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Vol 15, No 2 (2020)

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Open Access Open Access
Restricted Access Access granted
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Boris Vladimirovich Afanasyev passed away

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Genes & Cells. 2020;15(2):7-9
pages 7-9 views

Cell transplantation for COVID-19 treatment: transmission of stem stomal (mesenchimal) cells

Deev R.V.


The review presents the modern concept of the pathogenesis of diffuse alveolar damage, including acute respiratory distress sYndrome in coronavirus infection. It has been established that the so-called "cytokine storm”, which consists in the increased release of substances that are biologically active against the vascular wall and effector cells, leading to the progressive damage to endotheliocytes and alveolocytes, the development of alveolar and interstitial pulmonary edema with fatal respiratory failure and coagulopathy. An important factor in interstitial aggression is the appearance of autoreactive clones of plasma cells, dissemination of virusinfected leucocytes throughout the body with the involvement of various organs and systems, which exacerbates multiple organ failure. A poor prognosis for patients, the likelihood of developing pulmonary fibrosis after infection, according to several researchers, can be corrected by cell therapy. Allogeneic multipotent mesenchymal stromal cells (mesenchymal stem cells) are considered as first-line therapeutic cells. The accumulated experience of preclinical experiments made it possible to urgently proceed to conduct clinical trials of the safety of their use in patients with ARDS and to search for optimal indications to obtain maximum benefits for patients after transplantation. The combined efforts of many research groups can lead to reliable information on the cell therapy benefit and the need to include it in the standards of treatment of patients with this extremely severe pathology.
Genes & Cells. 2020;15(2):10-19
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Cilia and ciliopathy

Indeykin F.A., Mavlikeev M.O., Deev R.V.


Cilia (cilia) are organelles that are characteristic exclusively for eukaryotes and are found in protozoa, on somatic and germ cells of multicellular, as well as gametes of many plants. In humans, two main types of cilia are distinguished: motile and sensory; also in embryogenesis, it is customary to isolate special nodular cilia necessary for the normal course of gastrulation and possibly subsequent histo- and organogenesis. Motile cilia provide the movement of the liquid medium relative to the cell in the respiratory tract, the ventricular system of the brain and the fallopian tubes, or the movement of the cell itself in the case of sperm. The main function of sensory cilia is the perception of changes in the external environment and the signal molecules inside it and their conversion into intracellular signals that regulate proliferation, differentiation, and programmed cell death. Ciliopathies, a group of pathological conditions associated with impaired development, structure, and functioning of cilia, are of clinical interest. The most studied ciliopathies include polycystic kidney disease, nephronophysis, Barde-Beadle, Joubert, Mekel, Kartagener, Karoli etc. Clinical nephronophthisis and morphological analysis of the case of Caroli, syndrome is given.
Genes & Cells. 2020;15(2):20-32
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Epicardium as a new target for regenerative technologies in cardiology

Dergilev K.V., Komova A.V., Tsokolaeva Z.I., Beloglazova I.B., Parfyonova Y.V.


Epicardium is actively involved in the embryonic heart development and its repair after injury, which allows it to be considered as a potential target for the treatment of heart diseases. In this regard, the study of the mechanisms of its development, the components of the microenvironment, as well as the signals regulating the behavior of epicardial progenitor cells, is the most important area of modern cardiology. This review considers the results of recent studies of homeostasis of epicardial cells and technological advances to modulate their activity, which is essential for the development of new therapeutic agents.
Genes & Cells. 2020;15(2):33-40
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New therapeutic strategies for the treatment of metachromatic leukodystrophy

Shaimardanova A.A., Chulpanova D.S., Solovyeva V.V., Mullagulova A.I., Kitaeva K.V., Rizvanov A.A.


Metachromatic leukodystrophy is an autosomal recessive hereditary neurodegenerative disease belonging to the group of lysosomal storage diseases, which is characterized by the damage of the myelin sheath that covers most of the nerve fibers of the central and peripheral nervous systems. Metachromatic leukodystrophy caused by the deficiency of arylsulfatase A (ARSA) lysosomal enzyme (OMIM 250100) or sphingolipid activator protein B (SapB or saposin B) (OMIM 249900). Clinical manifestations of metachromatic leukodystrophy are progressive motor and cognitive impairment in patients. ARSA and SapB protein deficiency are caused by the mutations in the ARSA and PSAP genes, respectively. The severity of clinical signs in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. There is currently no effective treatment for this disease. Clinical cases of bone marrow or cord blood transplantation have been described, however, the therapeutic effectiveness of these methods remains insufficient to prevent aggravation of neurological disorders in patients. Encouraging results were obtained using gene therapy for delivering the wild-type ARSA gene using vectors based on various serotypes of adeno-associated viruses, as well as using mesenchymal stem cells and combined gene-cell therapy. This review discusses therapeutic strategies for the treatment of metachromatic leukodystrophy, as well as diagnostic methods for this disease.
Genes & Cells. 2020;15(2):41-50
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Clinical trials for the treatment of hereditary diseases by genome editing

Slesarenko Y.S., Lavrov A.V., Smirnikhina S.A.


New effective and easy-to-use genome editing tools open up the possibility of treating various diseases, including hereditary, oncological and infectious. The review provides information about clinical trials of developing therapies for monogenic diseases using genome editing systems such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). Clinical trials are carried out for six hereditary diseases: mucopolysaccharidosis types I and II, sickle cell anemia, β-thalassemia, hemophilia B, and Leber congenital amaurosis 10. Knowledge about safety and efficacy of genome editing are still limited and the long-term effects of such intervention have to be studied.
Genes & Cells. 2020;15(2):51-57
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Neuroglia in rat spinal cord contusion injury with cell-mediated delivery of a combination of VEGF165, GDNF, and NCAM1 genes in combination with epidural electrical stimulation

Fadeev F.O., Bashirov F.V., Izmajlov A.A., Sokolov M.E., Markosyan V.A., Garifulin R.R., Davleeva M.A., Pahalina I.A., Minyazeva I.S., Shevchenko R.V., CHelyshev Y.A., Islamov R.R.


Neural networks disturbed due to spinal cord injury are capable to restore that is largely determined by post-traumatic remodeling. It is known that information exchange between neurons is carried out by electrical impulse, which ensures the transmission of excitation in synapses, that is realized through neurotrophic factors according to the concept of neurotrophic interactions. Objective: to study the effect of a combination of epidural electrostimulation above and below the site of neurotrauma during training on the treadmill and intrathecal administration of human umbilical cord blood mononuclear cells, which simultaneously delivered three therapeutic genes encoding vascular endothelial growth factor (VEGF165), glial neurotrophic factor (GDNF) and neuronal cell adhesion molecule (NCAM1), to post-traumatic reorganization of neuroglia cells in a model of dosed concussion injury of rat spinal cord at the Th8-Th9 level. 30 days after the simulation of neurotrauma by the immunofluorescence method, a change in the number of macro- and microglia cells in the segment caudal from the damage epicenter was revealed. Electrostimulation did not affect the number of GFAP+-cells in the gray matter, but the combined effect of gene and electrotherapy restrained the increase in their number. Differences were found in the reactions of astrocytes in white and gray matter in response to electrical stimulation. In the zones of gray matter, the supporting effect of the combination of gene and electrotherapy on the number of Olig2+-cells was most clearly manifested. In this group of animals, the inhibition of the increase in the number of Iba1+-microglia cells in the gray matter can also be interpreted as a positive factor contributing to neuroregeneration.
Genes & Cells. 2020;15(2):58-65
pages 58-65 views

Regenerative histogenesis in a skeletal muscle defect with local implantation of gene-activated hydrogel based on hyaluronic acid in the experiment

Deev R.V., Bozo I.Y., Mavlikeev M.O., Bilyalov A.I., Titova A.A., Indeykin F.A., Babkova A.R., Presnyakov E.V., Yasinovsky M.I., Trofimov V.O., Baranov O.V., Odintsova I.A., Komlev V.S., Isaev A.A.


Optimization of the reparative regeneration of striated skeletal muscle tissue is actual for clinical practice. Volumetric muscle loss usually heals through the fibrous scar formation. Herein, there are numerous of methods under developed focused on reparative myogenesis induction. One of the promising approaches in this area is formed by gene-activated materials, particularly, in the hydrogel form. We developed a gene-activated hydrogel based on hyaluronic acid and plasmid DNA with the gene of vascular endothelial growth factor A (VEGF-A). Firstly, we showed a biocompatibility of the product in the subcutaneous test in mice. Using marker plasmid DNA carrying the luciferase gene, prolonged delivery of gene constructs to cells in vivo with a peak in transgene expression at day 7 was confirmed, while the same plasmid DNA in an aqueous solution provided a maximum level of delivery at day 1. Being implanted into a volumetric defect of the anterior tibial muscle in rats the gene-activated hydrogel activated angiogenesis in 2 weeks after surgery and induced MYH7B+-muscle fibers formation in the central zone of the defect at average number 50,0±16,1 and 21,8±10,5 in 2 and 4 weeks, respectively, whereas a hydrogel without plasmid DNA did not have any myogenic effects. Thus, plasmid DNA with VEGFA in the sodium alginate-based hydrogel induced angiogenesis in the volumetric muscle loss model and stimulated reparative myogenesis that could be used for further development of products effective for treatment of patients with muscle pathology.
Genes & Cells. 2020;15(2):66-72
pages 66-72 views

Investigation of genetic factors leading to cardiovascular diseases in persons with risk of sudden cardiac death

Kachnov V.A., Koliubaeva S.N., Tyrenko V.V., Nagibovich O.A., Chirsky V.S., Protasov O.V., Myakoshina L.A., Buntovskaya A.S., Trandina A.E., Koreshova E.I., Eliseeva M.I., Brazhnikova O.G., Sveklina T.S.


About 85% of all sudden death are of cardiological origin. Predisposition to sudden cardiac death is known for the young and adult patients with a hereditary heart disease that can cause sudden cardiac arrest. The purpose of the work was to study the genetic predisposition for cardiovascular diseases in people with a risk of sudden cardiac death. We examined patients aged 19,7±2,1 years with a risk of sudden cardiac death based on specific complaints and medical history, and considering the known markers of the life-threatening arrhythmias. Of the 1000 patients, 167 with a risk of sudden cardiac death were selected according to the questionnaire. In 80 randomly selected patients from this group, gene polymorphisms associated with the development of thrombophilia and hypertension were studied by real time PCR, and in 59 patients the polymorphisms of genes associated with impaired carbohydrate and lipid metabolism were studied. A number of differences were revealed according to the standard 12-channel electrocardiography in comparison with practically healthy individuals. In the study of genetic factors predisposing the development of thrombophilia, hypertension, type 2 diabetes mellitus, lipid metabolism disorders, a high percentage of hetero- and homozygous individuals was revealed by the risk allele of the PAI-1 (83.3%), ITGA2 (69.2%), AGT genes (72.5%), NOS3 (58.8%), PON1 (56%), LEPR (64.3%). The data obtained indicate a significant role of genetic factors in the development of sudden cardiac death, and the synergistic effect of genes, as a result of which the presence of a risk allele in one gene can enhance the expression of another gene.
Genes & Cells. 2020;15(2):73-80
pages 73-80 views

Association of TNF, MMP9, CYBA polymorphism with subclinical arterial wall changes and cardiovascular diseases risk factors

Akopyan A.A., Kirillova K.I., Strazhesko I.D., Samokhodskaya L.M., Leonov S.L., Gelfand E.M., Sorokina A.G., Orlova I.A.


Chronic inflammation and oxidative stress play key role in arterial wall changes and cardiovascular diseases. There is limited evidence on influence of genotypes, which are correlated with dironic inflammation and oxidative stress at arterial wall changes (pulse wave velocity, carotid artery intima-media thickness, endothelium-dependent vasodilation, presence of atherosclerotic plaques) and risk factors of cardiovascular diseases. We examined association of TNF-238G>A polymorphism, MMP9 -1562C>T polymorphism, CYBA c.214Т>С polymorphism with arterial wall changes and risk factors of cardiovascular diseases in 160 healthy people of different ages. GG genotype of TNF -238G>A polymorphism was associated with lower levels of aldosterone (p=0,021), higher levels of glycated haemoglobin (p=0,02) and insulin-like growth factor (p=0,032). СТ genotype of MMP9 -1562C>T polymorphism was associated with most commonly found obesity (p=0,05). CC and TC genotypes of CYBA c.214Т>С polymorphism were associated with shorter leucocyte telomere length (p=0,011). There wasn't found any association of TNF, MMP9, CYBA polymorphism with arterial wall changes. Association was found between TNF -238G>A polymorphism and MMP9 -1562C>T polymorphism with metabolic parameters, CYBA c.214Т>С polymorphism with leucocyte telomere length.
Genes & Cells. 2020;15(2):81-88
pages 81-88 views

Prognostic significance of tumour infiltrating lymphocytes in different molecular subtypes of invasive breast carcinoma

Tashireva L.A., Lyapunova L.S., Buzenkova A.V., Pankova O.V., Zavyalova M.V., Perelmuter V.M.


Metastasis is the main cause of death from cancer, including breast cancer, so the search for simple and effective prognostic parameters is becoming a priority for researchers. The number of tumor-infiltrating lymphocytes is a proven prognostic factor for triple negative and Her2-positive, but not luminal, molecular subtypes of breast cancer. Possible reasons for the failure of this prognostic parameter for luminal subtypes of breast cancer may be the tumor morphological heterogeneity. Objective: to assess the prognostic significance of the tumor-infiltrating lymphocytes number in the invasive breast carcinoma of a non-specific type (IC NST) of various molecular subtypes, taking into account its morphological heterogeneity. 152 patients with IC NST (T1-3N0-2M0) aged 29 to 75 years were enrolled in the study. The molecular subtype was determined using immunohistochemical analysis of the expression of estrogen and progesterone receptors, Ki-67 and Her2/neu. TILs were assessed in accordance with the recommendations of the International TILs Working Group. It was shown that TILs near the structures of various types is heterogeneous only in patients with the luminal Her2-negative subtype of IC NST. In addition, was found that the development of hematogenous metastases and worse metastatic-free survival in this cohort of patients is associated with a high TILs near solid structures and also depended on Ki-67 level. Thus, TILs near solid structures is a potential prognostic factor for the development of distant metastasis in the luminal Her2-negative and Ki-67 level less 20% subtype of IC NST.
Genes & Cells. 2020;15(2):89-95
pages 89-95 views

Cell-free DNA and IL-8 in follicular fluid of women within in vitro fertilization program

Andreeva E.A., Khonina N.A., Demchenko E.N., Gavrilova E.D., Ostanin A.A., Pasman N.M., Chernykh E.R.


The effectiveness of the in vitro fertilization (IVF) program does not exceed 40% and mostly depends on the oocytes quality, that is affected by the composition of the follicular fluid: a content of cytokines, growth factors, cell-free DNA (cfDNA), et al. Increased level of cfDNA in the follicular fluid is associated with indicators of ovarian reserve, as well as the effectiveness of stimulation in the IVF program. One possible reason for the high level of cfDNA can be considered an increase of IL-8 concentration. However, the role of IL-8 in regulation of reproductive processes is ambiguous and is presented in a few studies. In this connection, the aim of the study was to investigate a content of cfDNA and IL-8 in the follicular fluid of women, as well as the relationship between them, depending on the parameters of folliculo- and oogenesis, early embryogenesis and IVF outcomes. 62 women with infertility and undergoing IVF treatment have been enrolled in the study. We collected follicular fluid samples from dominant follicles using transvaginal ultrasound aspiration. The concentration of IL-8 in the follicular fluid was evaluated by flow fluorimetry. Measurement of cfDNA in the follicular fluid was performed by fluorimetric method. A negative correlation between IL-8 level in the follicular fluid and the number of received oocytes, as well as the quality of embryos was revealed. At the same time, a higher level of cfDNA was recorded in women with low blastocyst quality and non-developing pregnancy. Correlation analysis showed the absence of a significant direct relationship between IL-8 and cfDNA in the whole group. Moreover, in subgroups characterized by a higher IL-8 level, we found a weak negative correlation between cfDNA and IL-8 concentrations. The results suggest that enlarged level of cfDNA in the follicular fluid is not a consequence of IL-8 increase; the levels of IL-8 and cfDNA in the follicular fluid are two independent factors with multidirectional effects involved in various stages of reproductive process.
Genes & Cells. 2020;15(2):96-100
pages 96-100 views

Poor oocyte quality as a cause of embryo fragmentation in IVF program: clinical case report

Maysina E.N., Salimov D.F., Lisovskaya T.V.


High degree of embryo fragmentation correlates with absence of implantation in IVF programs. The aim of the work was to determine the most probable cause of embryo fragmentation and ineffective in vitro fertilization (IVF) program on the example of a specific clinical situation and based on the analysis of literature data. In contrast to the common form of infertility, associated with the absence of ovulation and constituting 35-40% in the structure of infertility factors, , this clinical situation is unusual due to the fact that pregnancy as a result of repeated IVF programs did not occur due to the production of fragmented embryos with a preserved ovarian reserve and the exclusion of other infertility factors. The successful solution of reproductive problems in this couple is obviously associated with the use of the oocyte donation program.
Genes & Cells. 2020;15(2):101-103
pages 101-103 views

Regulatory considirations for cellular products development: how to accelerate the marketing authorisation in Russia and EAEU

Niyazov R.R., Deev R.V., Dranitsyna M.A., Yasniy I.E., Gavrishina E.V., Vasiliev A.N.


The environment for the development of products containing live cells as an active substance is being set up in Russia for several years. However, the acceptable regulatory framework, which would have allowed to develop and place cell therapy products on the market, complying with international requirements for safety, efficacy, and quality, has not been yet established. Moreover, in addition to the national legal framework, the Eurasian Economic Union regulatory model has emerged that introduces in parallel a more straightforward pathway for the development and clinical use of this important medical product category. In this paper we address the domestic and Eurasian regulatory systems for products containing live cells as an active ingredient and suggest certain possible approaches to support this area of biotechnology.
Genes & Cells. 2020;15(2):104-110
pages 104-110 views

Instructions for authors

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Genes & Cells. 2020;15(2):111-113
pages 111-113 views

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