[Modern approaches to studying the molecular mechanisms of lung functioning in normal and pathological conditions]. / Sovremennye podkhody k izucheniyu molekulyarnykh mekhanizmov funktsionirovaniya legkikh v norme i pri patologii.

Problems with breathing and lung function are caused by the development of various lung diseases associated with lifestyle, harmful environmental factors and genetic predisposition. Knowledge of the molecular mechanisms of the development of the pathological process will allow on time identification of the disease or the development of targeted therapy. The article provides an overview of modern methods that make it possible to most accurately reproduce the structural, functional and mechanical properties of the lung (organ-on-a-chip), to perform non-invasive molecular studies of biomarkers of bronchopulmonary pathology using saliva diagnostics, as well as using DNA and RNA aptamers, verify tumor markers in biological samples of human tissue. Analysis of alterations in the pattern of protein glycosylation using glycodiagnostic methods makes it possible to detect lung cancer in the early stages.

[Caldesmon and tumor growth: prospects for optimizing diagnosis and targeted therapy]. / Kal'desmon i opukholevyi rost: perspektivy optimizatsii diagnostiki i targetnoi terapii.

Tumor invasion plays a key role in the progression of tumors. This process is regulated by the interactions of cells and tissues, in which physical, cellular and molecular determinants undergo changes throughout the entire period of progression of tumor growth. Tumor invasion is triggered and maintained by specialized signal cascades that control the dynamic state of the cytoskeleton in tumor cells, the processes of rearrangement of cell-matrix and intercellular connections, followed by cell migration to neighboring tissues. Studying the mechanisms of regulation of cell motor activity and determining its main regulators is an important task for understanding the pathophysiology of tumor growth. Caldesmon is an actin, myosin and calmodulin binding protein. It is involved in the regulation of smooth muscle contraction by inhibiting actin and myosin binding, in the formation of actin stress fibers, and in the transport of intracellular granules. Currently, caldesmon is considered as a potential biomarker of tumor cell invasion, migration, and metastasis. The study of signaling molecules involved in tumor progression, such as caldesmon, is necessary to predict response to chemotherapy and radiotherapy. This review highlights the main functions of caldesmon and analyzes its role in oncological pathology.

[Slowdown of replicative aging of fibroblasts by hyaluronan complexes with gold nanoparticles.]

Determination the activity of the genes of sirtuin-1, hyaluronidase, TGF-ß cytokine, calreticulin in the process of replicative aging of human fibroblasts in vitro and the effect of hyaluronan preparations with gold nanoparticles on the activity of replicative cell aging. Compared the expression of proteins of the studied genes using specific markers at 7 and 14 passages of cultivation of fibroblasts isolated from human skin, without drugs and in the presence of drugs in the growth medium. This work shows a decrease in the activity of the sirtuin 1 gene and an increase in the expression of hyaluronidase in the process of replicative aging of human fibroblasts. Found a means of slowing down replicative aging by activating the SIRT-1 gene and reducing the activity of hyaluronidase in action in the growth medium of hyaluronan preparations with gold nanoparticles. The discussed variants of cell transitions to the pathological state, caused by replicative aging and the mechanisms of slowing down the replicative aging of human fibroblasts.

[Investigation of signal molecules in saliva: prospects of application for diagnostics of myocardial infarction and the aging rate of different age people.]

Among the diseases of the cardiovascular system in elderly people, ischemic heart disease and myocardial infarction (MI) occupy the first place in the structure of mortality. One of the main causes of disability and death from MI is late diagnosis. In this regard, the search for new, highly informative and non-invasive methods for diagnosing MI is an important task of molecular gerontology. An enzyme immunoassay showed that the concentration of TNF-α, IL-8 cytokines and p16 aging marker in saliva in elderly people without cardiovascular pathologies (CP) increases in 2,1-4,8 times as compared with middle-aged people. At the same time, in elderly people without CP the concentration in the saliva of the hormone irisin (FNDC5) decreases by 1,8 times as compared with middle-aged people. In middle-aged patients with MI the concentration of IL-8, TNF-α, MMP8, MMP9 in saliva increases 4,3-15,3 times, and FNDC5 decreases 1,8 times compared with those parameters without CP in this age group. In elderly people with MI the concentration of IL-8, TNF-α, MMP8 and MMP9 in saliva increases 4,3-7,1 times as compared with elderly people without CP. Thus, the study of the concentration of signaling molecules IL-8, TNF-α, MMP8, MMP9 in saliva can be used as a non-invasive method for diagnosing MI in people of middle and elderly age. To assess the rate of aging of the organism in middle-aged and elderly people without CP, a study of the concentration of p16 and FNDC5 molecules in saliva is recommended.

[The personalized medicine and organization of geriatric care of population].

The article presents advisability of applying approaches of personalized medicine to solve problems of modern gerontology and geriatrics. The actuality of issue is conditioned by population aging due to rapid increasing of both percentage and absolute number of elderly people in total population of most countries. The ideology of personalized medicine or P4 medicine is targeted to developing individual preventive and therapeutic activities for specific personality. The fundamental basis of developing personalized medicine is ensured by biomarkers, specific for every patient and certain disease. The elderly people health is characterized by increased susceptibility to diseases, polymorbidity and heterogeneity in health status. The solution of actual problems in gerontology and geriatrics improvement of basic principles of health care is needed with an emphasis on prognostication, prevention and personalized approach applied to elderly patients with the purpose of ameliorating their quality of life. The development and promotion of complex inter-disciplinary programs of personalized treatment of elderly patients is required.

[Molecular markers of Alzheimer disease early diagnostic: investigation perspectives of peripheral tissues.]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of elderly and old age people. For intravital diagnosis of the expression of signaling molecules - AD markers, cerebrospinal fluid (CSF) and peripheral tissues are used: lymphocytes and blood platelets, buccal and olfactory epithelium, skin fibroblasts. There are several changes in the production of hyper phosphorylated form of τ-protein, BACE1 and peptide Аß42 in CSF in case of AD, but CSF taking may have a number of side effects. Less traumatic taking of sampling tissues for the diagnosis of AD is in use of epithelium biopsy and blood portion. An increase in the expression of the hyper phosphorylated form of τ-protein is shown in blood lymphocytes of AD patients. An increase in the content of high molecular weight forms of phosphorylated t-protein and amyloid precursor protein-APP was also revealed in blood platelets of AD patients. Changes in the amount of 2 miRNA families - miR-132 family and miR-134 family were revealed in blood cells 1-5 years before the manifestation of clinical signs of AD. An increase in the concentration of bound calcium, synthesis of peptides Aß40 and Aß42, τ protein was observed in AD skin fibroblasts. In the olfactory and buccal epithelium an increase in the expression of hyper phosphorylated form of τ-protein and Aß peptide was detected in patients with AD. Verification of AD markers in peripheral tissues for biopsy have the important significant for life diagnostics, prevention and and target AD treatment.

Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer.

AIM: Preclinical study of the specific anticancer pharmacological activity of the formulation containing active substance 3,3ʹ-diindolylmethane (DIM), cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E), in vivo in a xenograft animal model of LNCaP. MATERIALS AND METHODS: The DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) formulation was intragastrically administered to BALB/c-nude (nu/nu) mice during 33 days post inoculation at the dose of 133 mg/kg/day. Antitumor activity of the test drug was estimated by the rate of tumor growth inhibition (T/C% - treated versus control), dividing the tumor volumes from treatment groups with the control groups. RESULTS: Statistically significant tumor xenograft regressions have been shown in group which received the DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) on the 37(th) day of observation post inoculation. The highest antitumor activity was achieved on the 39(th) day (T/C = 16,8%). Therapeutic effect lasts for 6 days after the end of therapy period. CONCLUSION: Our findings demonstrate inhibitory effect of the formulation on tumor development in the xenograft animal model due to the tumor growth rate reduction.

[The Russian and international standards of age-related allocation of population for medical statistics, medical demographic analysis and risk assessment].

The actual European standard of age-related allocation of population in action is largely implemented in medical demographic studies of international (WHO etc.) and national organizations. The Rosstat also implements this standard in its demographic yearbooks and other publications. The standard is applied in computing the standardized indicator of population mortality in different countries and territories and also in assessing risk factors. The standard is based on the idea of evaluating mortality with an integrated standard in order to compare between different countries mortality of population, genders and calendar years. The analysis of results of testing calculations of values of standardized indicator of mortality of population of Russia and EU countries applying European standard in action revealed serious shortcomings. For example. unfounded overstating of values of standardized indicator, of mortality for males and its understating for females artificially increases already wide difference in mortality of males and females in the Russian Federation. The calculation on this background of standardized indicator of mortality for particular causes of death results in erroneous values due to neglected concurrence of risks. Because of necessity of improvement of standard a new concept of development of national and international standards is proposed. This concept is based on application of notion of balanced age-related allocation of population and its number values.

Cancer-associated immune-mediated syndromes: Pathogenic values and clinical implementation.

The ability of tumors to provoke formation of cancer-associated secondary immunodeficiency (CASID) with predominant suppression of CMI and cancer-associated secondary immunodeficiency with clinical autoimmunity syndrome (CASICAS) with triggering of a set of the autoimmune deviations is appearing to be a key event in the restriction of hosts' anti-tumor immunity. Earlier the existence of the above-mentioned syndromes was demonstrated in BCC and GBM patients. In order to reach a point where immunological phenotypes in GBM and BCC can be clarified clinically and, partly, pathogenically, we have conducted a series of studies of typical and atypical types of immune responsiveness in patients with GBM and BCC. For GBM and BCC three scenarios of the involvement of the immune responsiveness have been established in a series of our studies, i.e., (i) malignancy with no immunopathology, (ii) malignancy as CASID, and (iii) malignancy as CASICAS. All of those scenarios demonstrated significant differences in their immune-mediated manifestations which, in turn, were proven to reveal close associative relationships with a specific clinicopathologic type and clinical manifestations of the tumor. CASID and CASICAS share two common features, i.e., (i) signs of immunodeficiency and (ii) a tandem of the deviations within the adaptive and innate links of the host immune responsiveness. At the same time, CASID and CASICAS are distinct pathogenically and clinically, and in terms of depth of the immune deviations observed, CASID patients manifest a breakage in both links, whereas in CASICAS patients, a breakage in the adaptive link would dominate. To get these differences clarified, we summarized major types of the immune imbalances and sets of clinical and clinicopathologic manifestations to illustrate the above-mentioned features in CASID and CASICAS patients. There are distinct close correlations between clinicopathologic features of the disease course and sets of the immune-mediated imbalances in patients harboring the tumors. The latter implicates a panel of the new immunodiagnostic and immunoprognostic criteria for patients with solid tumors, i.e., BCC, MCC and GB, which is of great value for clinical practice. In particular, the blood levels of some of the immunocompetent cells, state of their functional activity, serum titers of the antigenic markers and autoantibodies, apoptotic parameters, and others may be accepted as additional and clinically informative criteria to be implemented for immunological monitoring and immunotherapy of patients with solid tumors.

[Anatomical pathology and molecular diagnosis].

150 years ago, R. Virchow proposed a "cellular pathology" theory that forced one to revise many concepts of the mechanisms responsible for the development of disease and marked the beginning and further development of anatomical pathology as an independent discipline. Rapid progress in immunology, genetics, biotechnology, and cellular and molecular biology in the late 1980s to the early 1990s gave rise to a new field, namely molecular medicine. Damage changes the profile of expression some genes, activates various signal systems, and, due to of intercellular and cellular-matrix interactions, then spreads first at the level of organs, then at that of the whole body if a pathological process cannot localize. By involving some cells, the pathological process cannot cause characteristic morphological changes and therefore traditional studies yield a negative result. Molecular pathology became a necessary additional tool in the work of a pathologist, by allowing him to obtain the information that had been earlier beyond the reach, which increased the validity of diagnosis. Some points of the Virchow "cellular pathology" theory are supported by molecular pathology.

[Prognostic value of the expression of thyreoglobulin and oncomarkers (p53, EGFR, ret-oncogene) in different types of papillary carcinoma of the thyroid: clinicomorphological and immunohistochemical studies].

The surgical material obtained from 57 patients was immunohistochemically studied. Immunohistochemistry with quantitative and semiquantitative analyses of the results of test was used to define the expression of oncomarkers p53, EGRF, ret-oncogene, and thyreoglobulin. The expression of thyreoglobulin, EGRF, and ret-oncogene reflects the malignant potential of papillary carcinoma of the thyroid and and may be recommended as a predictive marker. The low expression of thyreoglobulin and the high expression of p53 and ret-oncogene are markers of a poor prognosis and tumor recurrence. EGFR expression is not of predictive value. MB3 proposed by the authors may be recommended for the determination of the malignant potential of papillary carcinoma of the thyroid.

[Immunohistochemistry of biomolecular markers of early thyroid cancer]. / Immunogistokhimiia biomolekuliarnykh markerov raka legkogo.

Surgery material from 28 cases was studied. Thyroid adenoma differs from thyroid carcinoma by a lower level of expression of Ki-67 and bcl-2, while the mutated p53 expression is lacking. These indices may be used for early and differential diagnosis of thyroid carcinoma. Medullary carcinoma is a tumor with the highest malignant potential and p53 and bcl-2 may serve as markers of a higher degree of malignancy. Ki-67 may serve a marker of proliferative activity of tumors belonging to the same histological type. Thus, its high expression in follicular carcinoma is an index of a high proliferative activity of its cells, correlates with its rapid growth and should be taken into consideration in therapy and prognosis. Expression of bcl-2 clearly correlates with neuroendocrine differentiation of carcinoma and its highest expression was found in the medullary carcinoma as well as in the chromogranin positive cells of the papillary thyroid carcinoma. APUD amyloid deposits in medullary carcinoma and high levels of c-myc in adenomas indicate some genetic restructurizations in malignant and benign thyroid tumors.