Cancer-testis antigens (CTA) are antigens expressed by tumor cells of various histological types, but practically absent in cells of normal tissues, with the exception of germ cells. CTA includes more than 100 proteins, most of which are grouped into large families. Currently, the use of CTA for immunotherapy in the treatment of oncological diseases has been tested in many studies, and an increase in survival time has been achieved for many cases. Therefore, they can be promising targets for the creation of antitumor drugs, targeted therapy of tumors and as diagnostic biomarkers.

The purpose of this review was to study the GAGE family of antigens, one of the CTA groups recognized by T cells. Proteins of this family, expressed in tumor cells, stimulate the development of a humoral and cellular immune response against them. It follows from this that they fully meet the requirements for targets for tumor immunotherapy. The review provides information about the structure and sequence of genes encoding proteins of the GAGE family. The question of the role of GAGE in apoptosis is considered in detail and the results of studies proving that GAGE-7C makes cells resistant to apoptosis mediated by interferon γ or Fas are presented. The results of clinical studies of the expression of GAGE group genes and proteins in various types of tumor diseases are considered and examples of the reported correlation between GAGE expression and poor prognosis in some types of cancer are given.

Thus, the proteins of the GAGE group, with a detailed study, can become a possible diagnostic and prognostic marker of cancer diseases, and in the future be used to assess malignancy and monitor tumors for the selection of treatment tactics.

Breast cancer is the most common malignant tumor in women. The tumor structure in breast cancer is characterized not only by morphological heterogeneity of tumor cells, but also by a high degree of heterogeneity of tumor microenvironment, which contains immune cells, cell matrix elements, and other components that may have procarcinogenic or anticarcinogenic effects. Therefore, personalized approaches to selecting the most effective breast cancer treatment protocols cannot be used without comprehensive analysis of the target cancer markers and cellular microenvironment biomarkers.

This review is aimed at systematizing the data on tumor microenvironment biomarkers and evaluating the prognostic value of the analysis of tumor microenvironment biomarkers in breast cancer.

Biomarkers of the tumor microenvironment are important prognostic factors. Molecular genetic analysis of the profile of these biomarkers, as well as immunohistochemical studies of the mutual arrangement of tumor cells and tumor microenvironment can be used for high-accuracy cancer diagnosis and for the selection of effective personalized therapy in breast cancer. This comprehensive research is necessary because of the plasticity of tumor microenvironment cells, which can either support tumor growth, block immune response, and provide resistance to drugs, or exhibit antitumor activity.

The key elements of the tumor microenvironment in breast cancer have been analyzed, and examples of interaction between tumor cells and the microenvironment, as well as data on the prognostic and diagnostic values of tumor microenvironment biomarkers, have been summarized. The tumor microenvironment has been shown to affect the formation of drug resistance and the efficiencies of various breast cancer therapies.

Quality Risk Management (QRM) is an important aspect of pharmaceutical development in the Quality-by-Design paradigm, since it determines the Design Space, critical quality attributes and critical process attributes.

The purpose of this review is to systematize and analyze the main aspects of the QRM system in relation to each element of pharmaceutical development. This review article discusses the following key elements of QRM such as: risk analysis, risk control, risk communication, risk verification. For risk analysis, the advantages and disadvantages of QRM tools such as Preliminary Hazard Analysis, Failure Mode Effects Analysis, Fault Tree Analysis are presented and analyzed, Hazard Operability Analysis and Hazard Analysis and Critical Control Points. In addition, a description of the methods of mathematical planning and design of experiments for pharmaceutical development and QRM is given and their significance for these systems is determined. Elements of QRM such as root cause analysis, brainstorming, and a corrective and preventive action procedure are given as risk control and mitigation tools.

In this paper, the main stages of QRM are considered and conclusions are formulated regarding the main advantages and disadvantages of the methods of identification, analysis, control, risk reporting, and the main ways for further improvement of the presented system are proposed.

Background. The article presents data on somatic mutations found in the Russian population of patients with non-small cell lung cancer (NSCLC), their frequency, distribution depending on the histological type of tumor.

Aim. To study the molecular genetic profile of Russian patients with stage I–IIIA localized NSCLC, the frequency of occurrence of various somatic mutations, variants of the switching status.

Materials and methods. Genetic testing for a panel of 78 genes using the Next Generation Sequencing method of tumor material obtained after surgical treatment of 65 patients with localized stage I–IIIA NSCLC. Processing of the received data was carried out by methods of descriptive statistics.43

Results. Mutations in the EGFR, ALK, ROS1, RET, BRAF, KRAS, MET, HER2 genes were found only in adenocarcinoma. Among non-targeted mutations in adenocarcinoma, TP53, STK11, FGFR3, EML4, NF1, RB1, and KMTC2 mutations were the most common. In squamous cell lung cancer, TP53, KMT2C, TSC1, EML4, PTEN, NF1, COL22A1, CDKN2A, RB1, BRCA1 were the most common. Mutations in the EGFR gene were most often associated with mutations in TP53 (30 % of cases), RB1 (15 % of cases), COL22A1 (15 % of cases); ALK was combined with TP53, NF1, WT1 – in 33 % of cases, ROS1 with DDR2 (33 % of cases), ERBB2 was combined with NTRK1, GPC3, HIP1, KIF5B, TP53, XPC, COL22A1 – in 14 % of cases, BRAF was most often associated with mutations in the TP53 gene (14 %) and COL22A1 (13.8 %); a mutation in the RET gene was associated with a TP53 mutation; ROS1 translocation in 50 % of cases was associated with mutations in the TRIM33 and TP53 genes.

Conclusion. The data obtained give an idea of the frequency of occurrence of somatic mutations among Russian patients with NSCLC, which is important for the selection of diagnostic panels, interpretation of their results, and also potentially for the development of original custom Next Generation Sequencing testing panels.

Backgraund. Currently, immunotherapy is firmly established in the standard of cancer treatment. The basis for the appointment of immunotherapy are immunological tumor markers, which include lymphoid infiltration, a detailed study of which has received increasing attention in the last decade. An undoubted interest is the study of lymphoid infiltration, not only depending on the morpho-clinical parameters of breast cancer (BC), but also on the immune system of the bone marrow.

Aim. To evaluate the infiltration of the primary tumor by lymphocytes depending on the morpho-clinical characteristics of BC and immune responses in the bone marrow.

Materials and methods. This study included 125 patients with BC who received treatment at the “N.N. Blokhin National Medical Research Center of Oncology” of the Ministry of Health of Russia. Tumor stage II was prevailed, а moderate degree of differentiation (G2) was more often noted. The luminal BC – 67 %, non-luminal – 33 %. Immunophenotyping of the primary tumor: cryostat sections, ZEISS Axioscope luminescent microscope (Zeiss AG, Germany). CD45+, CD38+, T- and B-cell infiltration were assessed. Bone marrow: CD3+, CD4+, CD8+, CD19+, CD16+, CD56+ lymphocytes and their subpopulations were studied (FACSCanto II flow cytometer, Kaluza Analysis v2.1 program (Beckman Coulter, USA)).

Results. CD45+ infiltration was noted in 50.5 % of cases (severe in 30 %, moderate – 26.4 %). CD8+ cells significantly infiltrated the tumor in 21.4 % of cases. CD38+ infiltration was observed in 40 %. In the non-luminal BC, severe CD45 infiltration was observed more frequently than in the luminal (33 % vs 26 %). CD38+ infiltration is expressed in non-luminal BC (p = 0.016). CD45+ infiltration was positively correlated with earlier stages (p = 0.071) more pronounced in infiltrative ductal BC, than in lobular BC: 59.2 % vs 20 % (p = 0.05). The content of CD45RO+cells in bone marrow in the luminal BC is higher than in the non-luminal: 37.3 ± 2.3 % vs 28 ± 2.8 % (p = 0.04). The number of CD19+CD38+ cells, on the contrary, is less: 24.2 ± 2 % vs 34.8 ± 6 % (p = 0.041). Tumor-infiltrating lymphocytes highly correlated with bone marrow lymphoid populations: CD38+ cells with NK-bone marrow cells; CD4+ cells with the B-precursors; CD8+cells with the B1-lymphocytes.

Conclusion. Lymphoid infiltration of BC is associated with stage, tumor size, histological type and biological subtype. Intratumoral populations CD38+, CD4+, CD3+, CD8+ cells are in a negative correlation with bone marrow lymphoid populations.

Background. Colorectal cancer is the most commonly diagnosed cancer among all malignant neoplasms. This disease is accompanied by the development of anemic syndrome (AS). This complication not only worsens the results of treatment and, as a result, reduces overall survival, but also reduces the quality of life of patients, reduces adherence to treatment.

Aim. To study the expression of hepcidin 25 (HP25), prohepcidin (PROHP), ferritin (FR), interleukin 6 (IL-6) and metabolites of nitric oxide (NO_x) in the peripheral blood of patients colorectal cancer, to assess their relationship with the clinical course of the disease and with AS.

Materials and methods. The study was conducted in 41 patients with colorectal cancer and AS. The content of FR, PROHP, HP25, IL-6 was determined using enzyme immunoassay. The total content of NOx in blood serum was determined using the Griess reagent after the reduction of nitrate to nitrite with cadmium granules in the presence of zinc.

Results. There are three types of AS. A characteristic feature of which was microcytosis (MCV – 74.3 ± 2.1 fl) and hypochromia (MHC – 22.9 ± 1.2 pg) of erythrocytes. Type 1 of AS – iron deficiency anemia (IDA), type 2 – anemia of chronic diseases (ACD) in combination with iron deficiency erythropoiesis and type 3 – ACD with functional iron deficiency (FID). True IDA was detected in 15 (36.6 %) patients, which was classically characterized by: low concentration of FR, PROGP, GP25, IL-6 and NO_x. A less significant group (9 patients, 21.9 %) had a high concentration of FR and low PROHP, GP25, IL-6, NO_x, which indicated iron deficiency against the background of ACD. It differed from the first group with IDA in a significant concentration of FR, which may indicate the transition of IDA to the chronic phase of AS. Third group (17 patients, 41.5 %) – with FID – turned out to be the most numerous and characterized by a high concentration of FR (386.7 ± 41.2 ng/ml), GP25 (43.2 ± 7.1 ng/ml), PROHP (283.3 ± 18.5 ng/ml), IL-6 (24.8 ± 5.5 pg/ml), NOx (39.7 ± 5.5 µmol/l), the values were significantly higher (p <0.001) than in patients with IDA and ACD with iron deficiency erythropoiesis.

Conclusion. In patients with a widespread tumor process, AS with FID is most often detected. FID was accompanied by hyperproduction of FR, IL-6, GP25, PROGP and NO_x. A close correlation was noted between the studied parameters with an increase in the T-stage of colorectal cancer. This may indicate the relationship of these proteins in the development of cytokine-induced anemia in cancer patients. The data obtained can be widely used to assess the state of metabolic disorders in anemia associated with malignant neoplasms for the differential diagnosis of AS variants and adequate treatment.

Background. The development of highly oriented conjugates of quantum dots (QDs) and single-domain antibodies (sdAbs) as innovative fluorescence imaging nanoprobes that specifically recognize tumor biomarkers, in particular, epidermal growth factor receptor (EGFR), is a promising approach to improving immunohistochemical tumor typing.

Aim. The study was aimed at developing fluorescent nanoprobes based on QDs and sdAbs that specifically recognize EGFR, as well as evaluating their functional characteristics (size and optical properties) and functional activity.

Materials and methods. QDs were obtained using high-temperature organometallic synthesis and transferred into the aqueous phase by means of stepwise replacement of ligands on the QD surface. The QDs and sdAbs were conjugated in an oriented manner using a bifunctional cross-linking agent. Detailed characteristics of the resulting conjugates were analyzed by the dynamic light scattering and immunoassay methods. Functional activity was assessed on the model human epidermoid carcinoma cells line A431.

Results. The QD–sdAb conjugates have been standardized in terms of control parameters determining their functional activity, in particular, hydrodynamic diameter and efficiency of binding with target tumor cells. They are characterized by high dispersity, homogeneity, and specific functional activity towards their molecular target.

Conclusion. The results demonstrate the potential use of the designed QD–sdAb conjugates for EGRF detection in immunohistochemical typing of tumor.

Background. Present day in medicine can be assessed as an active period of the fight against cardiovascular diseases. This group of diseases cannot be considered obsolete in any way, and even taking into account the emerging new pathology – coronavirus infection – cardiovascular diseases have consolidated their dominant position. Among the drugs used for appropriate pharmacotherapy, stands out nifedipine (1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridindicarboxylic acid dimethyl ether) – a drug that can inhibit the flow of calcium into the cardiomyocytes of vascular smooth muscle cells. The drug has been on the domestic pharmaceutical market for quite a long time, but it is still in demand. However, nifedipine has quite pronounced side effects, including those associated with its oral administration – nausea caused by irritation of the gastrointestinal tract, rarely gum hyperplasia. And at the same time, the main modern dosage form of nifedipine is tablets. Therefore, expanding the range of its dosage forms is an urgent issue. Moreover, well-chosen dosage forms reduce the side effect of the drug. This is especially true for extended versions. So pharmaceutical development in relation to the creation of original dosage forms of nifedipine is quite appropriate.

Aim. Determination of the possibility of absorption of nifedipine from the proposed dosage forms – transdermal patch and transdermal gel.

Materials and methods. To determine nifedipine in rat blood plasma samples, high-performance liquid chromatography was used (chromatograph “Millichrome A-02” (Institute of Chromatography “EcoNova”, LLC, Russia).

Results. Chromatograms of blood plasma samples of all animals on whose skin a transdermal gel or patch was applied revealed a peak coinciding in retention time with the peak of the standard sample of nifedipine.

Conclusion. The possibility of penetration of nifedipine from the patch and transdermal gel through intact animal skin has been confirmed.