Cell therapy is a promising direction in medicine, which can significantly improve the results of treatment of various diseases, including local radiation injuries (LRI). The purpose of the study was to compare the results of using decellularized human amniotic membrane isolated and together with lyophilisates of conditioned media of MSCs from the human gingival mucosa and MSCs from human placental tissue and their effect on tissue regeneration in LRI. Material and methods: The study included 42 laboratory animals (white male rats of the Wistar line), randomly divided into 6 groups: K – control group without therapy, on the 21st day after irradiation, groups using: Am+LD – application of lyophilisate of the conditioned medium of MSCs of the human gingival mucosa (LD) under the decellularized amniotic membrane, Am+LP – application of lyophilisate of the conditioned medium of MSCs of human placental tissue (LP) under the decellularized amniotic membrane, Am – application of the decellularized amniotic membrane, AmCl – application of the decellularized amniotic membrane with medical glue BF-6, Kl – application medical glue BF-6. Modeling of LRI in animals was carried out on an LNK-268 X-ray unit at a dose of 110 Gy and observed until the 112th day after irradiation, monitoring of the ulcerative surface of the skin and the course of the inflammatory process of LRI was carried out with calculation of the area of ​​the total changed skin in the ImageTool software. Planimetric and histological analyzes were performed. Results: It was demonstrated that, when compared with the control, the use of decellularized amniotic membrane in LRI on days 77 and 112 after irradiation increased the healing rate by 4.6 and 18 times, respectively; decellularized amniotic membrane with lyophilisate of placental MSC conditioned medium increased the rate of wound healing by 13.5 and 27 times, respectively; and a dellularized amniotic membrane with lyophilisate of MSCs from the human gingival mucosa to 100 % healing. Healing of the ulcer surface area of the LRI in 83.5 % of animals in the Am group demonstrated the effectiveness of using isolated decellularized amniotic membrane even in the absence of human MSC lyophilisates. At the same time, healing of the ulcer surface area of the LRI in the AmCl group was 20 % of cases, where the decellularized amniotic membrane was fixed with BF-6 medical glue, which was less effective compared to other groups. Conclusion: The proposed combined use of decellularized amniotic membrane with lyophilisates of the conditioned medium of mesenchymal stromal cells (MSCs) of the placenta and mucous tissue of the human gums and the isolated use of decellularized amniotic membrane led to complete epithelization of the ulcer surface, a pronounced favorable course of grade IIIb–IV LRI in laboratory animals and a reduction in healing time , the absence of local or systemic complications can be considered as a promising method of conservative treatment for LRI of the skin and a new therapeutic approach in the treatment of non-healing and chronic wounds.

This article describes the process of developing a tissue-engineered structure that meets the biocompatibility and biodegradation parameters necessary for replacing cartilage tissue defects. The study was carried out using 3D bioprinting technology, which represents a promising research direction in the biomedical field. It is known that, due to the specifics of its structure, cartilage tissue is not capable of complete regeneration of damage. The methods currently used for treating arthrosis are associated with a number of limitations and disadvantages, which makes research aimed at developing alternative methods for arthrosis treatment particularly relevant. The development of tissue-engineered structures by 3D bioprinting requires the materials not only certified for medical use but also exhibiting biocompatibility and biodegradation properties. Polylactide (PLA) and sodium alginate satisfy the above requirements; moreover, their availability and economic affordability make them one of the most popular materials for 3D bioprinting.

Purpose: To evaluate the frequency and spectrum of chromosome aberrations under X-Ray exposure at doses of 80, 250, and 1000 mGy in a human multipotent mesenchymal stromal cell (MMSC) cell line during long-term cultivation. Material and methods: MMSCs were isolated from human gingival mucosa by an enzymatic method and cultured in a serum-free medium. The presence of surface antigens was determined using the method of flow cytometry. The ability of the cell line to differentiate in the osteogenic, adipogenic, and chondrogenic directions was studied using induction media. Authentication was performed by genotyping of polymorphic STR loci, cytogenetic analysis was performed by multicolor fluorescent in situ hybridization (mFISH). Irradiation was carried out on an X-ray biological unit RUB RUST-M1 (Russia) at a dose rate of 40 mGy/min, a voltage of 100 kV, and a current of 0.8 mA. Results: At the first passage after irradiation, a statistically significant increase in the frequency of non-clonal CA compared with the control was recorded at a dose of 80, but not 250 and 1000 mGy. At the late stages of cultivation, the average frequency of breaks per chromosome in the group of non-irradiated cells did not differ from the values obtained after irradiation at doses of 80, 250, and 1000 mGy (p > 0.05). However, in MMSCs irradiated at a dose of 80 mGy, damage occurred more often in pairs of chromosomes 6 and 10, and at a dose of 1000 mGy, in a pair of chromosomes 9. A single irradiation of MMSCs in vitro did not affect the growth and progression of MMSCs characteristic of the studied primary cell line, of clonal cells with chromosome translocations and monosomy X, but led to an increase in the representation of a clone with tetrasomy 8. The total number of random clones with chromosome translocations that arose de novo increased after irradiation at a dose of 1000 mGy. Conclusion: Minor fluctuations in the proportion of cells with non-clonal CA, depending on the dose received in the early stages after irradiation (passage 1–4), disappeared at the later stages of cultivation (passage 8–14). There were no differences in mean frequencies between irradiated and non-irradiated MMSCs, but after irradiation, damage to some chromosomes could occur more frequently than others. A single X-ray irradiation of MMSCs can promote the growth and progression of primary pathological cytogenetic clones, regardless of the dose received, as well as an increase in the total number of de novo cell clones with chromosomal translocations that have arisen. A single X-ray irradiation of MMSCs can promote the growth and progression of primary pathological cytogenetic clones, regardless of the dose received, as well as an increase in the total number of de novo cell clones with chromosomal translocations that have arisen.

Background: Adjuvant radiation therapy (ART), an integral part of locoregional breast cance (BC) therapy, acting not only locally, but also systemically and leads to a shift in homeostasis, which is reflected in routine general clinical tests. Tumor necrosis factor (TNF) is a proinflammatory cytokine, the production of which can be influenced by the single-nucleotide substitution -308(G/A)TNF. The minor allele -308A can be included in the stable inherited haplotype AH8.1 of the HLA gene complex. At the same time, the carriage of the -308A without the AH8.1 haplotype is associated with a poor prognosis in patients with BC. The aim of the study was to evaluate the features of the systemic response to the course of ART in carriers of TNF-associated genotypes with BC. Material and methods: The sample is represented by 147 BC patients who underwent a course of ART (2 Gy in 25 fractions). Clinical and morphological characteristics and data of general clinical blood analysis were obtained from medical histories. Venous blood samples for the study were obtained at the beginning and at the end of the ART course. Alleles -308(G/A)TNF and marker alleles of haplotype AH8.1 (HLA-A×01, HLA-B×08 and HLA-DRB1×03) were determined by allele-specific PCR. sTNF concentrations were determined by the ELISA in 102 blood plasma samples. Results: TNF-associated comparison groups were identified based on genotyping: (1) 114 carriers -308GG of the TNF gene, regardless of the AH8.1 haplotype (77,6 %); (2) 23 carrier -308A(AH8.1pos) had at least one AH8.1 marker allele (15.6 %); (3) 10 carriers -308A(AH8.1neg) did not have any AH8.1 marker allele (6.8 %). In the -308A(AH8.1neg) group the average concentration of sTNF both at the beginning and at the end of ART was significantly higher and, unlike other comparison groups, did not significantly decrease at the end of the ART course. A significant decrease in absolute values was revealed during ART in a number of cases for leukocytes, platelets and lymphocytes, however within the reference values. In the group -308A(AH8.1neg) correlation analysis revealed a high strength of positive connections between sTNF and leukocytes (r=0.71; p=0.027), platelets (r=0.67; p=0.04), neutrophils (r=0.70; p=0.027) only at the end of ART, whereas at the beginning ART these correlations were weak (r≤0.3) and statistically unreliable. For other genetic groups, the revealed correlations were not strong enough. Conclusion: The revealed features of the systemic response to ART for carriers of a prognostically unfavorable genotype -308A(AH8.1neg) – a high concentration of sTNF and a positive correlation with the content of leukocytes (probably due to neutrophils) and platelets – can be considered as targets of individualized therapy.

Background: Radiation therapy (RT) is an important step in the treatment of primary breast cancer as it is one of the leading contributors to cancer incidence among women. Most patients with this disease acquire radiation-induced lymphopenia in the early post-radiation period; however, little is known about the effect of RT on the composition of lymphocyte populations in such patients. This study was aimed at investigating the effect of adjuvant remote RT—performed in the classical mode for patients with primary breast cancer—on the main components of cell-mediated immunity (major lymphocyte populations), including those in patients receiving chemotherapy. Methods: Between 2020 and 2022, 96 patients with stage I–III breast cancer were included in this study. All patients in the final stage of complex treatment received RT via a 3D conformal technique (3DCRT). The clinical target volume of this RT included the breast or chest wall and locoregional lymphatics. Flow cytometry was used to assess the levels and phenotypes of circulating lymphocytes before and after RT (no more than 7 days before and after RT). The evaluation of the impact of polychemotherapy (PCT) was conducted to determine whether it was a risk factor for the onset of radio-induced lymphopenia (RIL) in the context of RT. Results: When assessing the immune status in the general group of patients (n = 96), before the start of adjuvant external beam radiotherapy (EBRT), the average number of lymphocytes was 1.68 ± 0.064 × 109/L; after the course of adjuvant EBRT, it decreased to 1.01 ± 0.044 × 109/L (p < 0.001). When assessing the absolute indicators of cellular immunity in the general group of patients with BC after a course of adjuvant EBRT, significant dynamics were revealed by the changes in all cell populations of lymphocytes (paired t-test, p < 0.05). Conclusion: The adaptive immune system in breast cancer patients changed in the early post-radiation period. The absolute levels of B-, T- and natural killer cells significantly reduced after RT regardless of whether the patients previously underwent chemotherapy courses. RT for patients with primary breast cancer should be considered in clinical management because it significantly alters lymphocyte levels and should be considered when assessing antitumor immunity, as significant changes in T-cell immunity have been observed. In addition, the identified changes are critical if specific targeted therapy or immunotherapy is needed.

Tumor necrosis factor (TNF) plays an important role in the pathogenesis of breast cancer (BC). The -308(G/A)TNF polymorphism allele -308A is part of the autoimmune ancestral haplotype AH8.1 associated with elevated serum sTNF levels. Previously, we showed a decrease in overall survival for carriers -308A/AH8.1-. The aim of the study was to assess the effect of haplotypes AH8.1 on the level of sTNF and clinical and morphological characteristics of BC patients. The study included 100 people with adjuvant radiotherapy treatment. The concentration of sTNF was determined by the ELISA. Additionally, 30 archival DNA samples of primary BC patients carrying the allele -308A with a known sTNF level were genotyped. Alleles -308(G/A)TNF and marker alleles of haplotype AH8.1 (HLA-A*01, HLA-B*08 and HLA-DRB1*03) were determined by allele-specific PCR. Based on the polymorphism of -308(G/A)TNF and marker alleles of haplotype AH8.1, three comparison groups were identified: -308GG carriers of the TNF gene independently of haplotype AH8.1 (76

Purpose of the study. The aim of this work was to study the effect of conservation in various cryoprotectants on the biomechanical and morphological properties of the umbilical cord (UCA) arteries.Materials and methods. The material for this work was 12 umbilical arteries, which were divided into 4 study groups: (1) native UCA – control without freezing; (2) APC frozen in 5 % dextran with the addition of dimethyl sulfoxide (DMSO) to 10 % and 7.5 % human serum albumin (HSA); (3) APC frozen in glycerin and (4) UCA frozen in propanediol. For all groups, morphological and biomechanical studies were carried out. The statistical data were processed using the GraphPad Prism 9.2.0 program. Analysis of variance was used to find significant differences.Results. Freezing with 5 % dextran, 10 % DMSO and 7.5 % human albumin did not lead to significant changes in the morphology of vascular tissue compared to control. The conserved vascular tissue retains a moderate level of type I collagen, regardless of the method of conservation. The presence of statistically significant differences between the control and frozen UCAs was shown for Young's modulus (p < 0.05; 6.9 [6.8; 7.0] for the native artery; 2.3 [2.0; 2.6] for the artery preserved with the use of dextran, DMSO and human albumin; 2.3 [1.4; 3.2] for the artery preserved in glycerin and 0.8 [0.6; 1.0] – in propanediol, respectively).Conclusion. 1) Freezing and storage of UCA at 5 % dextran, 10 % DMSO and 7.5 % HSA does not lead to a significant change in the morphology of vascular membranes and cell nuclei; 2) The preservation of type I collagen according to the results of IHC is qualitatively reduced from a conditional indicator of +2 to +1 for frozen agroindustrial complexes compared with control ones; 3) Conservation leads to a significant decrease in the modulus of elasticity of the walls of the agroindustrial complex compared with control vessels (p < 0.05).

Purpose: Study of chromosomal aberration yields with a three-color FISH method in the peripheral blood lymphocyte cultures of patients with breast cancer before and after local irradiation. Material and methods: Venous blood was obtained from 24 patients aged from 33 to 79 years which suffering from cancer of the left or right breast after the implementation of a sectoral or radical resection of an affected organ with subsequent local adjuvant distant radiation therapy (DRT) to the scar area. Also it could be preceded by adjuvant polychimotherapy (PCT). A linear accelerator of the Trilogy system based on the Clinac iX platform was used for local irradiation. SOD was installed at 50 Gy per 25 fractions (daily 2 Gy). venous blood sampling produced to PCT and/or DRT and after 1 and/or 3 months after irradiation. A set of DNA probes to 1, 4 and 12 pairs of chromosomes was used for three-color FISH staining. Results: Levels of translocations, dicentrics and acentrics (per 100 cells) in peripheral blood lymphocyte cultures of patients up to DRT did not differ significantly with and without PCT and were amounted to average 0.63 ± 0.10; 0.10 ± 0.04 and 0.17 ± 0.06, respectively. The frequency of these chromosome rearrangements significantly increased after radiation therapy by an average of up to 4.62 ± 0.46; 1.48 ± 0.19 and 0.95 ± 0.14. The differences between 1 and 3 months of taking material after irradiation were absent. One of the patients, unlike the rest, was cytogenetically examined 11 years after a similar local irradiation, and the frequencies of translocations and dicentrics in her lymphocyte culture were 4.56 and 0.19 (per 100 cells), respectively, while they were varied from 1.63 to 10.00 for translocations and from 0.27 (0 in one patient) to 4.06 for dicentrics for other patients. Conclusion: When using a three-color FISH method there was a significant increase in the frequencies of translocations, dicentrics and acentrics in peripheral blood lymphocyte cultures of patients after DRT of breast cancer. At the same time there were more translocations than dicentrics and, apparently, they remain at the initial level for a long time. The frequency of translocations per 1 cell with translocations in the peripheral blood lymphocyte cultures in most cases exceeds 1 after local DRT of the breast cancer. The correlation between average physical doses to the whole body and cytogenetical estimates in individual patients was statistically insignificant.

Purpose: Evaluation of the effectiveness of the use of human decellularized amniotic membrane, both as an independent covering material and as a cell-free matrix for syngeneic regenerative cells of adipose tissue (stromal-vascular fraction – SVF, adipose tissue ‒ AT) in local radiation injuries (LRI) IIIb-IV severity in laboratory animals. Material and methods: 42 laboratory animals were studied. LRI modeling was carried out on an X-ray at a dose of 110 Gy. Animals were randomized randomly and divided into 6 groups depending on the type of treatment: 1st group (K) ‒ control group animals after irradiation did not receive specific treatment; the 2nd group (Gl) ‒ after irradiation, medical glue BF-6 was applied to the ulcer surface on the 21st day; 3rd group (Am) ‒ animals after irradiation on the ulcer surface was applied decellularized amniotic membrane, fixed with interrupted sutures on the 21st day; 4th group (Am-Gl) ‒ animals after irradiation on the ulcer surface was applied decellularized amniotic membrane, fixed with medical adhesive BF-6 for 21 days; 5th group (SVF-Gl) ‒ after irradiation, the SVF AT at a dose of 0.4×106 cells was applied to the ulcer surface after irradiation, followed by fixation with BF-6 medical glue for 21 days; the 6th group (Am-SVF) ‒ after irradiation, SVF AT was applied to the ulcer surface at a dose of 0.4×106 cells under the decellularized amniotic membrane, fixed with interrupted sutures on the 21st day. Results: On the 112th day, complete healing of the ulcer was observed in 100 % of animals in the Am-Gl group, in 70 % in the Am and Gl groups. There was no complete healing of the ulcer in the SVF-CGl and Am-SVF groups. The greatest reduction in the area of the total altered skin from 21 to 112 days of the experiment was noted in the groups Gl-SVF (34.7 %), K (31.6 %), Am-SVF (30.7 %). In the Am-Gl and Am groups, a reduction in the area of the total altered skin was recorded by 24.6 % and 14.7 %, respectively. In the GL group, the reduction in the area of the total altered skin was the smallest, by only 13.5 %. Conclusion: The use of a decellularized human amniotic membrane fixed with medical adhesive BF-6 can be considered as a promising method for the conservative treatment of LRI of the skin.

Introduction. Urethral stricture is a complex and urgent problem in operative urology. The main problem in the treatment of extended structures of the posterior urethra is the inability to form an adequate urethral site for augmentation urethroplasty with the common buccal graft, which has a priority in the treatment of penile strictures. The use of tissue acellular matrices may be promising in the development of reconstructive urology, which in the future will solve a number of problems associated with augmentation urethroplasty. The purpose of this article is to study the possibility of using a cell-free matrix of a donor artery as a free flat flap for stricture replacement urethroplasty on a model of laboratory animals (rabbits). Materials and methods. Donor blood vessels were Used, which were subjected to detergent-enzymatic perfusion decellularization. To assess the quality of the cell-free matrix, a histological study and an immunohistochemical study were performed. The cell-free flap of the donor artery was fixed to the protein envelope from the side of the simulated defect and posterior on-lay urethroplasty was performed.Results and discussion. The resulting matrix was characterized by the absence of detectable cell nuclei, preserved type I collagen, and a DNA content of no more than 50 ng / mg of tissue. In the postoperative period, normal motor activity of animals, normal urination, weight loss was not observed. The levels of C- reactive protein, creatinine, and urea in peripheral blood 5 months after surgery were within the normal range: 0.285±0.04839 mg / l, 93.5±8.057 mm / l, and 8.35±1.355 mm/l, respectively. If cystourethrography with the help of computer tomography data for stricture of the urethra is not revealed. During magnetic resonance imaging in the axial and sagittal projections, the patency of the urethra was indirectly confirmed. Conclusion. In a laboratory animal model, it was shown that the resulting cell-free flap has in vivo biocompatibility and can be used for replacement urethroplasty of posterior urethral strictures.

Chronic wounds do not progress through the wound healing process in a timely manner and are considered a burden for healthcare system; they are also the most common reason for decrease in patient quality of life. Traditional wound dressings e.g., bandages and gauzes, although highly absorbent and effective for dry to mild, exudating wounds, require regular application, which therefore can cause pain upon dressing change. In addition, they have poor adhesional properties and cannot provide enough drainage for the wound. In this regard, the normalization of the healing process in chronic wounds is an extremely urgent task of public health and requires the creation and implementation of affordable dressings for patients with chronic wounds. Modern wound dressings (WDs) are aimed to solve these issues. At the same time, hydrogels, unlike other types of modern WDs (foam, films, hydrocolloids), have positive degradation properties that makes them the perfect choice in applications where a targeted delivery of bioactive substances to the wound is required. This mini review is focused on different types of traditional and modern WDs with an emphasis on hydrogels. Advantages and disadvantages of traditional and modern WDs as well as their applicability to different chronic wounds are elucidated. Furthermore, an effectiveness comparison between hydrogel WDs and the some of the frequently used biotechnologies in the field of regenerative medicine (adipose-derived mesenchymal stem cells (ADMSCs), mesenchymal stem cells, conditioned media, platelet-rich plasma (PRP)) is provided.

The VHL gene alterations are the early and characteristic feature of clear cell renal cell carcinoma (ccRCC). We have examined VHL mutations in sporadic 98 ccRCC cases to evaluate their localization in relation to functionally important motifs of the VHL protein. The DNA samples were obtained from snap-frozen carcinoma biopsies and used for Sanger sequencing, while 62 ccRCC DNA cases were studied by next generation sequencing (NGS) analysis in parallel. In 73 (74.4 %) оf 98 ccRCC cases the somatic non-silent VHL mutations were identified. Loss of function VHL mutations (nonsilent, frameshifts or in splicing sites) were detected in 40 (40.8 %) ccRCC, while missense mutations – in 35 (35.7 %) ccRCC. In total 76 mutations important for VHL functioning were detected in 72 (73 %) ccRCC samples, of them 15 mutations (deletion / insertion in-frame or frameshifts) were identified for the first time. Four ccRCC cases contained two mutations each. Most of missense mutations disturb the sites of VHL interactions with HIF, РКС or kinesin. The pathogenicity of p.P154P silent mutation and intronic mutations near mRNA VHL splicing sites was discussed. The obtained results are important for understanding the role of VHL mutations in ccRCC progression and prognosis.

The VHL gene alterations are the early and characteristic feature of clear cell renal cell carcinoma (ccRCC). We have examined VHL mutations in sporadic 98 ccRCC cases to evaluate their localization in relation to functionally important motifs of the VHL protein. The DNA samples were obtained from snap-frozen carcinoma biopsies and used for Sanger sequencing, while 62 ccRCC DNA cases were studied by next generation sequencing (NGS) analysis in parallel. In 73 (74.4 %) оf 98 ccRCC cases the somatic non-silent VHL mutations were identified. Loss of function VHL mutations (nonsilent, frameshifts or in splicing sites) were detected in 40 (40.8 %) ccRCC, while missense mutations – in 35 (35.7 %) ccRCC. In total 76 mutations important for VHL functioning were detected in 72 (73 %) ccRCC samples, of them 15 mutations (deletion / insertion in-frame or frameshifts) were identified for the first time. Four ccRCC cases contained two mutations each. Most of missense mutations disturb the sites of VHL interactions with HIF, РКС or kinesin. The pathogenicity of p.P154P silent mutation and intronic mutations near mRNA VHL splicing sites was discussed. The obtained results are important for understanding the role of VHL mutations in ccRCC progression and prognosis.

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of a number of diseases, including oncological and autoimmune diseases. The –308(g / a)TNF and –238(G / A)TNF polymorphisms are included in the extended ancestral haplotypes covering the whole complex of HLA genes. We assumed that the previously found effect of these polymorphisms on the overall survival (OS) of breast cancer (BC) patients may be a consequence of cooperation with the genomic environment, namely, with the AH8.1 and B57 haplotypes associated with autoimmune conditions. The archival collection of DNA from 442 primary BC patients and 327 women from the control group with known –308(g / a)TNF and –238(G/A)TNF genotypes was used in the work. Four hundred and twelve BC patients were tested for AH8.1 and B57 markers. During the study, the association of –308a and –238A alleles of the TNF gene with haplotypes AH8.1 and B57, respectively, was confirmed. Analysis of the results of the study demonstrated that TNF gene polymorphisms do not affect the predisposition to BC disease, but significantly decrease the OS of BC patients; moreover, the final effect of the TNF gene polymorphisms on the disease prognosis depends on genomic context. At stage II of the disease, the carriers of the –308ag / –238GG genotype in the presence of marker AH8.1 alleles and the –308gg / –238GG carriers, regardless of AH8.1 markers, had a 10-year OS above 80%, while a 10-year OS was lower than 50% in the –308ag / –238GG carriers in the absence of AH8.1 markers and in the –308gg / –238AG genotype carriers ( p = 0.0076). The mechanisms of action of –308(g / a)TNF and ‒ 238(G / A)TNF differ, and a decrease in OS in the carriers of minor –238A allele is mediated by its association with HLA-B*57 , while a decrease in OS in the carriers of –308a , on the contrary, is not associated with the ancestral AH8.1 haplotype. Thus, two genetically determined BC patient groups that have an unfavorable prognosis in conditions of standard BC therapy were detected.

Inflammation and hormonal and growth factors play an important role in the development of breast cancer (BC). Genes TNF, ESR1, and HER2 have polymorphisms that affect the level of transcription or activity of their protein products. The objective was to evaluate the effect of functional polymorphisms of these genes on the clinical and molecular features of BC. The study included 140 patients with primary BC without distant metastases. The concentrations of serum sTNF were determined for 111 BC patients. Additionally, we used archival DNA samples with known genotype–238A/G TNF from BC patients and the control- group women. Polymorphisms–238G/A TNF,–308G/A TNF,–397C/T ESR1, and Ile655Val HER2 were determined by PCR. The analysis of the data revealed the connection of AG–238TNF genotype with the Luminal A molecular subtype of tumor. A synchronous decrease of the index of proliferation Ki67 and serum level of sTNF was noted for AG–238TNF and IleVal HER2 genotypes. At the same time, carriers of the AG–238TNF more often had IleVal HER2 genotype than did carriers of GG–238TNF (70 and 32%, respectively; p = 0.032). In general, the distribution of HER2 genotypes in carriers of the AG–238TNF BC patients differed from the GG–238TNF BC patients and from both genotypes (AG and GG–238TNF) of the control group. The dependence was confirmed on archived DNA samples from BC patients with AG–238TNF genotype. There was no connection of polymorphism 397C/T ESR1 with ER status of the tumor and no connection of polymorphism Ile655Val HER2 with overexpression and/or amplification of the cell receptor Her2. Thus, the polymorphism–238G/A TNF is associated with Ile655Val HER2 and affects the molecular characteristics of BC. It is suggested that the Val HER2 may be a risk factor for BC for carriers of the AG–238TNF genotype.

Tumor necrosis factor alpha (TNF) is a multifunctional cytokine, which possesses various biologic functions depending on the type of the cells and the physiological context. TNF is synthesized by immune cells as well as malignant cells. Accordingly, TNF plays an important role in the tumor and microenvironment communication as well as systemic response to the disease. TNF gene is located at HLA class III gene locus (6p21.3) and contains several sites of single nucleotide polymorphisms in promoter, which modify TNF gene expression. G to A substitution at position −238 (rs361525) decreases TNF gene expression whereas the G to A substitution at position −308 (rs1800629) increases the expression. Studies on the possible association of these polymorphisms with various malignancies risk yielded contradictory results depending on ethnicity. Breast cancer (BC) is a multifactorial disease with clinicomorphological heterogeneity. Pathways of the main BC associated molecules (ER, PR, Her2) have crossroads with TNF signaling. The goal of the study was to identify possible TNF polymorphism effects on BC predisposition and prognosis in Russian patients.

Abstract. Increased VEGF levels in cancer patients may be associated with decreased number of dendritic cells (DCs) and lower DC function. We investigated whether VEGF gene polymorphisms -2578C>A (rs699947) and +936C>T (rs3025039) are associated with efficacy of autologous DC-based immunotherapy in patients with malignant melanoma. Evaluation of VEGFR-1 and VEGFR-2 expression on mature monocyte-derived DC revealed a decreased VEGFR-1 level (18.9±0.7% on peripheral blood monocytes, as compared to 6.3±0.6% on mature DCs) and non-changed VEGFR-2 expression (13.1±0.4% and 15.9±0.4%, respectively). The АА genotype frequency of -2578C>A (rs699947) polymorphism of VEGF gene was 46.1%. АС heterozygous state was found in 38.5%, and СС, in 15.4% of cases. The VEGF -2578 AC and AA genotypes were directly associated with progression-free survival and efficacy of treatment. The median progression-free survival of patients with -2578 AA and AC genotypes was a significantly longer (8.4 months), as compared with that of patients with CC genotypes (2.7 months), p = 0.002. The established relationship between genotype and efficacy of immunotherapy can be used to develop modern methods for predicting melanoma progression and to personalize immunotherapy including a combination with antiangiogenic therapy.

Tumor-necrosis factor (TNF) is an inflammatory cytokine that is involved in pathogenesis of different malignancies. The single-nucleotide polymorphism −238(G/A)TNF (rs361525) has been investigated for detection of a predisposition to infectious, autoimmune, and oncological diseases. The goal of the study was to investigate the association of -238(G/A)TNF polymorphism (rs361525) with breast cancer (BC) prognosis. TNF allelic variants were detected by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). We did not reveal genotype-distribution disparities among groups with various stages of the disease and various levels of expression of estrogen, progesterone, and epidermal growth factor receptors. The AG genotype frequency was about 10%, and there were no BC patients with the AA genotype in all groups. However, the 5-year survival was significantly lower for AG than GG carriers with stage II or ER-positive BC. Our data suggest that −238(G/A)TNF polymorphism is not involved in the initiation of malignancies but is a substantial factor of BC prognosis.