Auditory neuropathy spectrum disorder (ANSD) is a specific auditory disorder caused by dysfunction of periphery part of the auditory system, in which the function of the outer hair cells is preserved, but the afferent input at the cochlear level suffers due to the pathology of the inner hair cells, neurons of the spiral ganglion and/or the auditory nerve, as well as synaptic contact between them. As a result, a specific condition is formed, in which a patient's otoacoustic emissions and/or cochlear microphonics are present, auditory brainstem responses are abnormal or absent, the discrepancy between the hearing level and the electrophysiological data, poor speech perception which may not correlate with the hearing thresholds. ANSD is a multifactorial disease. One of the main risk factors is perinatal pathology and, in particular, prematurity. The possible factors associated with prematurity that provoke the onset of the disease, features of the pathogenesis, clinical and audiological peculiarities of ANSD in premature infants, contemporary approaches to the habilitation of such patients are discussed in the article. The necessity of an individual, patient-oriented approach to the treatment of premature infants with ANSD is substantiated; such an approach should be based both on the genesis of the disorder, taking into account possible points of lesion in the auditory system, and the developmental peculiarities of a premature baby considering the presence of concomitant diseases associated with prematurity. In the article attention is focused on the main directions of habilitation work with such children, including a multidisciplinary approach, regular careful monitoring of the auditory, speech and language skills, intensive psychological and speech therapist support, the choice of an adequate way of intervention and its improvement as necessary.

To develop and evaluate the results of the modified surgical technique for transplantation of retinal pigment epithelium (RPE) differentiated from human induced pluripotent stem cells (iPSC-RPE) in the form of a cell suspension into the subretinal space of rabbits with previously induced RPE atrophy.

The understanding of the engrafted cell behaviors such as the survival, growth and distribution is the prerequisite to optimize cell therapy, and a multimodal imaging at both anatomical and molecular levels is designed to achieve this goal. We constructed a lentiviral vector carrying genes of ferritin heavy chain 1 (FTH1), near-infrared fluorescent protein (iRFP) and enhanced green fluorescent protein (egfp), and established the induced pluripotent stem cells (iPSCs) culture stably expressing these three reporter genes. These iPSCs showed green and near-infrared fluorescence as well as the iron uptake capacity in vitro. After transplanted the labeled iPSCs into the rat brain, the engrafted cells could be in vivo imaged using magnetic resonance imaging (MRI) and near-infrared fluorescent imaging (NIF) up to 60 days at the anatomical level. Moreover, these cells could be detected using EGFP immunostaining and Prussian blue stain at the cellular level. The developed approach provides a novel tool to study behaviors of the transplanted cells in a multi-modal way, which will be valuable for the effectiveness and safety evaluation of cell therapy.

Siglec-15 is an immune suppressor with broad upregulation on various cancer types and has emerged as a potential target for cancer immunotherapy. However, it remains unclear how SIGLEC15 expression is controlled in normal or cancer cells. In this work, we utilized reporter assays to evaluate the impact of the 5' UTR and the 3' UTR of SIGLEC15 mRNA on gene expression. We found that the 3' UTR dramatically reduced reporter protein production, whereas the 5' UTR showed modest inhibitory effect. Quantification of steady-state mRNA revealed the good coupling of protein amount and mRNA abundance that was associated with the 3' UTR. In contrast, the 5' UTR had little effect on mRNA abundance compared with the empty control. By measuring mRNA half-life, we showed that the 3' UTR markedly promoted mRNA degradation. Testing shortened 3' UTR fragments demonstrated five out of the six having notable inhibitory effect, with the one spanning 993-1317 had the most robust activity. More interestingly, the 993-1317 region contains a predicted 43-nt stem-loop structure that showed apparent inhibitory activity in four cell lines tested. These results suggested that the 3' UTR inhibited reporter gene expression by accelerating mRNA decay possibly via multiple cis-regulatory elements, but the 5' UTR repressed gene expression by inhibiting translation. Thus, our findings provided a clue to the molecular mechanism underlying the regulation of SIGLEC15 expression.

The article presents the main molecular mechanisms of the pathogenesis of renal cell carcinoma. The molecular pathways that determine the development of histological variants of renal cell carcinoma and the role of stem cells markers in the carcinogenesis of these tumors are considered.

The aim of the work is to attract the attention of specialists: dentists, oncologists, hematologists to thorough sanitation of the oral cavity of patients preparing for chemotherapy treatment, to transplantation of hematopoietic stem cells. Two clinical cases described in the article were observed at the R.M. Gorbacheva First Saint-Petersburg State Medical University from 2010 to 2019. They confirm the possibility of the occurrence of infectious complications with damage to the maxillofacial region caused by rare pathogens of invasive mycosis, which debuted as an odontogenic inflammatory process. The success of the treatment of Invasive Mycosis depends on early diagnosis and antimycotic therapy; active surgical tactics in relation to the affected tissues in a controlled course of the underlying disease and the restoration of effective hematopoiesis.

Infection caused by cytomegalovirus (CMV) is a serious problem for patients with weakened immunity, including patients with hematopoietic depression. The cases of complications associated with cytomegalovirus require antiviral therapy. However, during the natural mutation process, especially with prolonged use of drugs in suboptimal doses, CMV strains resistant to the action of antiviral drugs (such as ganciclovir, valganciclovir) may occur. Hypothetically, the emergence of resistance in the virus may cause a more aggressive course of infection, the ineffectiveness of antiviral therapy and, as a result, an increase in the number of deaths. In this regard, timely detection of mutations that can potentially lead to the resistance of the virus to antiviral drugs during hematopoietic stem cell transplantation (HSCT), as well as during organ and tissue transplantation, may be important when making a therapeutic decision. We describe three clinical cases for which the dynamics of the appearance of a mutant strain of CMV by the UL97 gene, which correlates with the viral load and clinical picture, is analyzed.The aim of the study was to determine the timing of the occurrence of mutations in CMV phosphotransferase UL97 gene associated with resistance to antiviral drugs in patients with hemoblastoses after allogeneic hematopoietic stem cell (allo-HSCs) transplantation.

The issue of auditory neuropathy spectrum disorders (ANSD) has been in a focus of specialists attention for a relatively short time, but during this time a huge amount of scientific and practical knowledge about this hearing disorder has been accumulated. ANSD is a specific auditory deficit caused by dysfunction of periphery part of the auditory system, which may affect the inner hair cells, the spiral ganglion neurons and the auditory nerve, as well as the area of synaptic contact between them, while the outer hair cells, as a rule, remain intact. As a result, a specific condition is formed, in which a patient's otoacoustic emissions and/or cochlear microphonics are present, auditory brainstem responses are abnormal or absent, electrophysiological data may not correlate with hearing level, the discrepancy between pure tone audiometry and speech discrimination is observed. ANSD prevalence, epidemiology, contemporary views on its etiology, including detailed information on hereditary forms of the disorder and its risk factors are considered in the review. The data on the basic rungs of the ANSD pathogenesis, which underlie the development of various forms of the disorder and mainly determine the rehabilitation approach, are presented. The detailed clinical and audiological characteristics of ANSD are presented; contemporary approach to ANSD diagnosis and rehabilitation, including indications for surgical treatment, are considered.

The novel molecular subtype of breast cancer (BC), named "claudin-low", was described in 2007. It was characterized by the consistently low expression of genes involved in the formation of epithelial tight junctions in combination with the high activation of genes associated with the epithelial-to-mesenchymal transition, as well as tumor stem cell markers. The similar claudin- low subtype was later identified at the transcriptional level in bladder cancer, gastric cancer, and serous ovarian cancer. However, only in relation to BC, attempts were made to create a surrogate panel for immunohistochemical identification of this subtype in a manner like the intrinsic molecular BC subtypes identified using three main markers, such as ER, PR, and HER-2. At the same time, the ambiguity in the expression of claudins among the subtypes of BC, which is defined by various authors at the immunohistochemical level, as well as the absence of both the confirmed set of immunohistochemical criteria and a unified approach to their assessment, complicate these efforts. The purpose of the review is to show that the immunohistochemical identification of claudin-low subtype of BC is a separate problem that has significant limitations, needs standardization and has not yet reached diagnostic value.

To evaluate effectiveness and safety of umbilical cord blood cells (UCBC) in children with ASD.

 Nowadays stem cells of adult type are attractive in case of active development of cell and genome technologies. They are the target of new therapeutic approaches, which are based on correction of mutations or replenishment of organs, that were damaged by autoimmune reactions, aging or other pathological processes. Also stem cells, including patient-specific (induced Pluripotent Stem Cells, iPSCs), and obtained by differentiation from them tissue cultures and organoids are the closest models to in vivo researches on humans, which gives an opportunity to get more relevant data while testing different therapeutic approaches and pharmacological drugs. The main molecular pathways, that are essential for homeostasis of a cortex of a adrenal gland - compound, structurally and functionally heterogeneous organ, is described the presented review. The adrenal cortex is renewing during the organism's ontogenesis at the expense of the pool of stem and progenitors cells, which are in tight junctions with differentiated steroidogenic cells and which are under constant control of endocrine and paracrine signals. The understanding of signaling pathways and interactions of different cell types will give an opportunity to develop the most suitable protocols for obtaining cells of adrenal gland cortex in a different stages of differentiation to use them in scientific and medical purposes.

The article present a case report of orbital granulomatous inflammation after a retrobulbar injection of allogenous stem cells. Experimental treatment resulted in an orbital tumor that required surgical excision. Lymphogranulomatous inflammation with a secondary abscess was verified by morphological and immunohistochemical analyses. This case demonstrates the possible dangerous complications of the "off-label" therapy amid the rising popularity of stem cells treatment.

Homeodomain transcription factors play a significant role in mesenchymal stromal cells (MSCs). Previously, the role of Meis1, Pbx1 and Prep1 proteins from the TALE (Three Amino acid Loop Extension) family in adipocytic and osteogenic differentiation of mouse mesenchymal stromal cells was established. In this work, using ChIP-seq and bioinformatic analysis we investigated the binding pattern of PREP1 with the genomic DNA of human heart MSCs, identified nearby genes, and analyzed their ontology. The target genes of the PREP1 factor in cardiac MSCs have been established. Based on the results, the possible involvement of transcription factor PREP1 in the direct reprogramming of fibroblasts into cardiomyocytes is discussed.

Direct reprogramming technology allows several specific types of cells, including specialized neurons, to be obtained from readily available autologous somatic cells. It presents unique opportunities for the development of personalized medicine, from in vitro models of hereditary and degenerative neurological diseases to novel neuroregenerative technologies. Over the past decade, a plethora of protocols for primary reprogramming has been published, yet reproducible generation of homogeneous populations of neuronally reprogrammed cells still remains a challenge. All existing protocols, however, use transcription factors that are involved in embryonic neurogenesis. This is presumably be the key issue for obtaining highly efficient and reproducible protocols for ex vivo neurogenesis. Analysis of the functional features of transcription factors in embryonic and adult neurogenesis may not only lead to the improvement of reprogramming protocols, but also, via cell marker analysis, can exactly determine the stage of neurogenesis that a particular protocol will reach. The purpose of this review is to characterize the general factors that play key roles in neurogenesis for the embryonic and adult periods, as well as in cellular reprogramming, and to assess correspondence of cell forms obtained as a result of cellular reprogramming to the ontogenetic series of the nervous system, from pluripotent stem cells to specialized neurons.

Non-small cell lung cancer (NSCLC) is prevalent worldwide and has a high mortality rate. Even if mesenchymal stem cells (MSCs) are suggested as cancer treatment, the studies of their effects on NSCLC cells contradict each other, mainly due to utilization of two-dimensional (2D) culture system. Three-dimensional (3D) culture systems resemble tissue organization in vivo. Here we comprehensively explore the inhibitory effects of MSCs on NSCLC cells in a 3D culture system. We confirmed that the inhibitory effects of 3D-cultured MSCs (3D-MSCs) on the proliferation and migration of NSCLC cells are greater than that of the 2D-cultured MSCs. 3D-MSCs overexpress IL-24, which serve as the key factor enhancing antitumor effects of MSCs. In these cells, IL-24 affects p38 MAPK and CXCR4/AKT pathways. Overall, this study provides the support for use of MSCs in tumor.

Autophagy is an evolutionarily conserved cellular process in which components of the cytoplasm are delivered to lysosomes for degradation and has been proposed to play a role in imatinib resistance in chronic myeloid leukemia cells. Chronic myeloid leukemia is a clonal myeloproliferative disorder arising from the neoplastic transformation of the hematopoietic stem cell. We used a Bcr-Abl-independent and imatinib-resistant K562 subpopulation (K562-IR) that we generated earlier in our laboratory for this study. We showed that in the presence of imatinib autophagy was triggered via LC3I/II transformation, p62 protein expression and acidic vacuoles accumulation in tyrosine kinase inhibitor-sensitive K562 cells; whereas in the cell line K562-IR which is imatinib-resistant and Bcr-Abl independent, autophagy is not triggered. With ongoing research and trails to combine tyrosine kinase inhibitors with autophagy inhibitors, our results suggest a model of resistance in which treatment with a TKI inhibitor does not increase autophagy, basically because its presence does not cause cellular stress due to Bcr-Abl signaling not being required for survival.

LiFraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome.

To analyze the results of treatment in patients with acute myeloid leukemia (AML) within protocols AML-17 and modified AML-17 (mOML-17) as part of two consecutive pilot studies in order to develop the best treatment strategy for AML patients aged below 60 years.

The aim of our study was to investigate the effectiveness of osteoplastic material based on MMSC - AT for the restoration of bone defects. To study the processes of bone remodeling, in the replacement of bone defects after tooth extraction, patients were divided into three groups. Group A - 26 patients where used "Kolapan-L" to fill the bone defect; group B - 28 patients where for augmentation used osteoplastic composition "Kolopan-L" + MMSC-AT + PRP; group C - 25 patients in whom the healing of the bone defect occurred under a blood clot. In the patients group B, after 1 year of observation, the activity of acid phosphatase was 13,35% p> 0.05 and 33,40%, p>0,05, p1<0.05 below the increase in alkaline phosphatase by 8,84, p> 0,05, and 15,35%, p>0,05 relative to similar data in groups A and C. The index of bone mineralization in patients of group B was 8,84% and 19,74% higher than in the operated groups A and C, respectively p, p1>0,05, p2<0,05. When conducting histological examination of bone biopsies after 6 months of observation, in patients of group B, the obtained trepan biopsies had the structure of bone tissue: bone marrow spaces and sometimes small particles of osteoplastic material were determined between trabeculae. Therefore, based on the results of the study, it is safe to say that our proposed osteoplastic composition based on MMSC - AT is a good alternative to traditional osteoplastic materials for use in modern dentistry.

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect almost all organs and tissues, cause genital herpes-the most common sexually transmitted disease-disorders of the central nervous system (CNS), and lead to severe complications in children. Despite the available drugs, the incidence of HSV-1/2 continues to rise. None of the prophylactic vaccine candidates have shown a protective effect in trials nor approval for use in clinical practice. We have investigated the protective properties of mesenchymal stem cells (MSC) isolated from the bone marrow of mice. A comparative analysis of the protective response to the introduction of primary and modified MSCs (mMSC) was carried out using the plasmid containing gene of the HSV and an inactivated virus in a model of lethal HSV-1 infection in mice. mMSCs were obtained by transfection of the Us6 gene encoding glycoprotein D (gD) of the HSV, the plasmid contained the same gene. After twofold immunization with primary MSCs, the formation of antibodies interacting with the viral antigen (according to enzyme immunoassay data) and neutralizing the infectious activity of HSV-1 in the reaction of biological neutralization was observed in the peripheral blood of mice. In addition, the introduction of primary MSCs induced the production of interferon gamma (INF-γ) which is detected in the peripheral blood of mice. After infection with HSV-1, the immunized mice showed significantly increased titers of virus-specific antibodies, an increased level of IFNγ, and were completely protected from lethal HSV-1 infection. The protective effect of the other three immunogens was lower and did not exceed 50-65%. Considering the wide availability of MSCs, the proven safety of intravenous administration, and the results obtained in this work on the ability to induce innate, adaptive and protective immunity to HSV-1, MSCs can be considered a promising basis for the development of new cellular vaccines for the prevention of herpesvirus and other viral infections.