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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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 660

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 633

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 780

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 560

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 685

Gavrilov PS, Kutukova SI, Polezhaev DA, Pischik VG, Manikhas GM

Non-AIDS-defining cancers represent one of the leading causes of death among people living with HIV in developed economies due to successful antiretroviral therapy. Malignant neoplasms (MNs) of the lung occupy leading positions in prevalence and mortality, affecting younger people compared to the general population. Despite the fact that the role of HIV in the direct mechanism underlying the lung cancer carcinogenesis has not been proven, the immunodeficiency-mediated effect, including that on the anti-tumor immunity, contributes to the earlier neoplastic process development and to the features of the disease course and anti-tumor treatment. HIV often becomes an exclusion criterion for multiple oncology clinical trials, and this group of patients is overlooked. The study aimed to assess the impact of the CD4/CD8 ratio as one of the key markers of the state of cell-mediated immunity on the lung cancer course prognosis during anti-tumor treatment. The data of 17 HIV patients with MNs of the lung and 31 non-HIV patients of the control group, who underwent treatment in 2018–2023, were analyzed. The analysis determined the threshold CD4/CD8 ratio value (≤ 0.57) and the fact of its decrease by more than 0.01, which reflected a significant overall survival worsening (p < 0.05) during lung cancer treatment. Furthermore, comparative analysis of patients of the index and control groups revealed no significant differences in progression-free survival and the number of therapy lines, which suggests comparable treatment outcomes in patients with lung cancer against the background of existing HIV (p > 0.05).

Received: 2025-07-20

Published online: 2025-08-16

DOI: 10.24075/brsmu.2025.037

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VIEWS 647

Ivanova AV, Lazareva PA, Kuzmichev IA, Vadekhina VV, Kosykh AV, Gurskaya NG, Abakumov MA

Due to the limited availability of advanced methods to diagnose Alzheimer's disease, small molecules and short peptides capable of specifically biniding β-amyloid are of special interest. The study aimed to perform comparative assessment of pharmacokinetics and biodistribution of two model peptides, HAEE (His-Ala-Glu-Glu) and HASS (His-Ala-Ser-Ser), as potential platforms for the development of diagnostic kits, as well as to determine the relationship between the peptide structure and organotropism. The study involving BALB/c mice (n = 10) was conducted using the fluorescence labeled compounds. We used in vivo IVIS imaging, ex vivo fluorescence microscopy, and pharmacokinetic analysis. The results showed fundamental differences: the negatively charged HAEE was accumulated mainly in the kidney (T½β = 4.39 h) due to tubular reabsorption, while neutral HASS was soon captured by the liver (T½β = 2.76 h). The data obtained demonstrate the key role of amino acid composition in determining organotropism and open prospects for the development of organ-specific peptide systems.

Received: 2025-07-10

Published online: 2025-07-31

DOI: 10.24075/brsmu.2025.036

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VIEWS 1008

Osikov MV, Shelomentsev AV, Boyko MS, Shishkova YuS, Fedosov AA

With limited efficacy and safety of the methods to treat ischemic stroke (IS), melatonin (МТ) can be considered a promising neuroprotective agent having a pleiotropic mechanism of action. The study aimed to assess the effect of MT contained in original rectal suppositories on the neurological status and microcirculation in the injury focus in experimental acute cerebral ischemia (EACI) in vivo. A total of 30 sexually mature rats were divided into three groups, 10 animals per group: shamoperated (SO) animals; animals with EACI; animals with EACI receiving original rectal suppositories weighing 100 mg with 2.5 mg of melatonin (МТ) throughout 7 days. On days 3 and 7, neurological status was assessed using the Garcia JH score, Placing test, Bederson test; microcirculation rate (MR) was assessed in the brain injury focus by laser flowmetry. A significant decrease in the Garcia JH scores by 58.3% (p = 0.001), Placing Test scores by 57.9% (p = 0.002), along with the significant increase in the Bederson Test scores in animals with EACI compared to SO animals was reported on day 3; the significant decrease in the Garcia JH scores by 75% (p < 0.001), Placing Test scores by 78.9% (p < 0.001) and the significant increase in the Bederson Test scores were reported on day 7. MR decreased by 30% on day 3 (p = 0.02), by 38% on day 7 (p = 0.005). The use of the MT-based rectal suppositories resulted in the neurological deficit restoration in the form of the significant increase in the Gаrcia JH scores by 53.3% (p = 0.008), Placing Test scores by 50% (p = 0.016) and the significant decrease in the Bederson Test scores by 50% (p = 0.029) on day 3; on day 7, the significant increase in the Garcia JH scores by 233% (p < 0.0001), Placing Test scores by 325% (p < 0.0001) and the significant decrease in the Bederson Test scores by 100% (p < 0.0001) were reported. MR increased by 12.5% on day 3 (p = 0.016), by 43.9% on day 7 (p = 0.005). The correlation analysis revealed the association between the neurological status and MR values: the neurological deficit improvement in animals with EACI in the context of receiving the MT-based rectal suppositories was associated with the MR increase in the ischemic focus in the brain. Thus, partial neurological status restoration in the context of using the MT-based rectal suppositories for EACI resulted from the MT vasoactive properties, which was reflected in the MR increase in the ischemic focus in the brain.

Received: 2025-06-24

Published online: 2025-07-26

DOI: 10.24075/brsmu.2025.035

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VIEWS 730