Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Stepanov AI, Putlyaeva LV, Didych DA, Galiakberova AA, Gurskaya NG, Lukyanov KA

The study of human induced pluripotent stem cells (iPSCs) and developing the technology for their practical use is one of the most knowledge-intensive areas of modern biomedical research. Despite the potential of using iPSCs in personalized medicine and to build cell-based models for disorders of various etiology, iPSC utilization remains challenging. Thus, the iPSC intercellular heterogeneity and the lack of effective identity determination and assessment methods considerably hamper reproducibility of such studies. The study was aimed to generate an iPSC line carrying the gene encoding the ATOH1 transcription factor controlled by the Tet-One expression induction system, along with TagBFP2 fluorescent protein and the puromycin resistance gene for cell selection. Molecular cloning, lentiviral transduction, cell culturing, immunofluorescence staining, and fluorescence microscopy were used during the study. The created cell model will allow analyzing the state of single cells and, therefore, has great practical potential for both laboratory and medical research.

Received: 2023-08-01

Published online: 2023-09-22

DOI: 10.24075/brsmu.2023.036

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VIEWS 1008

Mukhamedzhanov RK, Grigoryeva ES, Tashireva LA, Perelmuter VM, Zavyalova MV, Savelieva OE

Nowadays, great attention is paid to the study of circulating tumor cells (CTCs) due to their key role in distant metastasis. At the same time there is little data on the properties of circulating cells showing simultaneous expression of the leukocyte and epithelial markers and their possible role in tumor progression and chemotherapy resistance. The study was aimed to assess subpopulations of cells with hybrid epithelial/leukocyte phenotype and estimate the features of stemness, epithelial–mesenchymal transition (EMT), and integrin interface, which determine the cells’ possible metastatic properties in breast cancer (BC). The survey data from 128 patients with invasive breast carcinoma of no special type were included. Multicolor flow cytometry was used to assess the population structure and metastatic potential of the cells circulating in blood and primary tumor cells with hybrid phenotype. The primary tumor cell suspension was prepared by mechanical disaggregation. The high degree of heterogeneity was noted in the population of cells with hybrid phenotype, including the combination of the stemness and EMT features, and diverse integrin interface. Cells with hybrid phenotype are involved in the mechanisms underlying lymph node and distant metastasis. In lymph node metastasis, metastatic potential of these cells is associated with the stemness features (р = 0.0422) and co-expression of β3-, β4-, and αVβ5-integrins (р = 0.0338). In distant metastasis, metastatic potential of hybrid cells is associated with the stemness features (р = 0.015) and is not associated with the EMT features and integrin expression.

Received: 2023-07-04

Published online: 2023-08-31

DOI: 10.24075/brsmu.2023.033

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VIEWS 1167

Korshunov AS, Vagner VD, Belskaya LV, Kuryatnikov KN, Serov DO, Krasnov VA, Tigranyan GO, Bondar IA

Studying the mechanism underlying tooth eruption is an important and promising area due to the increased incidence of the diseases associated with tooth eruption abnormalities or difficulties that can result in purulent and septic complications. The study was aimed to explore variability and structural features of the hard tissue mineral component and organic matrix in mandibular third molars being at different stages of tooth eruption. Microscopic examination and biochemical testing of the enamel, dentin, and dentin–enamel junction of the study participants’ (n = 67; females aged 14–36) mandibular third molars were performed by scanning electron microscopy and Fourier transform infrared (FT-IR) spectroscopy. The association of the tooth eruption stage with the hard tissue structural features, such as the degree of mineralization and the size of dentinal tubules, orientation and size of the enamel prisms, was revealed. There were significant differences in the mandibular third molar hard tissue water content, which was demonstrated by metabolic processes and maturation rate (p < 0.05). According to the IR spectroscopy data, intensity of the collagen absorption bands in the enamel increases with age, while in dentin it decreases (1202, 1249, and 1342 cm–1). Furthermore the combination of the reduced intensity of the 1202 cm–1 band with the increase in the 1342 cm–1 dentin–enamel junction band confirms the important role it plays as a link between the enamel and dentin due to its metabolic, shock-absorbing, protective, and nutritional functions. The findings demonstrate significant changes in the wrapping and orientation of the collagen fibrils and fibers in the hard tissue, which affect primary spatial orientation and mandibular dental topography.

Received: 2023-07-31

Published online: 2023-08-31

DOI: 10.24075/brsmu.2023.035

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VIEWS 1100

Baranova NS, Gris MS, Baranov AA, Spirin NN, Artyuhov AS, Shakirova KM, Nasonov EL

There are persistent infections that contribute to the emergence and development of multiple sclerosis (MS) exacerbations; they are triggered by the Epstein–Barr, herpes type 6, herpes simplex types 1 and 2, varicella-zoster viruses. Cytokines are crucial to arresting the spread of a herpes infection in a body. If their production is out of balance, MS can progress faster. This study aimed at determining the level of cytokines in the blood serum of MS patients, assessing their clinical significance and how they affect reactivation of herpes infection. We examined 36 patients (12 male and 24 female) with confirmed MS (McDonald criteria) in remission. In 18 of them, we diagnosed reactivation of peripheral herpes virus. Serum levels of 15 cytokines (IL1ß, IL4, IL6, TNF-a, INF-γ, IL10, IL17A, IL17F, IL21, IL22, IL23, IL25, IL31, IL33, sCD40L) were determined with the help of xMAP multiplexing. Compared to the control group, MS patients had increased levels of IL10, IL33 (p < 0.001), with high IL33 identified most often (20 patients; 52.8%). During exacerbations, the average level of IL10 grew up (p < 0.01), as did that of IL31, the high levels of which were detected significantly more often (42.8 and 6.9%, respectively; p = 0.04). In addition, a prevailing scenario was the increased levels of IL33 and other cytokines (IL17A, IL17F, IL21, IL31) (57.1 and 6.9% of cases, respectively; p = 0.008). Reactivation of herpes translated into higher levels of IL1ß, IL23 and IL33 compared to cases without reactivation (p < 0.05 and p < 0.01, respectively). High levels of IL33 were significantly more frequently recorded in this group of patients (77.7 and 33.3%; p = 0.008). We discuss involvement of IL10, IL31, IL33 and other cytokines in the pathogenesis of herpes-associated MS.

Received: 2023-07-24

Published online: 2023-08-31

DOI: 10.24075/brsmu.2023.032

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VIEWS 1133

Lisitsyna OI, Ekimov AN, Atapina EE, Syrkasheva AG, Goryainova EG, Makarova NP, Trofimov DYu, Dolgushina NV

To date the world community is actively working to optimize the approaches to determining chromosomal abnormalities in embryos. The study was aimed to assess the possibility of using noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) through analysis of cell-free DNA in spent culture medium (SCM). We conducted niPGT-A of aneuploid embryos by analysis of cell-free DNA in SCM. All blastocysts were considered to be aneuploid based on the results of previous preimplantation genetic testing for aneuploidy (PGT-A) with trophectoderm (TE) biopsy. The study involved 11 embryos from seven couples. All the embryos were warmed and individually cultured in the 10 µL drops for 9 h. All SCM was collected and analyzed by niPGT-A. The results obtained were tested for concordance with previous PGT-A data. A total of 12 SCM samples were assessed: 11 samples, in which the embryos were cultured, and one control sample. Chaotic niPGT-A results not allowing the karyotype diagnosis were obtained in one case (9.1%) out of 11. Full concordance of the PGT-A and niPGT-A results was revealed in seven cases out of 10 (70%), while clinical concordance was found in nine cases out of 10 (90%). In one case (10%), the blastocyst was considered to have euploid karyotype based on the niPGT-A data. It has been concluded that niPGT-A can be a promising method of preimplantation embryonal chromosomal status diagnosis that requires no biopsy.

Received: 2023-06-18

Published online: 2023-08-30

DOI: 10.24075/brsmu.2023.034

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VIEWS 998

Kolomiets KV, Isaev IV, Kovalev VV, Grishchenko NV, Kokovihina DI, Morozova AA, Torosyan AR, Shashkova VV, Snegireva PV

In 85% of patients worldwide, gastric cancer (GC) metastasizes from the very beginning or within three years. In 30–50% of cases, metastases, both synchronous and metachronous, grow into liver. Multifocal liver metastases translate into an unfavorable prognosis: the median survival period is 10–15 months, with less than 10% of the patients surviving past three years. In such cases, the palliative treatment option is systemic chemotherapy. Combined with immunotherapy, transarterial chemoembolization (TACE), a relatively new method of local treatment of metastatic foci, offer new options of combating liver metastases. This work presents a clinical case of application of this combination coupled with chemotherapy to treat a patient with unresectable liver metastases spawned by HER2+ gastric adenocarcinoma. From the day of diagnosis, the patient's life expectancy was 42 months.

Received: 2023-06-27

Published online: 2023-08-29

DOI: 10.24075/brsmu.2023.031

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VIEWS 1170

Gusyakova OA, Smirnov SV, Kuznetsova OYu, Apergenova AR, Albikova AR

Parkinson's disease (PD) is a chronic neurodegenerative disease associated with specific neurological deficits in patients, it mainly affects dopaminergic neurons in the substantia nigra causing accumulation of the neurotoxic amounts of aggregated α-synuclein protein in the neuronal cell bodies. The paper reports the authors' view of certain pathochemical and biochemical aspects of the Parkinson’s disease development in terms of interplay between the metabolic pathways of catecholamines and pigments, particularly the possible pathway of neuromelanin synthesis in the neuronal cell bodies and its importance in the life of cells. Assessment of the use of certain neurodegenerative disorder biomarkers, which are of direct pathognomonic value, in the laboratory diagnosis of the disease is provided. It is suggested to use the results in the field of deeper understanding of biochemical patterns underlying neuronal death for early diagnosis of PD in individuals of different age groups, as well as for further study of pathogenesis based on fundamental biochemistry and pathobiochemistry of intracellular processes.

Received: 2023-07-24

Published online: 2023-08-29

DOI: 10.24075/brsmu.2023.030

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VIEWS 948

Pinaev SK, Venevsky S, Chakov VV, Tian L, Gong P, Kaprin AD, Starinsky VV, Chizhov AYa, Pinaeva OG

Russian Federal Far East District is a continental scale area where wildfires are frequent. We aimed to a) determine whether wildfires are related statistically to cancer for children and adults in the Russian Federal Far East District (FFED); b) to estimate time lags of such relationships and c) to find out which age groups are most vulnerable for wildfires. Annual number of fires (NF) in administrative units (AUs), normalized to the maximum value for all AUs in observation period 1992–2019, was taken as a characteristic of wildfires in our analysis. Annual cancer incidence (CI) for five cancer types for children up to 14 years and the entire population, normalized similarly to NF, was compared to normalized NF. ARIMA models were used for time series analysis for the period 1992–2019. Linear statistical analysis was done for NF and CI for short time series (10–12 years) for the central AU of FFED for “children up to 4 years”; Three additional embryonal types of cancer and five benign types of tumors were also focused in linear statistical analysis. ARIMA analysis revealed 27 associations between NF and CI with a lag from 0 to 3 years for two age groups, and five cancer types (p-values between 0.002 and 0.1). Linear statistical analysis for “children up to 4 years” revealed correlations for two from three embryonal types of cancer and three from five benign tumors (0.002 < p < 0.046). Incidences of hematopoietic, lymphoid, vascular, and soft tissue neoplasms, as well as CNS tumors had associations with wildfires for “children up to 4 years”, for “children up to 14 years” and “the entire population” age groups in many cases. Entire population and children up to 4 years in the central AU of FFED are most sensitive to wildfire — cancer interactions. Associations “number of fires — cancer incidence” as a rule have time lags from 0 to 3 years.

Received: 2023-04-25

Published online: 2023-08-26

DOI: 10.24075/brsmu.2023.028

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VIEWS 1352