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Introduction. There is currently no effective therapy for the treatment of glioblastoma. This is partly explained by the high degree of intra- and intertumor heterogeneity of GB, the source of which is believed to be glioblastoma stem cells (GSC). The question of the origin of GSC, which is important for improving clinical outcomes, still remains open. It is believed that GSCs can be formed as a result of oncogenic transformation of neural stem and progenitor cells (NSPcs), which have morphological and functional properties similar to them. Despite significant progress in elucidating the nature of GSCs, little is yet known about the specifically expressed genes and transcripts in these cells in comparison with NSPcs. In this regard, it becomes relevant to study the molecular mechanisms of gliomagenesis using model cell systems based on various clones of GSC.Aim. To conduct a comparative transcriptomic analysis of CD133+-NSPCs and CD133+-GSCs to study the molecular genetic differences between the phenotypes of these cells and identify potential targets for therapeutic effects on GSCs.Materials and methods. Used: highly sensitive transcriptomic analysis on high-density microarrays, cellular technologies, modern bioinformatics analysis.Results. Transcriptomic analysis of CD133+-GSCs and CD133+-NSPCs identified 1825 differentially expressed genes. The biological processes and signaling cascades activated in CD133+-GSCs have been established. It was shown that significant transcriptomic aberrations in CD133+-GSC compared to CD133+-NSPC are primarily due to a group of transcripts regulated by the Shh (Sonic hedgehog), mTOR (mammalian target of rapamycin), ALK (anaplastic lymphoma kinase) signaling cascades, transcription factors E2F1, PRC2, HOXA9, MYC, as well as oncogenes ERBB2 and KRAS. Six transcripts (AQP9, TOX15, HOXB2, STEAP3, TREM1, RFC2) highly expressed in CD133+-GSC and closely associated with the survival of patients with glioblastoma, which may be potential targets for therapeutic effects on CD133+-GSC associated with gliomagenesis, which may be potential targets for therapeutic effects on CD133+-GSC, have been identified and annotated.Conclusion. The data obtained indicate a number of significant molecular genetic differences between the two cell phenotypes, which can be used in the development of new therapeutic approaches for the treatment of glioblastoma.

Introduction. Glioblastoma (GB) is not yet curable despite recent advances in the treatment of other malignant solid tumors. The management of GB is based solely on histopathological features, imaging of the tumor and its genomic analysis (somatic mutations in the isocitrate dehydrogenase genes, methylation status of the O6-methylguanine-DNA methyltransferase gene promoter). To adapt the treatment to the most recent tumor evolution, molecular information should be received regularly throughout the course of therapy. However, tumor tissue is often not available for diagnosis as the disease progresses. In this regard, the development of less invasive methods, such as analysis of the proteome of biological fluids of patients, is of particular interest. Cerebrospinal fluid (CSF) is an important source disease biomarkers to monitor the presence and progression of the disease.Aim. To identify proteomic predictive biomarkers in the CSF of patients with GB.Materials and methods. During the study, samples of patients’ CSF samples, high-resolution proteomic mass spectrometry, modern biochemical methods and bioinformatic technologies were used.Results. For the first time, the analysis of proteomes of CSF samples of patients with GB obtained before and 7 days after the removal of the primary tumor was carried out. Potential biomarkers of GB have been identified. After their validation using open databases, 11 proteomic predictive markers of GB (S100A9, S100A8, PLA2G15, PPIB, LTBP2, VIM, LAMB1, STC1, NRP1, COL6A1, HSPA5) were selected and their role in the molecular mechanisms of gliomagenesis was assessed. Conclusion. The proposed panel of proteomic predictive CSF biomarkers in GB patients can be further used in the development of test systems for assessing the effectiveness of therapy and early detection of disease relapses.

Introduction. Treatment of glioblastoma multiforme remains little effective due to the rapidly developing recurrence of the tumor, due to its high tumorigenic potential, resistance to chemoradiation therapy and increased dissemination of glioma stem cells. The identification of potential therapeutic targets, which make it possible to more effectively destroy glioma stem cells, becomes topical. In this regard, the study of ferroptosis (FP), which can cause the death of tumor cells with a highly malignant phenotype, is of great importance. However, FP and its regulatory pathways in the GSC are not fully understood. At present, it is also not clear how FP differs for glioma stem cells and glioblastoma differentiated cells.Aim. To study the expression of ferroptosis signaling cascade determinants in CD133+ glioma stem cells and CD133- glioblastoma differentiated cells using high resolution proteomic mass spectrometry.Materials and methods. High-resolution proteomic mass spectrometry, cell technologies.Results. In total, 1970 proteins were identified, 15 of which are associated with ferroptosis and are present in both cell populations. Upregulation of 12 FP determinants (ACSL1, ACSL3, COPZ1, FTH1, FTL, GPX1, GPX4, PCBP1, SLC3A2, TFRC, VDAC1, VDAC2) was found in CD133+ glioblastoma stem cells compared to CD133- differential glioblastoma cells, 10 of which were more than 2-fold overexpressed.Conclusion. Important regularities have been established in the expression of ferroptosis determinants and proteins controlling this process in glioma stem cells, which can be used in the development of new approaches to the detection of potential targets for the therapy of glioblastoma multiforme.

Introduction. To a large extent, the resistance of glioblastoma multiforme to genotoxic therapy is associated with a dysregulation of responses to DNA damage and repair. Thus, suppression of DNA repair mechanisms is a priority pathway for increasing the survival rate of glioblastoma multiforme patients. Curcumin enhances the effectiveness of standard chemotherapy drugs, but its effect on DNA repair systems is not well understood.The study objective – to study the molecular mechanisms of curcumin action on excisional DNA repair in U251 glioblastoma multiforme cells.Materials and methods. high-resolution proteomic mass spectrometry, cell technologies.Results. In the proteomes of two types of glioblastoma multiforme cells (control and experiment), a total of 2757 proteins were identified, of which 39 % were differentially expressed. Significant changes have been found in many signaling cascades that play an important role in carcinogenesis.Conclusion. Curcumin suppressed excisional DNA repair by decreasing the expression of determinants APEX1, MSH6, PARP1. PCNA, POLD1, POLE3, RFC2, RPA.

Background. Glioblastoma multiforme (GBM) develops in the hypoxic microenvironment, which plays an important role in the pathogenesis of the disease and is closely associated with tumor growth, development and poor prognosis. Hypoxia increases the resistance of tumor cells (TC) to radiation therapy and chemotherapy, promotes the appearance of an aggressive TC phenotype, leading to the disease recurrence. The molecular mechanism of hypoxic action on the secretome of GBM cells, which is involved in the formation of the tumor microenvironment, remains unclear. Also, markers of the aggressive hypoxia-associated phenotype of tumor cells have not been established. The purpose of research – to study the molecular mechanisms of the hypoxia-associated effect on the secretome of the U251 GBM cells.Materials and method. High resolution proteomic mass spectrometry, cell technologies.Results. A total of 1432 proteins were identified in the secretomes of two types of GBM cells (control and experiment). After the action of hypoxia, statistically significant changes in the expression of 390 proteins were registered. 11 proteins showed increase in expression over two orders of magnitude. The intracellular signaling pathways which are responsible for the hypoxia-associated effects on the U251 GMB cells have been identified.Conclusions. Hypoxia significantly affected the proteomic composition of the GBM cells secretome. Five overexpressed secretome proteins, S100A6, HEY1, ZIP3, S100A4, ZEB2, have been proposed as potential markers of the hypoxiaassociated phenotype of GBM, for which participation in the pathogenesis of glioblastoma multiforme has been previously showed.

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patien’s median survival rate ranging from 12 to 15 months. Over the last fifteen years, the treatment for GBM has included maximal safe surgical resection with combination radiotherapy and adjuvant temozolomide chemotherapy. The low efficacy of mentioned therapies has forced researchers to explore an appropriate alternative or complementary treatment for GBM. It has been shown that curcumin has therapeutic potentials to fight against GBM via affecting on cell proliferation, apoptosis, cell cycle, invasion and angiogenesis pathways. In addition, curcumin possess a synergistic impact with chemotherapeutic agents. Herein, we summarized the current findings on curcumin as potential therapeutic agent in the treatment of GBM.

Background. Treatment of glioblastoma multiforme remains little effective due to the rapidly developing recurrence of the tumor, due to its high tumorigenic potential, resistance to chemoradiation therapy and increased dissemination of glioma stem cells (GSC). Molecular mechanisms of these cell interaction with extracellular matrix (ECM) are practically not studied. At present, it is also not clear the signaling of the ECM-receptor interaction (ECM-RI) differs for GSC and differentiated glioma cells (GDC).Objective: using high-resolution proteomic mass spectrometry to study the determinant expression of the ECM-receptor interaction signaling cascade in CD133+ GSC and CD133– GDC.Results. 1990 proteins are identified, 18 of which are associated with the ECM-RI process. Positive regulation of 14 ECM-RI proteins was found in CD133+ GSC compared with CD133– GDC, ten had more than 2 times increased expression. Increase in the CD133+ GSC level of 4 proteins activating the ECM-RI signaling cascade was noted.Conclusion. Important regularities are determined that could be used for the development of new approaches for detection of potential therapy targets of glioblastoma multiforme.

The Wnt-signaling pathway regulates various biological processes, such as embryonic development, self-renewal, proliferation, differentiation and migration of stem cells. The Wnt-signaling is involved in tumor progression by aberrant activation in stem-like cells, called cancer stem cells, in different kinds of tumor, including multiform glioblastoma. The Wnt-signaling promotes stemness, invasion, metastasis, therapeutic and immune resistance of cancer stem cells in multiform glioblastoma. To summarize, targeting the Wnt-signaling pathway as an oncogenic driver is the future hope for effective therapy of glioblastoma for which current standard therapy is not effective.In this review, we focused on functions of the Wnt-signaling in cancer stem cells and involvement of the Wnt-signaling pathway in gliomagenesis.

Background. Multiple myeloma (MM) is a hematologic malignancy of plasma cells. The microenvironment plays a key role in MM cell survival and drug resistance through release of soluble factors, expression of adhesion molecules and release of exosomes (EXs). The role that EXs, released by MM cells have in cell-to-cell communication and signaling in the bone marrow is currently unknown. EXs as a source of markers for MM diagnostics are also not studied.Objective: to use proteomic profiling of EXs as a tool to identify circulating tumor associated markers in MM patients.Results. The proteome composition of EXs obtained from plasma of patients with MM and multiple sclerosis was studied for the first time. nano-HPLC–MS/MS analysis identified a total of 332 proteins in the EXs of both groups of patients and determined the proximity of their qualitative composition. For the first time, 12 differentially expressed proteins were detected, the levels of which were significantly increased in EXs from patients with MM. This allowed us to consider them as potential markers of the disease.Conclusion. Proteomic analysis of EXs obtained from plasma of patients with MM is an important method for finding disease markers.

Background. The transforming growth factor beta 1 (TGF-β1) is one of the most important tissue factors secreted by the development of epithelial tumors. Increased expression of TGF-β1 in lung tumors promotes cancer cells survival enhancing their growth, migration, invasion, angiogenesis, immune system suppression.Objective: to study molecular mechanisms of TGF-β1 action on A549 human lung adenocarcinoma cells by means of proteomic high-resolution mass spectrometry. Results. Intracellular signaling pathways responsible for the involvement of TGF-β1 in the oncogenesis of non-small cell lung cancer have been found, which include the differential expressed proteins of the families of cullin, ETS oncogenes, histone diacelases, cyclin-dependent kinases, and the signaling pathway phosphatidylinositol 3-kinase (PI3K).Conclusions. Important patterns are determined that could be used for the development of new approaches for detection of lung cancer metastasis candidate markers and potential therapy targets of this decease.

Background. Increased expression of transforming growth factor beta-1 (TGF-β1) in malignant brain tumors promotes cancer cells survival enhancing their growth, migration, invasion, angiogenesis, immune system suppression.Objective is to study molecular mechanisms of TGF-β1 action on U87 human glioblastoma cells by means of proteomic high-resolution massspectrometry.Results. We have identified intracell signal pathways responsible for TGF-β1 involvement in malignant gliomas oncogenesis including differential expressed proteins of tight cell junctions, focal adhesion, histone deacetylases, heat shock, S100 family.Conclusions. Important patterns are determined that could be used for the development of new approaches for detection of glioblastoma metastasis candidate markers and potential therapy targets of this decease.

Glioblastoma multiforme, a World Health Organization grade IV malignant glioma, is the most common and lethal primary brain tumor with the median survival of approximately 15–25 months after treatment. Glioblastoma multiforme has been shown to be resistant to radiotherapy and chemotherapy and invariably recurs following surgical resection and chemoradiation. The characteristics of this tumor are exemplified by heterogeneous cell population with diverse biologic properties and genetic changes, the ability to form cancer stem cells (CSC) and divided into four molecular subtypes – proneural, neural, classical and mesenchymal. Despite some success, the mechanisms leading to the formation of the most malignant tumor subtype are unclear. The aim of this review was a synthesis of modern information about the role and biological characteristics of tumor stem cells in tumor progression and the pathogenesis of glioblastoma multiforme. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, adhesion, survival, resistance to standard cancer treatment and metastatic potential. The presence of aberrant signaling pathways (Notch, Hedgehog-Gli, Wnt/β-catenin, TGF-β/SMAD, PI3K/Akt/mTOR), both in the tumor and in the population of CSC, the dysregulation of microRNAs (miR-21, miR-128, miR-326, miR-34a), influence of epithelial-to-mesenchymal transition explains the availability of typical biological characteristics of the CSC. One needs to consider the influence of the therapy on normal stem cells in the development of drugs directed against the CSC. Regulatory mechanisms and markers found over the last decade can be used as the basis for creation of the new drugs with targeted action in the treatment of glioblastoma multiforme.

The proteome of ascites and pleural fluids (AF and PF) was mapped in patients with ovarian cancer (OC). 240 and 190 proteins were identi- fied with a high degree of assurance in A F and PF, respectively . The major portion w as extracellular and membrane proteins, whi ch ac- counted for 45 and 49 % in AF and PF, respectively. Analysis of the proteomic maps of AF and PF indicated that 82 proteins were common to these biological fluids whereas 81 and 49 proteins were unique to A F and PF, respectively. A list of 46 potential markers for O C metastasis and potential markers for tropic OC metastasis over the peritoneal (17 proteins) and pleural (11 proteins) surfaces is given.

The proteome of lysates of the breast tumor cell lines MCF-7, BT-474, and ZR-75-1 was mapped, resulting in the sequence of 340 proteins. The proteins associated with the biosynthesis of PGE2 and with the regulation of cyclooxygenase-2 expression were identified and their relative expression levels were determined. Potential goals for the targeted therapy of breast cancer, such as prostaglandin E2 and D2 receptors, pros- taglandin E synthase, 15-hydroxyprostaglandin dehydrogenase and leukotriene-A4 -hydrolase, are of special interest in this group.

Mass spectrometric mapping of proteomic lysate of a MCF-7 cancer cell line was carried out, which identified 153 proteins having molecular weights of 5000 to 630000 Da, a high proportion of which was cytoplasmic and nuclear proteins. The latter accounted for 60 % of their total number whereas the proportion of extracellular and membrane proteins constituted 13 %. After using some selection criteria to analyze the findings, the authors present a list of 31 potential biomarkers and describe 12 promising breast anticancer therapeutic targets.

At present, there is no screening test for the early detecting and monitoring of ovarian cancer, one of the most lethal form of gynaecological malig- nancy in the worldwide. In this study, the new methodology for the search of tumor markers of ovarian cancer, involving profiling the low-molec- ular blood plasma proteomes, is developed, unified and approved. The given approach included three basic components: pre-preparation of samples, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and bioinformatics software for mass spectral data process- ing. Opportunities and prospects of the developed approach for the detection of potential ovarian cancer markers were shown. For search of po- tential tumor markers, screening of 40 blood plasma samples from ovarian cancer patients and 48 control samples were carried out. As a result of the present research, peptides/polypeptides which can be used in future for detecting this pathology were found out.

Proteomics has recently found wide application to account for the molecular mechanisms of cancer and to search for biomarkers that may be used to diagnose and/or predict the development of the disease. The paper briefly reviews proteomic studies to detect ovarian cancer biomarkers, by taking into account different types of biological samples.

В результате многочисленных клинических наблюдений установлено, что инфекции грибково-бактериальной природы являются одним из наиболее часто встречающихся осложнений после иммуносупрессивной полихимиотерапии (ПХТ) у онкогематологических больных на фоне нейтропении. В клинической онкологии широко используется рекомбинантный человеческий гранулоцитарный колониестимулирующий фактор ( рчГ- КСФ - нейпоген, граноцит ) с целью лечения нейтропении . Способность рчГ- КСФ стимулировать пролиферацию , дифференцировку и активность НЛ вызывает интерес к его потенциальному применению при лечении инфекционных осложнений. Тем не менее недостаточно ясна роль рчГ- КСФ в биохимических механизмах изменения кислородзависимой антикандидозной и антимикробной активности НЛ онкогематологических больных. Целью настоящей работы явилось изучение действия рчГ - КСФ -терапии на НАДФН - и миелопероксидазозависимое образование АФК НЛ онкогематологических больных со смешанной грибково-бактериальной инфекцией . Суммируя полученные данные , необходимо отметить , что комплексная терапия (антигрибковая , антибактериальная и рчГ - КСФ ) приводила к нормализаци и показателей генераци и АФК покоящимися НЛ и стимулировал а МПО -зависимую антикандидозную и антимикробную активность НЛ. Таким образом, применение рчГ- КСФ в комплексной терапии больных с инфекцией грибково-бактериальной природы является целесообразным.

Онкологические больные подвержены высокому риску развития грибковых инфекций . Важнейшим фактором риска возникновения инвазивного кандидоза является продолжительная нейтропения, индуцированная цитостатиками. В этой связи особое внимание уделяется гранулоцитарному колониестимулирующему фактору (Г-КСФ), который стимулирует пролиферацию и дифференциацию нейтрофилов и усиливает их функциональную активность. Тем не менее, не достаточно изучено влияние Г-КСФ на антикандидозну ю активность нейтрофилов у онкологических больных.Цель исследования - Оценить влияние Г-КСФ на изменение кислородзависимой антикандидозной активности нейтрофилов у онкологических больных после цитостатической терапии.