Vol 28, No 4 (2024): ONCOLOGY

ONCOLOGY

Molecular genetic signatures of head and neck squamous cell carcinoma and their changes induced by proton irradiation

Jumaniyazova E.D., Lokhonina A.V., Sentyabreva A.V., Kosyreva A.M.

Abstract

Head and neck squamous cell cancer (HNSCC) is the seventh most common malignancy in the world. The overall incidence of HNSCC is increasing and is projected to increase by about 30 % annually by 2030. Clinically, HNSCC is characterized by an aggressive course: rapid local spread, resistance to various methods of antitumor treatment, and frequent recurrences. Despite improvements in diagnostic and therapeutic approaches over the last two decades, mainly due to the respective heterogeneity of these tumors, the outcomes of patients with HNSCC have not shown significant improvements, especially for patients with late TNM stage, with an overall five-year survival rate of 50 %. Approximately 75 % of HNSCC patients are treated with radiation therapy either alone or as part of a comprehensive treatment regimen. To date, one of the main ways to improve the efficacy of radiation therapy in HNSCC is considered to be a combination of maximum allowable increase of radiation dose in the target tumor and reduction and minimization of such dose in the surrounding healthy tissues. From this point of view, proton therapy (PT) has a pronounced advantage over various types of photon irradiation. Despite the growing interest of scientists in PT, studies aimed at identifying molecular and genetic changes induced by PT are scarce, while in our opinion they are very important for understanding intracellular mechanisms leading either to tumor cell destruction or to the development of radioresistance. This review summarizes the available knowledge on the changes in the main signaling pathways of HNSCC tumor cells under the influence of PT.

RUDN Journal of Medicine. 2024;28(4):413-426
pages 413-426 views

Chemotherapy-induced developmental trajectories of monocytes in breast cancer

Gerashchenko T.S., Patysheva M.R., Fedorenko A.A., Filatova A.P., Vostrikova M.A., Bragina O.D., Fedorov A.A., Iamshchikov P.S., Denisov E.V.

Abstract

Relevance . Monocytes are circulating immune cells which are traditionally divided into three subsets. The contribution of each subset to breast cancer pathogenesis is controversial. Moreover, there is no data regarding the programming of monocyte subsets towards antitumor activity induced by chemotherapy. Aim . To study the trajectories of monocyte subsets and transcriptomic changes in blood monocytes during neoadjuvant chemotherapy (NAC). Materials and Methods . Mononuclear cells were purified from the peripheral blood of nine triple-negative breast cancer (TNBC) patients before NAC and on the 3rd and 21st day after the first NAC cycle (AC regimen). Total cell concentration and viability (Calcein/DRAQ7) were assessed by flow cytometry. Single-cell RNA sequencing was performed on a Genolab M platform (GeneMind Biosciences) using the 10x Genomics technology for fixed samples. Data were analyzed using Seurat, SingleR, and the dynverse R package for trajectories. Results and Discussion . The trajectory analysis indicated that monocytes were clustered into three subsets: classical, non-classical, and intermediate. Classical monocytes were characterized by high expression of CD14 , CSF3R , S100A8 , S100A9 , VCAN , LYZ , SELL , and GRN genes, whereas non-classical monocytes expressed FCGR3A , MTSS1 , TCF7L2 , CSF1R , SPN , EVL , and LYN . The developmental trajectories of monocytes were significantly affected by chemotherapy. Transcriptionally, classical monocytes were subdivided into two clusters: one characterized by proliferative signals and the other by stress signals. By day 21st after NAC, developmental trajectories of monocytes and their subset composition were observed to recover. Chemotherapy promoted the pro-inflammatory activity of monocytes. Conclusion . Peripheral blood monocytes of TNBC patients are capable of recovering their subset composition after NAC by the 21st day after the first cycle of chemotherapy.

RUDN Journal of Medicine. 2024;28(4):427-438
pages 427-438 views

Tumor hybrid cells in non-small cell lung cancer: population structure and contribution to prognosis

Khozyainova A.A., Menyailo M.E., Tretyakova M.S., Bokova U.A., Korobeynikova A.A., Gerashchenko T.S., Rodionov E.O., Miller S.V., Denisov E.V.

Abstract

Relevance. Non-small cell lung cancer (NSCLC) is the leading cause of cancer-­related mortality worldwide due to the high recurrence and metastasis rates. It is generally accepted that metastases and recurrences are formed by tumor cells with a highly invasive, stem and chemoresistant phenotype. Tumor hybrid cells (THCs) formed by the fusion of tumor cells with a wide range of normal cells: macrophages, fibroblasts, mesenchymal stem cells, etc. are considered to be potential metastasis and recurrence-­initiating cells. However, the phenotypic diversity of THCs, and their association with disease progression remain poorly understood. The aim of the study was to characterize the population composition of THCs in NSCLC and its association with clinicopathological characteristics, metastasis and recurrence. Materials and Methods. A total of 50 patients with NSCLC were included. Fresh frozen samples of tumor tissue obtained during resection and morphologically verified were used to analyze types and number of THCs. THCs were analyzed by flow cytometry in primary tumors using markers for tumor cells, cancer stem cells, leukocytes, macrophages and fibroblasts. Results and Discussion. THCs were detected in all NSCLC patients. Most THCs demonstrated leukocyte, macrophage and stem characteristics. The number and frequency of THCs depended on neoadjuvant chemotherapy. THCs with leukocyte and stem cell markers (pan-­CK+CD45+CD44+CD73+) were associated with locoregional recurrence, whereas THCs with macrophage and stem cell markers (EpCAM+CD45+CD44+CD73+CD163+) — with distant metastases. Conclusion. This study is the first to comprehensively describe the population composition of THCs in NSCLC, their association with clinicopathological characteristics, neoadjuvant chemotherapy and disease prognosis. Detection of prognostically relevant THCs could be an effective approach for predicting the risk of metastasis and recurrence of NSCLC and the basis for the development of therapy focused on the prevention of cancer progression.

RUDN Journal of Medicine. 2024;28(4):439-451
pages 439-451 views

Molecular-biologic and immunohistochemical features of undifferentiated pleomorphic sarcomas

Kosyreva A.M., Jumaniyazova E.D., Dzhalilova D.S., Sentyabreva A.V., Miroshnichenko E.A., Fetisov T.I., Lokhonina A.V.

Abstract

Relevance. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of soft tissue sarcomas. The polymorphism of tumor cells and high degree of malignancy account for the aggressive potential of UPS. Due to the rarity of occurrence and high heterogeneity of UPS, the number of studies describing the cellular composition and molecular-­biological characteristics is very limited. Objective is to assess the cellular composition and gene expression of UPS. Materials and Methods. Biomaterial from 10 patients with UPS was analyzed in the study. In this study we used primary antibodies to CD163 (marker of M2 macrophages) and Fibroblast activation protein (FAP — marker of fibroblasts) and secondary Caprine-­Anti-­Rabbit IgG HRP were used. HRP-tagged secondary antibodies were manifested using DAB. Antibodies for automated BOND-III IHC stainer were used to evaluate the microenvironment: CD68‑marker of macrophages, CD19‑marker of B-lymphocytes, CD56‑marker of neuroendocrine tumors, metastasis protein, Ki67 antigen-­proliferation marker, Bcl‑2‑oncoprotein. Staining on an automated BOND-III IHC stainer was performed according to standard protocols. In homogenized samples of tumor tissue and peritumoral area with the number of cells 106/ml in order to assess the microenvironment of the tumor and surrounding tissue, cytofluorimetric study of the relative number of CD14+ and CD16+ monocytes, CD68+ macrophages, CD86+ M1 macrophages, CD163+ and CD206+ M2 macrophages, CD4+ helper T-lymphocytes and CD45+ leukocytes was performed on the MACS Quant Analyzer device. The mRNA expression levels of HIF1A, VEGF, MMP2, ARG1, NOS2, and EGFR were determined in tumor tissue and peritumoral samples by PCR. The RNA Solo RNA kit was used for RNA isolation, and the MMLV RT Kit was used for reverse transcription. The amplification reaction with real-time detection was performed on a DTprime Real-­Time Amplifier. Results and Discussion. The expression of CD56, FAP, CD68 is characteristic for UPS. Among the cells of the microenvironment, macrophages and CD16‑monocytes predominate in UPS. EGFR expression level is increased in tumor cells of the UPS compared to the peritumoral region. The expression levels of ARG1, NOS2, HIF1A, VEGF, and MMP2 in tumors have individual differences and are not specific to the UPS. Conclusion. In our study, we analyzed the cellular composition and gene expression in UPS samples. Further follow-up of patients is necessary to evaluate the clinical significance of each marker.

RUDN Journal of Medicine. 2024;28(4):452-465
pages 452-465 views

Malignant neoplasms ozone therapy

Andreev P.Y., Moshurov I.P., Korotkih N.V., Shishkina V.V., Samoilenko T.V., Goryushkina E.S., Antakova L.N.

Abstract

The development of effective therapeutic approaches for the treatment of malignant neoplasms is one of the priorities of modern biomedical research. Disappointing data from epidemiological indicators and statistical calculations of morbidity dictate the need to develop and implement increasingly effective treatment methods, as well as its modulation. In experimental work on cell lines, animal models and in clinical studies, the positive biological effects of ozone therapy are noted, consisting in the ability of ozone to have an antineoplastic effect on tumors and sensitize them to chemoradiotherapy. Therapy of malignant tumors is a key object of modern biomedical studies. The aim of this work was to summarize experimental and clinical data on the place of ozone therapy in the treatment of malignant neoplasms. The literature included in the current systematic review was obtained from an independent literature search performed in the following databases: Elibrary, Сyberleninka, Central Scientific Medical Library, Google Scholar, Semantic Scholar, PubMed and Cochrane. It was found that the biological effects of ozone are based on its reactions with organic compounds: water-soluble and lipophilic antioxidants, as well as unsaturated fatty acids, resulting in the generation of reactive oxygen species and lipid peroxides, which have messenger properties, interacting with various cellular and tissue structures. It is believed that early biological effects are realized due to reactive oxygen species, and late ones due to lipoperoxides. Conclusion. In a number of research works, which were carried out on many cultures of tumor cells, animal models and in clinical use, the positive biological effects of ozone therapy were established, associated with the fact that ozone has a cytotoxic and cytostatic effect on cyclic histogenesis and localization, and also sensitizes blastotransformed cells to ionizing agents and chemotherapeutic agents.

RUDN Journal of Medicine. 2024;28(4):466-487
pages 466-487 views

ГИСТОЛОГИЯ

Distribution of β-amyloid and pTau in brain cortex depending on age and mental state

Sentyabreva A.V., Vasyukova O.A., Zorkina Y.A., Andryuschenko A.V., Kostyuk G.P., Eremina I.Z., Kosyreva A.M.

Abstract

Relevance. Alzheimer’s disease (AD) is the most cause of disability and dementia, which is the 7th leading cause of death worldwide. Diagnosis of AD includes detection of amyloid plaques and hyperphosphorylated tau protein (pTau) in the brain. However, in recent years the amyloid hypothesis of AD development has been criticized and revised, and a growing pool of data emerges indicating more complex pathogenetic mechanisms leading to neurodegeneration in AD. The aim of our work was to evaluate the presence and distribution of amyloid plaques and pTau fragments in different regions of the cerebral cortex in patients > 60 years old with diagnosed dementia and without cognitive impairment, as well as in people < 60 years old. Materials and Methods. The amount of β-amyloid and pTau fragments in three groups of patients was measured on IHC stained histological sections in the regions of parahippocampal, temporal, and occipital cortex. Results and Discussion. Amyloid plaques were detected in all patients over 60 years of age (with and without dementia), while in younger individuals 60 years of age they were found in 66% of cases. The largest amyloid-β burden was observed in the occipital cortex. pTau was detected in all cortical areas in the three groups of patients. Also, the amount of pTau was higher in the occipital cortex in patients over 60 years of age both with and without dementia than in the group of people under 60 years of age. Conclusion. Thus, accumulation of pTau occurs earlier than β-amyloid. The amount of pTau was higher in patients over 60 years of age with clinically manifested dementia, while in some regions the amount of amyloid conglomerates is higher in cognitively intact patients. The findings point to much more complex mechanisms of the neurodegenerative diseases development with the formation of amyloid plaques being a consequence rather than cause of the disease.

RUDN Journal of Medicine. 2024;28(4):488-498
pages 488-498 views

SURGERY

The choice of the optimal mesh implant for hernioplasty operations depending on the properties of mesh implants

Protasov A.V., Mekhaeel M.S., Salem S.M.

Abstract

Silver and titanium were the first used elements in the era of hernia-strengthening biomaterials about a hundred years ago, reaching up to 150 types nowadays. The uniqueness of Deeken and Lake Mesh Classification system is its dependence of the properties of the used materials in classifying them, where three main categories of meshes was established; permanent synthetic, absorbable (of biological origin) derived; furtherly divided into composite, non-composite types, and hybrid meshes. The physical characteristics of each category are determined by the pore size, thread diameter, thickness and density. Moreover, tear resistance, suture retention, uniaxial tensile and planar biaxial tensile testing, ball burst, make it possible to refine the properties of the mesh implant. This article is devoted to understanding the types of mesh materials used for repair of the anterolateral abdominal wall hernias by highlighting the properties of their scaffold materials, coating and barriers, as well as their improvement through coating by different several materials improving their properties in order to meet the needs of sufficient and satisfactory hernia repair seeking for leadership in choosing mesh implants.

RUDN Journal of Medicine. 2024;28(4):499-507
pages 499-507 views

Stomatology

Alveolar clefts bone grafting: on the issue of modern treatment paradigm

Kuznetsov A.M., Imanova K.Z., Gusarov A.M., Yackevich O.S., Zorych M.E., Korotkova N.L., Kopylova U.O., Nagajchenko A.M.

Abstract

Relevance. One of the most common birth defects is congenital cleft lip, palate and alveolar ridge. Modern aspects of surgical correction of alveolar clefts are discussed in this literature review. Approaches to performing this operation have changed significantly over time. A unified concept does not exist to this day due to the fact that the intervention can affect the growth of the upper jaw, and the fact that approaches used in pediatric surgery may not be effective in adult patients. The choice of osteoplastic materials also remains a very pressing issue, since the results of using these materials for other pathologies vary. The aim of the study is to systematize data on osteoplastic surgeries for alveolar clefts in patients of different ages and analyze of published scientific works. Materials and Methods. The authors analyzed scientific data in the search engines PubMed, Google Scholar and eLibrary. Scientific literature published from 1901 to 2024 was analyzed. Results and Discussion. At the moment, most authors are inclined to perform the operation during the period of early mixed dentition in the presence of a lateral incisor rudiment, or late mixed dentition (before the eruption of the canine) in its absence. Performing surgery in adult patients is associated with a greater degree of graft resorption and additional difficulties. Among osteoplastic materials, preference is given to autologous bone. The most popular remains an avascular autograft from the iliac crest region. Attempts are being made to avoid the use of autologous materials and to reduce its quantity in order to reduce donor morbidity. In complex cases, it may be necessary to use techniques using revascularized autografts or prosthetics. Great importance is attached to the orthodontic preparedness of patients. Conclusion. The approach to patients with alveolar cleft should be differentiated. It is important to take into account the patient’s age, somatic and dental status to select the most correct management tactics.

RUDN Journal of Medicine. 2024;28(4):508-536
pages 508-536 views

PHARMACOLOGY

New approaches to quality control of drugs from the group of branched polymers on the example of dextran

Marchenkova L.A., Safdari A., Uspenskaya E.V.

Abstract

Relevance. Colloidal blood substitutes — polyglukins — have been used in infusion therapy for 70 years and are widely represented in modern pharmaceutical regulatory documentation. Glucose polymer with a (1→6) glycosidic linkages (dextran), as the main active pharmaceutical ingredient of polyglukins, has exceptional properties, such as long-term circulation in the bloodstream, inertness, volemic, detoxification, and antithrombotic effects. Quality authentication control of polyglukins usually includes FT-IR spectroscopy, while systems of polymeric micelles require characterization of dispersion and the electrophoretic properties that are in unambiguous correspondence with their biological activity. The aim of the study was to develop new approaches based on laser scattering methods to identify polymer-­based blood substitute drugs to complement existing regulatory documentation, and assess their biological activity using the Spirotox method. Materials and Methods. Reopolyglukin (Rpg) — an aqueous solution of dextran with a molecular weight of 30—40 kDa (Dex35) and 0.9% sodium chloride; water with different contents of the heavy isotope  , Malvern Zetasizer ZSP equipment for measuring hydrodynamic radius (d, nm), zeta potential of colloids (ξ, mV); Biotesting method with Spiostomum ambigia cell for evaluating survival time in different dilutions of Rpg. Results and Discussion. Determination of submicron dispersity in the initial Rpg and in dilutions of water isotopologues indicates the presence of particles d50(Median) = 10 nm with a volume concentration V = 18% and a low polydispersity index PDI ~ 0.2. It is shown that the size distribution of nanoparticles is influenced by a noticeable effect is the concentration of the isotope. Biopharmaceutical analysis with the usage of Protozoa based on the Arrhenius kinetic model showed a decrease in the toxicity of aqueous solutions of Rpg in an environment with a reduced content of the isotope  . New approaches based on the use of laser analysis methods have been developed to characterize the dispersion properties and colloidal stability of polymer-­based blood substitutes. Conclusion. The results obtained can be included into the new edition of a pharmacopeial article on Reopolyglukin preparations.

RUDN Journal of Medicine. 2024;28(4):537-547
pages 537-547 views

GINECOLOGY

Risk factors for recurrence of vulvovaginal infections

Kolesnikova E.V., Osipova L.K., Zharov A.V.

Abstract

Relevance. Currently, inflammatory and non-inflammatory infections of the lower urogenital tract are a serious medical problem and are one of the main reasons for seeking medical help from gynecologists. These infections account for a significant share (from 55 to 80 %) of diseases of the reproductive system. The most common symptoms of vulvovaginal infections (VVI) are discomfort in the genitals, discharge, itching, superficial dyspareunia and unpleasant odor. In addition to the main clinical signs of inflammation, there may be the symptoms of vaginal dysbiosis that occurs without obvious signs of inflammation. Thus, VVI is manifested by a wide range of clinical symptoms and is a collective term for several nosological entities. Conclusion. Despite the existence of various methods for diagnosing and treating VVI, the problem of recurrent vulvovaginal infections, which can lead to various pathological conditions both in the reproductive system and in the psychoemotional and sexual sphere of patients, remains extremely relevant and complex. These diseases require timely detection and effective treatment. Therefore, scientific research aimed at identifying the causes (risk factors) of relapse of the disease is becoming especially relevant today. However, even with the exclusion of general risk factors, the exacerbation of vaginal dysbiosis in patients is often impossible to prevent.

RUDN Journal of Medicine. 2024;28(4):548-559
pages 548-559 views

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