Background . One of the factors of the pathogenesis of atherosclerosis and other cardiovascular diseases is induced endothelial senescence. In this regard, the urgent task of molecular biology and medicine is the search for molecules that affect the process of vascular endotheliocytes senescence. The aim . To assess the expression of Sirt-1,3,6 and chemokines IL-4, CXCL11 in the replicative and induced senescence of human endotheliocytes. Materials and methods . The study was conducted on the primary culture of isolated human umbilical vein endothelial cells (HUVECs). HUVECs were cultured under conditions of replicative (natural) and lipopolysaccharide induced senescence. Results . The synthesis of Sirt-1,3,6, IL-4 and CXCL11 was evaluated using western blot analysis. We revealed a decrease in Sirt-1,3,6 synthesis by 1.6–1.8 times (р < 0.05) in the conditions of HUVEC replicative senescence. Induced senescence of endotheliocytes is characterized by a more pronounced decrease (1.7–3.4 times; р < 0.05) in the Sirt-1,3,6 synthesis. CXCL11 synthesis increases by 1.4 times (р < 0.05) in replicative and by 3.4 times (р < 0.05) in induced HUVEC senescence. IL-4 synthesis increases by 4.7 times in conditions of induced HUVEC senescence and doesn’t have changes in replicative senescence of endotheliocytes. Conclusion . These data obtained indicate that sirtuins and chemokines play an important role in the development of endothelial dysfunction observed in natural and induced senescence.

Секреторный фенотип, ассоциированный со старением (SASP), - гетерогенный фенотип клеток, секретирующих провоспалительные цитокины, факторы роста, апоптоза и протеазы. SASP является одним из трех основных признаков стареющих клеток. Нарушение регуляции синтеза молекул, формирующих SASP, приводит к развитию ассоциированных с возрастом заболеваний, в том числе сердечно-сосудистой патологии. Цель исследования - охарактеризовать SASP эндотелиоцитов человека при репликативном и индуцированном старении. Для моделирования репликативного и вызванного воспалением старения использовали линию изолированных эндотелиальных клеток пупочной вены человека HUVEC. Установлено, что молекулами, формирующими SASP при репликативном и индуцированном воспалением старении HUVEC, являются факторы апоптоза (p16, p21, p53), адгезии (Е-селектин, VCAM-1) и цитокины (IL-1β, IL- 6). При репликативном старении эндотелиоцитов в большей степени повышается синтез молекул апоптоза. Для индуцированного воспалением старения HUVEC характерно многократное увеличение синтеза молекул адгезии и провоспалительных цитокинов. The aging-associated secretory phenotype (SASP) is a heterogeneous phenotype of cells secreting pro-inflammatory cytokines, growth factors, apoptosis’ regulatory molecules, and proteases. SASP is one of the three main hallmarks of senescent cells. Dysregulation of the synthesis of SASP-forming molecules leads to the development of age-associated diseases, including cardiovascular pathology. The aim of this study is to characterize the SASP of human endotheliocytes during replicative and induced aging. Isolated human umbilical vein endothelial cells HUVEC were used to model replicative and inflammation-induced aging. It has been established that the molecules that form SASP during replicative and inflammation-induced aging of HUVEC are molecules that control apoptosis (p16, p21, p53), adhesion (E-selectin, VCAM-1) and some cytokines (IL-1β, IL-6). With replicative aging of endotheliocytes, the synthesis of apoptosis’ regulatory molecules increases to a greater extent. Inflammation-induced aging of HUVEC is characterized by a multiple increase in the synthesis of adhesion molecules and pro-inflammatory cytokines.

Objective To evaluate the results of surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. Material and methods There were 32 patients who underwent surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. Structural changes of carotid artery wall were analyzed using immunohistochemical survey. Considering destructive changes revealed, we divided all patients into 2 groups in order to assess long-term postoperative outcomes: 1 - ICA resection followed by anastomosis in end-to-end fashion; 2 - ICA replacement. Postoperative analysis included incidence of stroke, thrombosis and deformities of anastomosis zone, regression of cerebrovascular insufficiency. Results The main «phenotype» of arterial wall in patients with ICA kinking following fibromuscular dysplasia is a large number of smooth muscle cells releasing matrix matelloproteinases-2 and -9 and low level of their tissue inhibitor type 1. Postoperative deformities are more common within a year after surgery. Maximum incidence is observed after 12 months. Both ICA resection and replacement are followed by similar incidence of deformity later. No severe deformities were diagnosed. Resection of ICA kinking on the background of fibromuscular dysplasia is followed by comparable results with ICA replacement regarding the incidence stroke, thrombosis and regression of cerebrovascular insufficiency. Conclusion Despite degradation of extracellular matrix, destruction of elastic fibers and their fragmentation, no significant deformities are observed in long-term postoperative period in patients with ICA kinking and fibromuscular dysplasia.

The paper describes 2 cases of immature ovarian teratoma with elements of nephroblastoma (ICD-0 code 9080/3) in patients aged 61 and 70 years. Microscopic examination revealed that both cases had blastemal cells with scant cytoplasm and basophil nuclei sticking together. Epidermal, glandular, rhabdomyoblastic, chondroid, bone, neuroectodermal, and histiocytic components were determined. Papillary and glomeruloid structures and primitive tubules were immured in the sarcomatous stroma. Immunohistochemical studies showed a strong reaction with Wilms tumor 1 (WT1), paired box gene (PAX-2), cytokeratin 7, desmin, smooth muscle actin, and α-1 antitrypsin. The recurrent tumors displayed a 1.8- to 6.1-fold increase in the level of p53. At the same time, the molecular genetic study revealed p53 gene mutation. In both cases, serous ovarian cystadenocarcinoma was misdiagnosed, ineffective chemotherapy was performed, and a recurrence occurred. The literature review revealed only 8 such cases.

Описание случая полиомавирусной нефропатии в сочетании с острым клеточным отторжением в динамике. Подтверждение диагноза потребовало анализа не только морфологической картины, но и результатов иммуногистохимического исследования, клинических и лабораторных данных.

The paper describes a case of chromophobe renal cell carcinoma growing into the muscular layer of the descending colon and with metastases in 4 lymph nodes of paranephral tissue in a 66-year-old woman. The tumor had a zonal structure with an alternation of epithelioid and sarcomatoid structural sites and with the signs of grades I, II and III according to the grading system by Paner and et al. (2010). The sarcomatoid renal component occupied about 70.0% of the tumor. There was a pronounced immunohistochemical reaction with VEGF-A (5 scores), a high Ki-67 proliferation index (70%), and a large number of tumor cells with nuclear p53 expression (85%) in the areas with minimal differentiation and sarcomatoid elements (Grade III). These signs can serve as criteria for the aggressive behavior of the tumor. A large volume of the sarcomatoid carcinoma component and a strong reaction with VEGF-A are indications for targeted therapy with anti-VEGF drugs.

The paper describes a case of solitary epithelioid hemangioendothelioma concurrent with nodular parenchymal AL amyloidosis of the lung and Rosai-Dorfman disease in a 70-year-old woman. The core of the tumor was represented by bone tissue with dendriform ossification, as well as by amyloid that showed green apple birefringence at polarized light microscopy. The peripheral portions of the tumor and the myxohyaline stroma exhibited slit-like structures, epithelioid and fusiform cells with small cytoplasmic vacuoles. These cells expressed CD31, CD34, factor VIII, and cytokeratins 7 and 18. The Ki-67 proliferation index was 10%. S100- and CD68-positive histiocytes with the phenomenon of emperipolesis were revealed in the tumor and in the lymph nodes of the mediastinum and lung hilum. There was a positive reaction to immunoglobulin lambda light chains in the lymphocytic infiltration around amyloid clumps. The frequency of epithelioid hemangioendothelioma was less than 1 case per million people annually. We found only one case of its concurrence with pulmonary amyloidosis in the English-language literature. No relationship could be revealed between this tumor and Rosai-Dorfman disease.

We studied the expression of MMP-2, MMP-9, and inhibitor TIMP-1 in myocardial autopsy samples from subjects of different age and in cardiomyocyte cultures in the norm and in dilated cardiomyopathy. In autopsy samples of normal myocardium and in cardiomyocyte cultures, expression of molecules involved in extracellular matrix remodeling did not change during aging. In dilation cardiomyopathy, expression of MMP-2, MMP-9, and TIMP-1 and their ratios in autopsy material and in cultures was elevated by 1.5-9 times. Remodeling of extracellular matrix plays an important role in the pathogenesis of dilated cardiomyopathy. MMP-2, MMP-9, and their inhibitor TIMP-1 and the MMP/TIMP ratios can be regarded as promising predictors of dilated cardiomyopathy and used for evaluation of the effectiveness of treatment of this conditions in patients of different ages.

Cardiovascular diseases caused by atherosclerosis are one of the most important social and economic problems in many countries of the world due to the high morbidity and mortality rate of the working population. An immunological theory of atherosclerosis and coronary heart disease (CHD) has been actively developed of late, and markers of inflammation characterizing immuno- and atherogenesis have been sought. The buccal epithelium (BE) can be used as biological material for in vivo molecular-cellular studies, allowing CHD diagnosis via inflammation markers. The purpose of the work was a comparative study of the expression of IL-1β, IL-6, IL-10, MCP-1, and GDF-15 in BE in patients of different ages with CHD and without cardiovascular disease. The BE material in healthy donors and patients with second-stage CHD was divided into groups according to the age classification of the WHO: the first group included middle-aged people (45–59 years), and the second included elderly people (60–74 years). Control material was obtained from people of middle and old age without cardiovascular disease. According to the immunocytochemical study, the area of IL-1β expression in BE is three times higher in middle-aged CHD patients and 4.4 times higher in elderly people as compared to healthy individuals of the same age group. The area of IL-6 expression in middle-aged and elderly CHD patients was 7.9 and 7.4 times higher, respectively, than in the control group. In middle-aged and elderly CHD patients, the IL-10 expression was 1.6 and 2.8 times higher, respectively, as compared to healthy donors of the same age group. The MCP-1 expression in the BE of middle-aged and elderly people with and without ischemic heart disease did not differ. GDF-15 expression is 6.8 and 6.6 times higher in middle-aged and elderly CHD patients than in healthy people of the same age. The findings showed that the expression of the cytokines IL-1β, IL-6, IL-10, and GDF-15 increase in the BE of patients with CHD in middle-aged and elderly people as compared with persons of the same age group without cardiovascular disease. Thus, the BE can serve as an informative material for noninvasive molecular diagnosis of CHD in people of different ages.

This review summarizes contemporary researches about the role of the resident immune cells in different organs – pineal gland, placenta, ovary, endometrium, liver, skin, gastro-intestinal tract, bronchial system. Mechanisms of the immune response realization reflects the relationship between different cells, tissues and organs, and thus support the notion of the unity of the nervous, immune and endocrine systems. It was established that the interaction of these systems is complex. Populations of various immune cells have common structural and functional features what is the foundation of a safety mechanism of the immune system. Reduction in the correlation of different subpopulations immune cells number in the organism is the foundation of various pathological processes.

The paper describes a case of eosinophilic granuloma of the parietal bone in a 32-year-old man. Histological examination revealed a large number of bean-shaped Langerhans cell histiocytes with lobed nuclei and nuclear grooves. The histiocytes alternated with the foci of obvious eosinophilic infiltration and with eosinophilic microabscesses. There were osteoclast-like multinucleated giant cells, bone resorption, and numerous bone rods covered with osteoblast chains. The histiocytes expressed CD1α, langerin, CD68, S100, and p53 (in 90.0% of the tumor cells). The Ki-67 proliferation index was 18.0%. A molecular genetic study identified BRAFV600E mutation (nucleotide substitution s.1799 T>A (p.V600E) in the heterozygous state). Clinical and morphological data and the results of molecular genetic studies led to the conclusion that there was eosinophilic granuloma of the right parietal bone (the unifocal form of Langerhans cell histiocytosis (LCH), type I, group A1, with the monoossal nature of lesion and with BRAFV600E mutation). In adults, this disease is extremely rare (2-5 cases of LCH per million people, bone loss in the fourth decade of life in 2.5% of the patients).

The present article was designed to report the results of the analysis of the cases of traumatic and spontaneous ruptures of the organs affected by the tumours based on the original observations and the literature data. It is shown that the probability of the tumour rupture depends on its histological type, localization, the size, and the distance from the capsule of the affected organ, the degree of involvement of the major blood vessels, the severity of the necrotic changes, the presence of cysts in the neoplasm, and the regimens of radio- and chemotherapy. Moreover, the rupture can be facilitated by anticoagulation therapy, intake or oral contraceptives, pregnancy, concomitant diseases, alcoholic intoxication, splenomegaly, and hypocoagulation resulting from dissemination of the neoplastic process or the metastatic lesions of the liver. Even a minimal injury to the skin can provoke the tumour rupture associated with the fatal hemorrhage. A delayed rupture within a few hours or days is possible.

To paper describes a case of paucicellular anaplastic cancer in the presence of tall cell variant papillary thyroid carcinoma. Microscopic examination showed that the differentiated component of the tumor was composed of papillary structures with tall cells, the height of which exceeded 3-4 times the width. Its anaplastic component consisted of fibrous tissue with occasional spindle-shaped cells and focal lymphocytic infiltration to the extent of 70%. The spindle-shaped cells expressed cytokeratins, β-catenin, p53, and vimentin. The tumor cells and lymphocytes showed an association with Epstein-Barr virus. Molecular genetic study of the tumor revealed the following mutations: BRAF p.Val600Glu (p.V600e was), HRAS p.His27His (p.H27H), PIK3CA p.Glu545Lys (p.E545K), TP53 p.Arg248Gln (p.R248Q).

AIM to study changes in the expression of angio- and vasculogenesis markers in colorectal adenocarcinoma metastases to the liver during combined cytotoxic and targeted anti-VEGF therapy versus cytotoxic monotherapy. SUBJECTS AND METHODS Intraoperative samples from 96 patients with colorectal adenocarcinomas metastases to the liver were immunohistochemically examined. The investigation enrolled patients who had preoperatively received either combined FOLFOX6 cytotoxic therapy and targeted anti-VEGF therapy with bevacizumab or only FOLFOX6 therapy, as well as patients who had not received preoperative anti-tumor drug treatment. The expression of SDF1α, CXCR4, CXCR7, and VEGF-A was compared in these groups. Statistical significance was accepted at p<0.05. RESULTS The expression of CXCR4 in the vessel endothelial cells was significantly less frequently detected in the patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy as compared to those had not drug therapy. Comparing the patients treated with cytotoxic drugs with those who had not received anti-tumor therapy revealed similar results in the women. CXCR7 expression in the tumor cells and stromal cells from the metastatic foci was significantly more common in the group of male patients treated with cytotoxic drugs according to the FOLFOX6 regimen. The expression of SDF1α in the tumor cells was significantly more often observed in the male patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy than in those who had not drug therapy. VEGF expression in the stromal cells was significantly less frequently seen in the patients who had received the combined therapy. CONCLUSION Combined cytotoxic therapy and targeted anti-VEGF therapy for colorectal adenocarcinoma metastases to the liver leads to some suppression of the alternative pathway in the formation of new vessels, by reducing the expression of CXCR4 in the vessel endothelial cells and that of VEGF in the stromal cells from the metastatic foci. In men, this therapy simultaneously causes an increase in the expression of SDF1α in the tumor cells and in that of CXCR4 in the stroma. Preoperative FOLFOX6 therapy significantly increases the expression of CXCR7 in the tumor cells and stromal cells in the male patients, which may suggest that this pathway in vessel formation can be activated.

Тo compare morphological changes and results of immunohistochemical (IHC) identification of viruses (polyomaviruses, adenoviruses, and herpesviruses) in the biopsy specimens with their clinical manifestations in recipients of renal transplants.Morphological and IHC studies were conducted using 71 needle renal transplant biopsy specimens from patients in the study group and 10 renal biopsy specimens from those in the control group. A number of clinical indicators were estimated.IHC examination revealed the expression of adenoviral antigens more commonly in patients with posttransplant nephritis than in recipients without nephritis or in control individuals (p<0.05). The association of patient age and time after kidney transplantation with the severity of viral damage was confirmed: graft loss in children occurred within the first months of surgery (p<0.05). Polyomavirus was detected by PCR in patients with the morphological patterns of polyomavirus nephropathy. Determination of HSV-1 and HSV-2 in the biopsy specimens showed no significant associations with morphological changes.By taking into account a variety of factors that influence the development of viral nephritis, morphological and IHC examinations should be combined with evaluation of clinical findings.Цель исследования - сопоставление морфологических изменений и результатов иммуногистохимического (ИГХ) определения вирусов (полиомавирусы, аденовирусы, герпесвирусы) в биоптатах с клиническими проявлениями у реципиентов почечных трансплантатов. Материал и методы. Морфологическое и ИГХ-исследование проведено на материале 71 пункционной биопсии почечных трансплантатов и 10 биоптатах собственных почек пациентов контрольной группы. Оценен ряд клинических показателей. Результаты. При ИГХ-исследовании экспрессия антигенов аденовируса чаще выявлялась у пациентов с посттрансплантационным нефритом, чем у реципиентов без нефрита или в контрольной группе (p<0,05). Подтверждена связь возраста пациентов и сроков после трансплантации почки с тяжестью вирусного поражения: у детей потеря трансплантата наступала в первые месяцы после операции (p<0,05). У пациентов с морфологической картиной полиомавирусной нефропатии выявлен полиомавирус методом ПЦР. Определение HSV-1 и HSV-2 в биоптатах не показало достоверных ассоциаций с морфологическими изменениями. Заключение. Учитывая разнообразие факторов, влияющих на развитие вирусного нефрита, целесообразно сочетать морфологическое и ИГХ-исследование с оценкой клинических данных.

The review considers various aspects of myocardium aging in normal and dilated cardiomyopathy (DC). There is a partial fibrosis of the heart tissue due to accumulation of collagen type 1, and accumulation of amyloid during normal aging. Men myocardial aging is accompanied by loss of cardiomyocytes and increased volume of the remaining cells, whereas in women this effect is absent. There is an expression of nuclear proteins decrease (lamin A and C), the accumulation of lipofuscin, increased content of reactive oxygen species, reduction of protein synthesis Sirt1 in cardiomyocytes with aging. Sirt1 has a cardioprotective effect, supports the balance of lipid metabolism, inhibits the development of inflammation and the formation of atherosclerotic plaques. Reduction of its expression not only indicates the accelerated pace of myocardial aging, but can be a predictor of the development of DC. In DC occurs stretching of the heart cavities and systolic dysfunction, predominantly in the left ventricle. DC is characterized by the development of inflammation in the myocardium. Its markers is increased expression of ICAM-1 adhesion molecule, MMP-2, MMP-9 matrix metalloproteinases, TIMP-1 tissue inhibitor of matrix metalloproteinases and decreased expression of MMP-1 matrix metalloproteinase.