regulation in colorectal cancer (CRC) is not well understood. The expression of CTA coding genes (CT genes) and possible mechanisms for its regulation, including expression and copy number of DNA methyltransferase genes, copy number of CT genes, microRNA expression, and LINE-1 methylation in CRC were analyzed in this study. The relative expression levels and copy number variation of 19 genes, MAGE-A1, -A2, -A3, -A4, -B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NY-ESO1, SSX2, SCP1, PRAME1, DNMT1, DNMT3A, and DNMT3B, were determined using real-time quantitative PCR. Quantitative methylation of LINE-1 CpG sites was evaluated by pyrosequencing, and multiple parallel sequencing was used to determine the level of microRNA expression. It was found that in colon tumor tissue a multidirectional destabilization of the transcriptional activity of DNMT3A and DNMT3B, associated with copy number variation and a change in expression of the CT genes BAGE, SSX2 and PRAME1, is observed. A strong positive correlation was found between copy number and expression of the BAGE, SSX2, and PRAME1 genes. As a result of multiple parallel sequencing, 6 differentially expressed microRNAs (hsa-miR-143-3p, hsa-miR-26a-5p, hsa-miR-25-3p, hsa-miR-92a-3p, hsa-miR-21-5p, and hsa-let-7i-5p), targeting the CT genes GAGE1, SSX2, PRAME, SCP1, and the gene for DNA methyltransferase 3A (DNMT3A), were found. Data on the mechanisms of the transcriptional activity regulation of CT genes in malignant colon tumors are important for the development of CTA-dependent immunotherapeutic approaches for the treatment of this type of tumor.

Sorafenib has been used in acute myeloid leukemias with FLT3-ITD mutation improving the outcomes. However the high incidence of treatment - emergent adverse event may be associated with treatment using sorafenib with cytotoxic chemotherapy. We have reported a case of severe thyroiditis in patient with a relapse of acute myelomonocytic leukemia.