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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Kalinchuk AYu, Patskan IA, Stadelman MM, Grigoryeva ES, Tashireva LA

Understanding subtype-specific variability of functional programs in FAP+ tumor-associated fibroblasts (TAFs) is fundamental for developing effective therapeutic strategies targeting stromal components. The aim of this study was to identify subtype-specific signaling pathways, markers, and molecular features of FAP+ TAFs. Using spatial transcriptomic analysis, we demonstrated that FAP+ TAFs in luminal breast cancer exhibit a phenotype characterized by extracellular matrix organization (GO:0030198, FDR q-value = 0.0307) and expression of genes associated with metastasis (COL10A1, MMP13, CXCL14, TSPAN8). In contrast, FAP+ TAFs in triple-negative breast cancer display a pronounced immunomodulatory phenotype with overexpression of immunosuppressive genes (CD36, PLA2G2A, CHI3L1) and enrichment of immune response-related pathways (immune response (GO:0006955, FDR q-value = 7.85e-17), inflammatory response (GO:0006954, FDR q-value = 2.79e-11), regulation of cytokine production (GO:0001817, FDR q-value = 3.39e-10)). We also identified subtype-specific gene signatures related to radioresistance: luminal A and B subtypes showed activation of DNA repair pathways (IGF1R, ERBB3, CRIP1), while triple-negative tumors demonstrated enrichment of epithelial-mesenchymal transition and stemness markers (ZEB2, NOTCH4, FOXM1). These findings emphasize that FAP+ fibroblasts are not a homogeneous population but functionally specialize depending on tumor subtype — acting as stromal architects in luminal breast cancer and as regulators of immune response in triple-negative breast cancer.

Received: 2025-09-10

Published online: 2025-10-16

DOI: 10.24075/brsmu.2025.046

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VIEWS 41

Chepeleva EV, Kozyr KV, Vaver AA, Khakhalkin VV

The materials used to restore bone defets have a number of systemic limitations. The metal implants showing high mechanical strength have an insufficient osseointegration capability, while ceramic and polymer materials have better biocompatibility, but do not meet the requirements of mechanical reliability in the zones of considerable load. In this regard, the study of new classes of materials combining the strength characteristics with the osseogenic potential seems to be a promising area. The study aimed to assess cytocompatibility of the boron carbide (B4C)-based porous ceramic material to confirm the possibility of its use for bone defect replacement. The B4C semi-finished products were manufactured by pressureless sintering at 1900–2100 °C; ultrastructure of the resulting sample surface was examined by atomic force and scanning electron microscopy. Citotoxicity of the B4C samples was estimated by an indirect method relative to human mesenchymal stem cells. The following cell survival rates were reported: 102.1% (24 h) and 99.1% (72 h) for the samples autoclaved; 110.0% (24 h) and 94.4% (72 h) for those treated with ethylene oxide. No significant intergroup differences were revealed (Mann–Whitney U-test). The findings allow us to consider B4C ceramics as a promising solution for bone grafting. However, further research is required to assess its clinical potential, including the development of sterilization protocols for larger and complex-shaped samples.

Received: 2025-09-10

Published online: 2025-10-12

DOI: 10.24075/brsmu.2025.044

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VIEWS 69

Matveeva KS, Sheverev DV

Accumulation of senescent cells in the tissues is associated with functional impairment and the development of age-related disorders. The key role in this process is played by the senescence-associated secretory phenotype (SASP) contributing to chronic systemic inflammation, which is associated with the increased risk of autoimmune disorders and cancer, as well as the decreased resistance to infections. Normally, the immune system eliminates senescent cells, but the effectiveness of this process decreases with age, including due to the immune system aging. The study aimed to assess age-related alterations in the main lymphocyte and myelocyte populations in the spleen and bone marrow samples of senile mice. The study involved groups of young (n = 8) and elderly (n = 4) С57BL/6 mice. Populations were tested by flow cytometry using the fluorescence-labeled antibodies. The aging phenotype was assessed based on the β-Gal enzyme activity with pre-treatment with bafilomycin А1, ensuring lysosomal alkalinization and allowing one to detect the increased enzyme activity typical for the aging cells (SA-β-Gal). As a result, the significantly increased levels of myeloid populations, CD11c+ B cells, double-negative T cells, along with the decreased levels of the CD8α+ dendritic cells, were reported in elderly mice. Furthermore, aging was associated with the significant increase in the levels of SA-β-Gal-positive cells, especially in the populations of myeloid cells. The data obtained suggest that the age-related alterations are of systemic nature and reflect the so-called myeloid shift, as well as accumulation of pro-inflammatory populations in the myeloid and lymphoid compartments.

Received: 2025-08-27

Published online: 2025-09-30

DOI: 10.24075/brsmu.2025.043

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VIEWS 169

Makhachev DR, Bulanov DV, Shovkhalov MM, Bekmurziev BZ, Geroev IA, Netsvetova AM, Zhusupova AR, Gubich DS, Manovski AM

High-grade non-anaplastic (HGFC-NA) thyroid tumors belong to a rare and aggressive category of neoplasms that occupy an intermediate position between differentiated and anaplastic carcinomas. There are high mortality rate and limited standard treatment options, which usually include surgical tumor removal with subsequent radioiodine treatment and levothyroxine suppression therapy. Targeted tyrosine kinase inhibitors are additionally considered in radioiodineresistant forms, but the efficacy of those is limited. A clinical case of differentiated high-grade thyroid carcinoma (DHGTC) in a 62-year-old female patient post hemithyroidectomy is presented. Histological assessment, immunohistochemistry (TTF-1, PAX8, CK19, p53, Ki-67), and the key marker (TERT, TP53, BRAF) molecular testing methods were used. The tumor size was 3.4 × 2.8 × 2.5 cm; the tumor showed pronounced architectonic heterogeneity, focal necrosis, high mitotic activity — 8–10 mitoses per 10 fields of view at ×400 (corresponding to ≥ 5 per 2 mm2), and the Ki-67 proliferation index reached 35%. IHC was used to detect the TTF-1 and PAX8 expression, mutational p53 pattern of expression, suggesting the TP53 mutation. Molecular testing revealed no alteration of the TERT and BRAF genes. These characteristics made it possible to verify the diagnosis of DHGTC. A conclusion was drawn about the need for comprehensive morphological and molecular diagnosis of HGFC-NA tumors, since the mitotic activity quantitative parameters, Ki-67, and TERT/TP53 status determine the prognosis and the personalized therapy selection.

Received: 2025-09-02

Published online: 2025-09-24

DOI: 10.24075/brsmu.2025.042

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VIEWS 283

Grechenko VV, Gromova TV, Ogurtsova AD, Muradyan TG, Zhuravleva ER, Gankovskaya LV

During the aging the immune system alterations are accompanied by developing the systemic, sterile inflammation: inflammaging. Successful and pathological aging phenotypes are distinguished. Inflammaging severity depends largely on the ratio of pro- and anti-inflammatory mediators, especially IL6 and IL10. The study aimed to conduct the analysis of IL6 and IL10 production in the cultures of the patients’ peripheral blood mononuclear cells (MNCs) as a possible approach to determining the aging phenotype. The data of elderly patients (n = 80), senile patients (n = 100), and centenarians (n = 30) were included in the study. Among those the groups were allocated with the successful and pathological phenotypes, along with the comparison group (young adults). The stimulation coefficient (SC) was assessed based on the ratio of the levels of stimulated and induced cytokine production. For the successful phenotype in elderly and senile individuals, as well as centenarians, a decrease in the IL6 SC to 5.3 [2.2–14.3] (p < 0.01), 5.3 [3.01–7.8] (p < 0.01), 6.5 [5.2–14.1], respectively, was reported, against the comparison group, where the value was 17.6 [13.7–31.1] (p < 0.05). With the pathological phenotype, the IL6 SC values of the studied age group showed no significant differences from that of the comparison group. For the successful phenotype in senile individuals, the increase in the IL10 SC to 6.9 [3.8–13.8] relative to the values of the group with the pathological phenotype — 3.3 [2.0–5.9] (p < 0.01) and the comparison group — 2.0 [1.9–2.2] (p < 0.001) was reported. In the group of centenarians with the pathological phenotype, there was a significant increase in the IL10 SC (11.2 [5.4–18.1] vs 2.7 [2.3–6.5] p < 0.001) in the group with successful aging, which can indicate the pronounced compensatory anti-inflammatory reserve being a factor of survival and long life in the context of the presence of a large number of age-related disorders in this group.

Received: 2025-08-03

Published online: 2025-08-30

DOI: 10.24075/brsmu.2025.041

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VIEWS 360

Kirshina AS, Shepelkova GS, Khlebnikova AS, Maslov AA, Kozlova AV, Kunyk DA, Yeremeev VV, Ivanov RA, Reshetnikov VV

The success of mRNA-based vaccine formulations against viral infections motivated many researchers to develop mRNA vaccines against bacterial infections. The development of new anti-tuberculosis vaccine is an urgent task since the only approved BCG vaccine is not effective enough in terms of infection prevention, despite the fact that it reduces the risk of severe disease. The study aimed to compare two anti-tuberculosis mRNA vaccines based on the classic linear mRNA (mRNA-MTBmEp-5-1) and circular RNA (circRNA-MTB-mEp-5-1) by immunogenicity and the capability of protecting I/St mice against M. tuberculosis infection. The efficacy of mRNA vaccines in the formulations with lipid nanoparticles was compared with the BCG efficacy. The findings suggest that immunization with the mRNA vaccine based on the linear mRNA resulted in the cell-based and humoral immune response (OD IgG = 0.36 ± 0.12) that was less pronounced than after BCG vaccination (OD IgG = 0.54 ± 0.14). At the same time, immunization with the mRNA vaccine and BCG ensured comparable reduction of bacterial load in the lung and spleen of experimental mice (CFU in lung tissue for BCG: 4.00 × 105 ± 2.13 × 105, p = 0.0068; mRNA: 4.72 × 105 ± 3.44 × 105, p = 0.0059; LNP: 4.91 × 106 ± 3.89 × 106, ns; PBS: 4.01 × 106 ± 1.69 × 106) and increased survival of mice after getting infected with M. tuberculosis. Immunization with the vaccine based on the circular RNA resulted in developing humoral mmunity only (OD IgG = 0.52 ± 0.13) and did not ensure protection after getting infected with M. tuberculosis (CFU in the lung for circRNA: 2.12 × 106 ± 5.30 × 105, p = 0.85). Thus, in our studies, anti-tuberculosis vaccines based on circular RNAs are inferior in effectiveness to formulations based on linear RNAs.

Received: 2025-07-22

Published online: 2025-08-26

DOI: 10.24075/brsmu.2025.040

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VIEWS 478

Dzhandarova TI, Tabunshchikova MO, Kubanov SI, Domenyuk DA

Moderate exercise not only has a positive impact on overall health, but also can serve as a rather accessible preventive measure for maintaining health, particularly the cardiovascular system health. The study aimed to assess the cardiovascular system adaptive capacity in chronic heart failure with moderate exercise in different age groups. Moderate exercise was induced in 6- and 19-month-old rats by forced swimming in a water bath at 32–34°C. During training, chronic heart failure was induced by intraperitoneal administration of the anthracycline antibiotic doxorubicin (Teva) at a cumulative dose of 15 mg/kg, divided into 6 injections over 14 days. Serum levels of brain natriuretic peptide and corticosterone were determined by ELISA every seven days throughout the experiment in all rats. It was found that with chronic heart failure and moderate exercise, myocardial adaptation was significantly higher in both age groups. It was most pronounced in aging rats, as evidenced by the dynamic changes of serum natriuretic peptide levels throughout the experiment. In both fertile-age and aging rats, the body's adaptive capacity in the event of cardiac dysfunction with moderate exercise is higher than in the absence of training.

Received: 2025-08-07

Published online: 2025-08-23

DOI: 10.24075/brsmu.2025.039

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VIEWS 340

Fokin VF, Abaimov DA, Ponomareva NV, Medvedev RB, Konovalov RN, Lagoda OV, Krotenkova MV, Shabalina AA, Tanashyan MM

The study of the role of catecholamines (CAs) in cerebral organization of functions in patients with chronic cerebral ischemia (CCI) is relevant, since their important role as neurotransmitters is well known, along with the association with stress severity and cortisol. The study aimed to assess the impact of stable combinations of dopamine (DA), norepinephrine (NA), and adrenaline (ADR) on the organization of cerebral functions. A total of 76 patients with CCI were assessed based on the fMRI data (n = 21) converted into a network structure using the SPM-12 and CONN-18 software tools. Significance level estimation involved adjustment for multiple comparisons. Stable combinations of CAs reflecting mutual positive correlation of DA, NA and BP significantly affected cerebral organization of patients with CCI. CA combinations were associated with salivary cortisol (F = 4.8; p = 0.038) and memory (F = 7.5; p = 0.011) indices: the CA level increase was associated with increased cortisol levels and worse memory indices. Based on fMRI data the differences were revealed in connectivity organization of CCI patients with high and low levels of all three CAs. Patients with the CA content below median are characterized by the presence of closed neural networks extending to both brain hemispheres, which contributes to information integration and retention. It is assumed that such networks may be associated with the long-term potentiation mechanisms playing an important role in memory processes and changes in the synaptic connection strength. Thus, the use of non-invasive biochemistry testing methods and fMRI has made it possible to obtain new data on the ring organization of brain neural networks associated with stable CA combinations. Such neural network organization is likely to affect cognitive functions. High catecholamine levels in CCI patients are associated with increased cortisol levels, memory deterioration, and decreased connectivity in neural network of the brain.

Received: 2025-07-29

Published online: 2025-08-21

DOI: 10.24075/brsmu.2025.038

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VIEWS 410