Changes in Oncogene Expression in Experimental Glioblastoma 101.8 Rats during Therapy with PLGA Nanoparticles Loaded with Doxorubicin.

We compared the expression of the main glioblastoma oncogenes during therapy with doxorubicin (Dox) and Dox in nanoparticles based on a copolymer of lactic and glycolic acids (Dox-PLGA) at a delayed start of treatment. Late initiation of Dox-PLGA therapy of glioblastoma showed an increase in the expression of multiple drug resistance genes, such as Abcb1b and Mgmt, and a decrease in Sox2 expression. Increased expression of other oncogenes (Melk, Wnt3, Gdnf, and Pdgfra) were observed during both Dox and Dox-PLGA therapy. These changes indicate increased tumor aggressiveness and its resistance to cytostatics at the late start of therapy.

[Extracellular vesicles for diagnosis and therapy of gliomas: problems and opportunities]. / Vnekletochnye vezikuly v diagnostike i terapii gliom: problemy i perspektivy.

Glioblastoma is a primary brain tumor and one of the most aggressive malignant neoplasms. The prognosis remains poor with a short survival period after diagnosis even in the case of timely detection and early treatment with the use of advanced chemotherapy, radiation therapy and surgical treatment. In this regard, the research of the main pathogenetic links in the glioblastoma development continues. The current focus is on studying the molecular characteristics of tumours, including the analysis of extracellular vesicles, which play an essential role in intercellular communication processes. In this review, in order to provide up-to-date information on the role of extracellular vesicles in the diagnosis and therapy of gliomas, the analysis of the achieved results of Russian and foreign research related to this area has been carried out. The main goal of this review is to describe the features of extracellular vesicles as the containers and glioma marker transporters, as well as nucleic acids used in diagnosis and therapy.

[Principles of biobanking and biobanks of central nervous system tumors in world practice]. / Printsipy biobankirovaniya i biobanki opukholei nervnoi sistemy v mirovoi praktike.

Biobanks of central nervous system tumors are created in parallel with development of modern technologies for evaluation of molecular features of human diseases. In modern world practice, no one doubts that creation of biobanks of tumors is necessary and critical for personalized medicine. An important aspect of recent improvements in biobanks has been the expansion of tumor sample storage conditions. Development of cell technologies has made it possible to create cell cultures from tumor material that made it possible to evaluate further therapy before affecting the patient himself. Biobanks have become especially attractive in the study of brain tumors, where the peculiarity of location and blood-brain barrier complicate treatment approaches. This review describes the approaches to creation of biobanks of CNS tumors in world practice, sample storage conditions, ethical and legal regulation of biobanks, as well as experience of biobanking in different countries.

[Molecular markers of neuro-oncogenesis in patients with glioblastoma]. / Molekulyarnye markery neiroonkogeneza pri glioblastome golovnogo mozga.

The problem of current treatment approaches to brain gliomas is short-term life expectancy in these patients. Apparently, it is required to change treatment approach via analysis of glioma stem cells rather cells with overexpression of marker genes. This review is devoted to similarities and differences between neurogenesis and neuro-oncogenesis characterized with molecular markers (CD133 as an example). The role of tumor stem cells and their relationship with neural stem cells are considered regarding development of glioma. The authors analyzed CD133 as a marker of glioma stem cells. In the future, stem cells will be important target for eradication during target therapy. A single molecular marker cannot characterize tumor stem cells as supported by CD133 studies. A set of molecular markers specific for certain cell type is required, and their combination will provide more accurate establishment of tumor stem cells.

[Cell cultures of human CNS tumors as in vitro model for individualized therapeutic approach]. / Kletochnye kul'tury opukholei TsNS cheloveka kak in vitro model' dlya individual'nogo podkhoda k terapii.

Tumor cell lines and cultures are widely used in biomedical research. They are excellent model systems for analysis of oncological mechanisms and understanding the biology of tumor cells. Cell cultures are used to develop and test new anticancer drugs, radiosensitizers and radiotherapy methods. Clinical application of tumor cell cultures is directly related to development of personalized medicine. Using tumor cell culture in a particular patient, physicians can select treatment considering molecular genetic characteristics of patient and tumor. In addition, it is possible to choose the optimal drug or radiotherapy regimen with obvious effectiveness in certain cell culture. This review describes the advantages of such an approach.

[Protein CD133 as a tumor stem cell marker]. / Belok CD133 kak marker opukholevykh stvolovykh kletok.

The CD133 protein is a large transmembrane glycoprotein. Despite multiple studies, the role of CD133 protein in cells is still poorly understood. Nevertheless, there is an association of CD133 protein with neoplastic transformation. This review summarizes data on CD133 protein, its structure, regulation of expression, molecular interactions and representation in cells that have undergone malignant transformation. Available data suggest that CD133 may have a great potential for predicting survival in various solid tumors. This protein can also be a marker of glioma.

[The role of glial cell line-derived neurotrophic factor isoforms in human glial tumors]. / Rol' izoform neirotroficheskogo faktora glial'noi kletochnoi linii (GDNF) v glial'nykh opukholyakh cheloveka.

Glial cell line-derived neurotrophic factor (GDNF) has a wide range of actions and positively affects viability, proliferative activity and migratory ability of cells in nervous system. That is why GDNF is being considered as a therapeutic molecule in the treatment of neurodegenerative diseases, in particular Parkinson's disease. However, GDNF has the same effect on high-grade glioma cells promoting their growth, resistance to therapy and dissemination. Expression of this factor in tissues and cultures of gliomas is up to five times higher than in intact brain matter. It was revealed that epigenetic modifications in GDNF gene promoter contribute to overexpression. Target suppression of GDNF gene transcription slows down growth of glioma and decreases cell migration. This review is devoted to the effect of GDNF on glioma cells, causes and consequences of its overexpression. Further analysis of expression and function of various GDNF isoforms in glial tumors may be valuable to develop new treatment methods for these dangerous diseases.

[Multimodal method of tissue differentiation in neurooncology using Raman spectroscopy, fluorescence and diffuse reflectance spectroscopy]. / Mul'timodal'nyi metod differentsiatsii tkanei v neiroonkologii s ispol'zovaniem spektroskopii kombinatsionnogo rasseyaniya, fluorestsentsii i diffuznogo otrazheniya.

BACKGROUND: There is a need to expand the possibilities of urgent analysis of intracranial tumor type during resection. These measures are necessary to improve resection quality with preservation of intact tissues and avoiding recurrence and neurological impairment in postoperative period. OBJECTIVE: To create optical-spectral method for differentiating the intracranial tumor types. MATERIAL AND METHODS: We used a combination of certain methods such as fluorescence spectroscopy to analyze the content of endogenous and exogenous fluorophores in samples, diffuse reflectance spectroscopy to analyze structural integrity of tissues according to light scattering and blood filling according to hemoglobin spectrum absorption, as well as spontaneous Raman spectroscopy detecting individual molecular components of tissues. The study was conducted at the Laboratory of Neurosurgical Anatomy and Conservation of Biological Materials of the Burdenko Neurosurgical Center and included 93 tissue samples from 60 patients diagnosed with glioblastoma (n=28), meningioma (n=12), astrocytoma (n=9), oligodendroglioma (n=5), and metastasis (n=6). RESULTS: Different types of intracranial tumors that cannot be differentiated using one of the considered spectroscopy modes can be distinguished in another one. Thus, we can conclude possible advantages of combined optical-spectral approach.

[Cell cultures in assessing radioresistance of glioblastomas]. / Ispol'zovanie kletochnykh kul'tur dlya otsenki radiorezistentnosti glioblastom.

To date, no modern methods of treatment allow overcoming malignant potential of glial neoplasms and significant increase of survival. Analysis of glioblastoma radioresistance using cancer cell cultures is one of the perspective directions, as radiotherapy is standard and available treatment method for these neoplasms. This review summarizes current studies identifying many factors of radioresistance of glial tumors, such as hypoxia, microenvironment and metabolic features of tumor, stem cells, internal heterogeneity of tumor, microRNA, features of cell cycle, DNA damage and reparation. We obtained data on involvement of various molecular pathways in development of radioresistance such as MEK/ERK, c-MYC, PI3K/Akt, PTEN, Wnt, JAK/STAT, Notch, etc. Changes in activity of RAD51 APC, FZD1, LEF1, TCF4, WISP1, p53 and many others are determined in radioresistant cells. Further study of radioresistance pathways will allow development of specific target aptamers and inhibitors.

Computer-aided Evaluation of Polyvalent Medications' Pharmacological Potential. Multiphytoadaptogen as a Case Study.

Many human diseases including cancer, degenerative and autoimmune disorders, diabetes and others are multifactorial. Pharmaceutical agents acting on a single target do not provide their efficient curation. Multitargeted drugs exhibiting pleiotropic pharmacological effects have certain advantages due to the normalization of the complex pathological processes of different etiology. Extracts of medicinal plants (EMP) containing multiple phytocomponents are widely used in traditional medicines for multifactorial disorders' treatment. Experimental studies of pharmacological potential for multicomponent compositions are quite expensive and time-consuming. In silico evaluation of EMP the pharmacological potential may provide the basis for selecting the most promising directions of testing and for identifying potential additive/synergistic effects. Multiphytoadaptogen (MPhA) containing 70 major phytocomponents of different chemical classes from 40 medicinal plant extracts has been studied in vitro, in vivo and in clinical researches. Antiproliferative and anti-tumor activities have been shown against some tumors as well as evidence-based therapeutic effects against age-related pathologies. In addition, the neuroprotective, antioxidant, antimutagenic, radioprotective, and immunomodulatory effects of MPhA were confirmed. Analysis of the PASS profiles of the biological activity of MPhA phytocomponents showed that most of the predicted anti-tumor and anti-metastatic effects were consistent with the results of laboratory and clinical studies. Antimutagenic, immunomodulatory, radioprotective, neuroprotective and anti-Parkinsonian effects were also predicted for most of the phytocomponents. Effects associated with positive effects on the male and female reproductive systems have been identified too. Thus, PASS and PharmaExpert can be used to evaluate the pharmacological potential of complex pharmaceutical compositions containing natural products.

[Nitric oxide donor nitrosorbide potentiates the antitumor effect of doxorubicin against experimental glioblastoma]. / Donor oksida azota izosorbida dinitrat povyshaet protivoopukholevyi effekt doksorubitsina pri khimioterapii eksperimental'noi glioblastomy.

BACKGROUND: Doxorubicin is a well-known antitumor drug that is not employed for chemotherapy of brain tumors. Indeed, doxorubicin does not penetrate across the blood-brain barrier in therapeutic concentrations. OBJECTIVE: To study the antitumor effect of doxorubicin combined with nitrosorbide on intracranial experimental glioblastoma 101/8 in rats. MATERIAL AND METHODS: Male Wistar rats (n=86) with intracranial implanted glioblastoma 101/8 received doxorubicin (i.v. 1.5 mg/kg thrice) alone or in combination with nitrosorbide (i.v or orally, 0.5 mg/kg thrice) in 2, 5 and 8 days after implantation. Efficacy was assessed considering survival and brain tumor volume in 14 days after tumor implantation. RESULTS: Combination of doxorubicin and nitrosorbide significantly increased survival (57% and 155%, respectively) and slowed down tumor growth (16±12 and 8±6 mm3, respectively) compared to doxorubicin alone. Effectiveness of nitrosorbide alone was trivial. CONCLUSION: Nitric oxide donor nitrosorbide considerably potentiated the antitumor effect of doxorubicin against intracranial 101/8 glioblastoma in rats.

[Risk of Multiple Sclerosis: Analysis of Interactions Between Variants of Nuclear and Mitochondrial Genomes].

There is increasing evidence that the interaction of the mitochondrial and nuclear genomes substantially affects the risk of neurodegenerative diseases. The role of mitonuclear interactions in the development of multiple sclerosis, a severe chronic neurodegenerative disease of a polygenic nature, is poorly understood. In this work, we analyzed the association of multiple sclerosis with two-component mitonuclear combinations that include each of seven polymorphic variants of the nuclear genome localized in the region of the UCP2, and KIF1B genes and in the PVT1 locus (MYC, PVT1, and MIR1208 genes) and each often polymorphisms of the mitochondrial genome, as well as individual genetic variants that make up these combinations. Association of the individual components of these combinations with multiple sclerosis was also evaluated. 507 patients with multiple sclerosis and 321 healthy individuals were enrolled in the study, all participants were ethnic Russians. Two mitonuclear combinations associated with multiple sclerosis were identified: the UCP2 (rs660339)*A + MT-ATP6 (rs193303045)*G combination was characterized by p-value = 0.015 and OR= 1.39 [95% CI 1.05-1.87], and the PVT1 (rs2114358)*G + MT-ND1 (rs1599988)*С combination - by p-value = 0.012 and OR = 1.77 [95% CI 1.10-2.84]. Only one of the individual components of these combinations, allele rs660339*A of the nuclear gene UCP2 encoding uncoupling protein 2 of the mitochondrial anion carrier family, was independently associated with multiple sclerosis (p = 0.028; OR = 1.36 [95% CI 1.01-1.84]). This study expands the current understanding of the role of mitonuclear interactions and variance of nuclear genes, whose products function in mitochondria, and in risk of MS.

The effect of biodegradable silk fibroin-based scaffolds containing glial cell line-derived neurotrophic factor (GDNF) on the corneal regeneration process.

Corneal injury due to ocular trauma or infection is one of the most challenging vision impairing pathologies. The aim of the work was to study the effect of biodegradable silk fibroin-based scaffolds containing GDNF on the corneal regeneration process. During cultivate the highest keratocytes proliferative activity was registered with scaffolds containing 250 ng/ml and 500 ng/ml GDNF. In mice with an experimental model of epithelial-stromal damage to the cornea, silk fibroin-based scaffolds containing GDNF in various concentrations were used (in groups 1, 2 and 3 silk fibroin-based scaffolds containing GDNF in a concentration of 50 ng/ml, 250 ng/ml and 500 ng/ml, respectively; in group 4 - silk fibroin-based scaffolds without GDNF; in group 5 - a solution of GDNF with concentration of 500 ng/ml; group 6- control). The area of the corneal epithelial defect in groups 2, 3, and 5 was less than in the other groups. The most pronounced positive immunohistochemical reaction with antibodies to Bcl2, Bax, phosphoERK1/2 and phospho-JNK1/2, Ki67, Gap43 was observed in groups 2 and 3. Thus, silk fibroin-based scaffolds with GDNF stimulate the epithelialization process, proliferative activity of epithelial cells and keratocytes, accelerate the formation of the stromal nerve plexus and exhibit anti-apoptotic activity.

[Intraosseous metastasis of K27-mutant glioma]. / Vnutrikostnoe metastazirovanie K27-mutantnoi gliomy.

Glioma metastasis outside the central nervous system is a quite rare phenomenon. The disease in a young woman manifested itself as back pain and loss of vision in the left eye. Magnetic resonance imaging (MRI) revealed a tumor of the optic nerve; positron emission tomography showed multiple secondary bone changes. At the same time, MRI detected no signs of neoplasm in the midline brain structures (the brain stem and subcortical nuclei) and spinal cord. Two biopsies (superior iliac spine trephine biopsy and optic nerve tumor biopsy) were performed. There were similar histological tumors; the optic nerve tumor was found to have K27M mutation in the H3F3A gene, whereas the metastatic tumor lacked this mutation (possibly due to the quality and quantity of DNA isolated from the tumor cells). The interesting features of this case are the simultaneous detection of primary and metastatic tumors before receiving any treatment and the absence of the K27M mutation in the H3F3A gene in the metastasis.

[Theranostics for glioblastoma with monoclonal antibodies to the epidermal growth factor receptor]. / Perspektivy teranostiki glioblastomy s pomoshch'yu monoklonal'nykh antitel k retseptoru epidermal'nogo faktora rosta EGFR.

A review is devoted to analysis of the prospects of theranostics for multiform glioblastoma with monoclonal antibodies to the epidermal growth factor receptor (EGFR). Treatment of various malignancies demonstrated high potential of the use of EGFR. However, in case of glioblastoma, the effectiveness of monoclonal antibodies to EGFR is constrained by the absence of informative criteria for assessing the effectiveness of diagnosis and treatment of disease.

[Secondary prevention of chronic tonsillitis exacerbations by bacteriophage medications]. / Vtorichnaia profilaktika obostrenii khronicheskogo tonzillita bakteriofagal'nymi sredstvami.

Chronic tonsillitis is one of the most common diseases to modern people, which treatment requires a preventative care course approach. The general purpose of the present research could be framed as follows: to estimate clinical efficiency of bacteriophage medications, in the case of 'Ostophag' mixture for preventative care. Study population consisted eighty people. Participants were divided into two groups (forty patients in each) both diagnosed compensated and decompensated forms of chronic tonsillitis with pathogenic microflora in the lacunae of the palatine tonsils. In the first group we built monotherapy on bacteriophage medications use, whereas in the second one monotherapy was founded on antiseptic implication. The results of the present investigation showed high efficiency of bacteriophage medications a means of chronic tonsillitis salvage care.

Advances in the Application of Modified Nucleotides in SELEX Technology.

Aptamers are widely used as molecular recognition elements for detecting and blocking functional biological molecules. Since the common "alphabet" of DNA and RNA consists of only four letters, the chemical diversity of aptamers is less than the diversity of protein recognition elements built of 20 amino acids. Chemical modification of nucleotides enlarges the potential of DNA/RNA aptamers. This review describes the latest achievements in a variety of approaches to aptamers selection with an extended genetic alphabet.

[Organization of the quality control service for the forensic medical expert activity at the Saint-Petersburg state budgetary healthcare facility 'Bureau of Forensic Medical Expertise']. / Organizatsiia sluzhby kachestva sudebno-meditsinskoi ékspertnoi deiatel'nosti v SPb GBUZ 'Biuro sudebno-meditsinskoi ékspertizy'.

The Saint-Petersburg Bureau of Forensic Medical Expertise has created the universal system of the internal quality control oriented toward the more rational exploitation of the available resources, material and technical facilities, and systemic management of the quality of forensic medical activities. The system serves as a basis for the timely identification of undesirable problematic situations, efficiently predict and/or prevent them and the resulting deterioration of the quality of expert work leading to the inadequate provision of finance and resources. Moreover, the system makes it possible to optimize and correct the operational management of the Bureau activities and develop programs for successful carrying them out in the future. The results of the evaluation of all forms of control are used to work out the modern technologies for the management of forensic medical expertise activities together with the final concluding reports and analytical reviews of the positive experience and of the typical imperfections in forensic medical expertise operations are distributed among the structural departments of the Bureau. These materials are used as a basis for the development of the measures and recommendations for the improvement of forensic medical expert activities of the Bureau, compilation of analytical reviews, specification of the criteria for the effectiveness of the forensic medical expertise, improvement of the procedures for the specialist screening studies (in conformity with the internal standards adopted by the Bureau), the subject matter and the schedule of advanced expert training, contents and procedures of instructions, the systems of delegation of authorities and empowerment with responsibilities, provision of economic incentives for the staff members, etc.

FACTORS GOVERNING THE PATTERN OF SPINDLE MICROTUBULE REGROWTH AFTER TUBULIN DEPOLYMERIZATION.

We analyzed the pattern of spindle microtubule (MT) regrowth after cold- or colcemid-induced MT depolymerization in Drosophila S2 cells. Cold-induced MT disassembly at low temperature (­2 °C) destroyed kinetochore-driven MT regrowth without affecting astral MT formation. Conversely, colcemid-induced MT depolymerization strongly impaired centrosome-dependent MT nucleation, allowing kinetochore-driven MT regrowth. Collectively, these results indicate that the kinetochore- and the centrosome-mediated MT assembly pathways exploit molecular mechanisms that are at least in part different.

NEUROGENIC NICHE OF THE ADULT MAMMALIAN BRAIN.

At the moment, the main location of the regional areas of neural stem cells in the adult brain is considered to be subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampal formation. However, the neural stem cells are not located chaotic in these areas, and they are localized in special niches ­ structural microenvironment that enables them to maintain identity, affect its proliferation and the fate of her descendants. The components of this microenvironment are intercellular interactions, the relationship with the blood vessels, extracellular matrix and specialized areas of basement membrane. The article describes of the neurogenic niches and the mechanisms controlling cell division and differentiation of progenitor cells.