REVIEWS
In 2000 Claudio Franceschi first used the term “inflammageing” derived from the English words “inflammation” and “age”. This term refers to the development of chronic inflammation in the elderly, which is characterized by a high level of pro-inflammatory markers of cells and tissues. Cellular aging can be triggered by a variety of factors: critical telomere shortening, permanent DNA damage, epigenetic damage, mitochondrial dysfunction, and an increase in the number of molecular fragments associated with cell damage.
A large number of markers have been found to reveal the pro-inflammatory status, such as interleukin (IL) 1, IL-1ra (IL-1 receptor antagonist protein), IL-6, -8, -13, -18, C-reactive protein, interferons α, β, transforming growth factor β, tumor necrosis factor α and its soluble receptors and SAA-1 (serum amyloid А1). The molecular mechanisms associated with aging and age-related diseases are not clear yet, while sluggish chronic inflammation is one of the leading mechanisms for the atherosclerosis development. Remodeling of the immune system with the increasing production of pro-inflammatory cytokines and NLRP3 inflammasomes also play a key role in the maintenance of chronic inflammation due to its ability to pick up a variety of age-related dangerous signals that trigger the immune response and subsequent inflammation and may act as a factor of the atherosclerosis development.
Thus, pro-inflammatory factors of the immune system play an important role in pathogenesis of atherosclerosis,
especially at an early stage, involving various mechanisms of action that boost atherosclerotic changes.
In experimental oncology there are multiple approaches have been developed to target tumor cells. Many of them are based on scaffolds, a 3D models that mimics the structure of tissue in normal and pathophysiological state. It is known that to deliver a viral load to target cells, cells-carriers undergo limited differentiation, and premature aging. Since viral agents require cells to be in specific proliferative state, the delivery of the virus to the target cell is the main goal of the functional framework such as scaffold. Over decade, multiple studies demonstrate the production of scaffolds using matrigel, polyalacinic acid, poly-lactide-co-glycolide, vinyl stilbens, or bioactive polymers. Our review will describe the potential benefits of delivering the viral vector using 3D scaffolds for virus-mediated expression of biologically active substances that prevent angiogenesis, neoplasm proliferation, or, conversely, stimulate wound healing. 3D materials such as hydrogels and scaffolds are among the key innovations in the field of material chemistry. Moreover, viral vectors provide specific delivery of genes to target cells. However, the immunogenicity of a viral capsid consisting of viral proteins hinders the clinical use of such vectors widely. These limitations can be surmounted by using scaffolds. Therefore, our review might interest researchers working in the fields of chemistry, materials science and natural sciences, as well as in the field of bioengineering and medical technologies.
Cytotoxicity is the main human killer cell property. The cytotoxicity reaction of human killer cells is achieved through a complex of molecules, including perforins, granzyme, cathepsin and others. However, only one molecule is enough for target cell death: granzyme. Other molecules are intended for granzyme activation and its delivery to the target cell cytoplasm. Granzymes are a whole family of serine proteases that perform their function in the human body as integral cytolytic effectors during programmed cell death of cancer and pathogen-infected cells. Secreted mainly by cytotoxic T-lymphocytes and NK-cells, granzymes initiate apoptosis via caspase-dependent and caspase-independent pathways. These natural properties make granzymes one of the most promising human enzymes for use in the development of targeted therapeutic strategies in the treatment of various types of cancer.
The most promising is granzyme B, because it has the most powerful effector properties. Due to the initiation of cascade reactions that activate apoptosis, granzyme is attractive as a basis for the development of medicines applicable in clinical oncology. At this time, several approaches have been developed for delivering granzyme molecules to tumor cells and facilitating its penetration through the cell membrane. Moreover, some solutions are proposed to overcome the resistance of target cells to granzyme-mediated apoptosis. These approaches are discussed in this review.
The purpose of this review was to systematize information on the use of granzyme B as a nanostructured drug delivery system in the treatment of solid and hematological malignancies. In addition, this review discusses ways to overcome the resistance of granzyme penetration into target cells.
ORIGINAL REPORTS
Introduction. In recent years, a separate publications have appeared indicating that interleukin 6 (IL-6) and the protein hepcidin 25 (GP25) play a significant role for the development of functional iron deficiency (FID) in oncological patients with a widespread tumor process. It is important to differentiate between FID and iron deficiency anemia (IDA), since they have the same morphological characteristics, but their treatment is fundamentally different.
The aim of this study was to study the main metabolites of ferrokinetics, IL-6 and C-reactive protein (CRP) expression parameters in patients with breast cancer on the background of neoadjuvant chemotherapy to develop individual approaches to the diagnosis and treatment of anemic syndrome (AS), prediction, early detection of anemia and its adequate correction.
Materials and methods. The study was conducted in 31 breast cancer patients, during of 6 cycles of chemotherapy. The main metabolites of ferrokinetics were studied: GP25, ferritin, soluble transferrin receptors, transferrin, iron, erythropoietin, IL-6 and CRP indices. The control group consisted of 29 apparently healthy women.
Results. AS was detected in 14 (45.1 %) of breast cancer patients. IDA prevailed with microcytic, hypochromic characteristics of erythrocytes, a low concentration of ferritin, iron, GP25, IL-6, CRP, and a high level of transferrin and soluble transferrin receptors. A some patients were diagnosed with FID, mainly with the III and IV stages of the disease. Unlike IDA, they had a high concentration of ferritin, CRP and significant production of GP25, IL-6. Erythropoietin level was not optimal for the majority of patients with AS. A few patients on the background of treatment with recombinant erythropoietins revealed a deficiency of vitamins B12 (cyanocobalamin) and folic acid.
Conclusion. Early diagnosis, a personalized approach to the prescription of iron preparations, recombinant erythropoietins, vitamins B12 and folic acid in patients with AS allowed for 6 cycles neoadjuvant chemotherapy without a significant decrease in erythrocytes, hemoglobin and hematocrit in most of them. The data obtained on IL-6, GP25, and CRP indicate relationship between them in the development of FID in breast cancer patients with a widespread tumor process and require further study.
Introduction. Melanoma of the skin has the highest potential for metastasis to the brain, ranking 15th in the frequency of occurrence among all malignant tumors – it is in third place in the incidence of intracerebral metastases. Modern methods of treatment of metastases of skin melanoma to the brain include neurosurgical treatment, radiation therapy and radiosurgery, antitumor drug therapy, including targeted therapy, immunotherapy and chemotherapy. The article discusses the indications for different methods of treatment, provides data on patient survival when using these methods of treatment alone or in combination. Additionally, a clinical case of long-term survival of a patient with skin melanoma with progression in the form of extra- and intracranial metastasis is discussed.
Purpose. Evaluation of the result of using modern methods of antitumor treatment in real clinical practice in a patient with skin melanoma metastases in the brain. Materials and methods. On a clinical example, a possible sequence of an individual approach to the treatment of a patient with extracranial and intracerebral metastases of skin melanoma based on modern methods of treatment and examination is considered.
Results. The use of modern methods of anticancer therapy has increased the overall survival and disease-free survival of patients with metastases of skin melanoma to the brain and reduces the need for neurosurgical interventions. As a confirmation of this, the life expectancy of the patient after the progression of skin melanoma in the form of metastases to the brain against the background of all the antitumor treatment carried out to date was 5.5 years, while neurosurgical treatment was not carried out at the request of the patient, although it was shown, but were used the possibilities of modern anticancer therapy, including sequential radiation therapy, targeted therapy and immunotherapy.
Conclusion. Modern methods of anticancer therapy can significantly increase the survival rate of patients with melanoma brain metastases and individualize the treatment plan.
Introduction. Immunotherapy based on the usage of mutant tumor neoantigens to activate the antitumor immune response is one of the most promising approaches to cancer treatment.
Purpose. Evaluation of individual immunogenicity of synthetic neoantigen peptides for the B16-F10 melanoma vaccine model.
Materials and methods. We studied 32 synthetic neoantigen peptides with a length of 25–27 amino acids, which were previously selected as potentially immunogenic by bioinformatic analysis of B16-F10 melanoma sequencing data and healthy tissues of C57Bl/6J mice. Groups of C57Bl/6J mice were immunized four times at weekly intervals with each individual peptide in combination with the adjuvant Poly(I:C), one of the groups was immunized only with Poly(I:C), and the control group was not immunized with anything. The immunogenicity of peptides was assessed by the production of interferon γ in splenocytes using the ELISpot method and by the level of serum cytokines Th1/Th2 using the ELISA method in immunized mice and in animals in the control group.
Results. Of the 32 peptides studied, 25 caused an increase in the number of interferon-γ-producing spleen cells in previously immunized mice, but 8 of these peptides caused a non-specific increase in the production of interferon γ by splenocytes in non-immunized animals. It was found that out of 32 peptides, only 11 caused an increase in the level of serum cytokines interferon γ and interleukin 4, which are responsible for the development of the immune response along the Th1 and Th2 pathways. But only 7 peptides affected an increase in the number of interferon-γ-producing splenocytes and an enhance of cytokines interferon γ and interleukin 4 levels.
Conclusion. Thus, the immunogenicity of 32 synthetic neoantigen peptides was evaluated, and 7 peptides were shown to activate the cellular immune response.
Background. For preclinical studies of radiopharmaceuticals there is a high need for development new methods of in vivo metastasis diagnosis in mice after tumor cells transplantation. The study was carried out to assess feasibility of lung metastasis diagnosis with magnetic resonance imaging (MRI) visualization in mice C57Bl6.
The aim of this study was to assess feasibility of MRI for verification of distant metastases of the solid B16-F10 melanoma with validation by anatomic dissection.
Methods. Metastatic lesions were caused by injection of B16-F10 murine melanoma cells into cavum medullare of the tibia. Imaging studies were performed on the 21th day after transplantation using 7T magnetic resonance tomograph, coronal and axial images were acquired. Validation of metastasis was made by anatomic dissection and histological examination.
Results. MRI method enables visualization of lung nodules with diameter at least 0.8 mm, because smaller nodules cannot be distinguished from heartbeat artifacts. Histological examination revealed that macroscopic anatomic dissection can precisely detect subpleural lung nodules.
Conclusion. This study demonstrated feasibility of in vivo lung metastasis verification with MRI method in mice: metastases comparable in diameter to the size of large bronchi can be detected by MRI as well as by ex vivo dissection. For centrally located lung metastasis MRI method is preferable because macroscopic dissection enables to visualize only nodules which are located subpleurally.
Introduction. The development of materials for bioresorbable implants is an urgent issue in medicine and materials science. Magnesium alloys are promising materials for this purpose. In particular, alloy WE43 (Mg-Y-Nd-Zr) has proven itself well in this field. However, the use of magnesium alloys is limited by a high degradation rate, which is often accompanied with nonuniform corrosion, which negatively affects the load bearing capacity of the product. In addition, the increased degradation rate usually seriously worsens the biocompatibility of magnesium alloys. Therefore, the study of the corrosion resistance of magnesium alloys, as well astheir biocompatibility, is an urgent task.
Purpose of the study was to investigate the effect of multiaxial deformation (MAD), aimed at increasing the mechanical characteristics of the alloy WE43, on its biodegradation kinetics, as well as on cell colonization.
Materials and methods. The alloy WE43 in two states – homogenized (WE43 hom) and strengthened by MAD (WE43 MAD) was investigated in this work. The kinetics of biodegradation was investigated on an xCELLigence RTCA Systems analyzer. A method for estimating the volume of hydrogen was used to study the process of gas formation, which was recorded using an automated digital microscope LionheartTM FX. The corrosive medium was a solution based on Dulbecco’s Modified Eagle’s Medium. A culture of mesenchymal multipotent stromal cells was used to study the colonization of the alloy surface by cells.
Results. MAD of the alloy WE43 leads to a decrease in the biodegradation rate and the intensity of gas formation. The period of stabilization of biodegradation for the alloy after the MAD is 16 hours versus 3 hours for the alloy after homogenization. In this case, the volume of released hydrogen was 65.0 ± 4.4 mm3H2/mm3 alloy and 211.0 ± ± 21.1 mm3H2/mm3 alloy for the alloy after MAD and homogenization, respectively. MAD improves the biocompatibility of the alloy WE43, stimulating the colonization of mesenchymal multipotent stromal cells.
Conclusion. MAD reduces biodegradation and improves the biocompatibility of the alloy WE43, which makes it a promising medical material, including for the purposes of oncoorthopedics
ISSN 1726-9792 (Online)