S-adenosylmethionine blocks tumorigenesis and with immune checkpoint inhibitor enhances anti-cancer efficacy against BRAF mutant and wildtype melanomas.

Despite marked success in treatment with immune checkpoint inhibitor (CPI), only a third of patients are responsive. Thus, melanoma still has one of the highest prevalence and mortality rates; which has led to a search for novel combination therapies that might complement CPI. Aberrant methylomes are one of the mechanisms of resistance to CPI therapy. S-adenosylmethionine (SAM), methyl donor of important epigenetic processes, has significant anti-cancer effects in several malignancies; however, SAM's effect has never been extensively investigated in melanoma. We demonstrate that SAM modulates phenotype switching of melanoma cells and directs the cells towards differentiation indicated by increased melanogenesis (melanin and melanosome synthesis), melanocyte-like morphology, elevated Mitf and Mitf activators' expression, increased antigen expression, reduced proliferation, and reduced stemness genes' expression. Consistently, providing SAM orally, reduced tumor growth and progression, and metastasis of syngeneic BRAF mutant and wild-type (WT) melanoma mouse models. Of note, SAM and anti-PD-1 antibody combination treatment had enhanced anti-cancer efficacy compared to monotherapies, showed significant reduction in tumor growth and progression, and increased survival. Furthermore, SAM and anti-PD-1 antibody combination triggered significantly higher immune cell infiltration, higher CD8+ T cells infiltration and effector functions, and polyfunctionality of CD8+ T cells in YUMMER1.7 tumors. Therefore, SAM combined with CPI provides a novel therapeutic strategy against BRAF mutant and WT melanomas and provides potential to be translated into clinic.

[Prospects and peculiarities of the procedure of ultrasound ablation of subcutaneous veins of the lower limbs]. / Perspektivy i osobennosti tekhnologii ul'trazvukovoi obliteratsii podkozhnykh ven nizhnikh konechnostei.

The last decade has seen active development of minimally invasive (endovenous) methods of surgical removal of lower limb varicose veins (LLVV); however, the problem of increasing efficacy of these methods and improving long-term results still remains of current importance. The authors of this work propose a method of ultrasound ablation of subcutaneous veins of lower extremities. Our experimental study was aimed at determining the pattern of venous wall damage after ultrasound exposure. Samples of segments of the trunk of the great saphenous vein (GSV) were divided into 5 groups: group 1 - the control group, group 2 - treatment with a sclerosant in the amount of 0.3 ml for 30 s, group 3 - treatment with ultrasound at a frequency of 26 kHz and amplitude 40 µm and 0.3-ml sclerosant for 30 s, group 4 - exposure to ultrasound at a frequency of 26 kHz and amplitude 40 µm and 0.3-ml sclerosant for 60 s, group 5 samples were exposed to ultrasound at 26 kHz and amplitude of 40 µm for 60 s. The results of analysing the histological sections of the samples of the 2nd and 3rd groups demonstrated that the degree of alteration in the GSV wall on combined exposure to ultrasound and a sclerosant was 4.5-fold higher as compared with treatment with a sclerosant solution alone. During ultrasound exposure, the maximum temperature of the venous wall of group 5 samples was by 20 °C higher than in samples of group 4. Analysing the histological sections demonstrated a similar pattern of structural alterations of the samples of group 4 and 5, thus suggesting a possibility of controlling the temperature of the venous wall during ultrasound ablation without changing quality of structural lesions. The obtained findings showed a possibility of initiating irreversible dystrophic alterations in the venous wall on exposure to ultrasound by means of combining the mechanisms of chemical, mechanical, and thermal ablation.

[Circulating immune complexes in families with positive history of ischemic stroke].

The concentrations and protein composition of immune complexes circulating in the blood of patients with residuals of ischemic stroke and their healthy relatives from families with positive history of stroke have been determined. The data obtained have been compared with the results of our previous study on determination of concentration and protein composition of immune complexes circulating in the blood of patients with acute ischemic stroke and healthy subjects. Basing on the results obtained we conclude that the elevated level of immune complexes in the blood of patients with residuals of stroke is not genetically determined but rather reflects alterations developing as the result of previous stroke. However, the protein composition of the immune complexes, particularly the presence of C-reactive protein, may, to a certain degree, reflect genetic predisposition to stroke.

[Kinetics of ligand binding to nucleic acids at random fillings].

Ligand binding with nucleic acids is described in frames of the theory of random processes. It is shown that the probabilistic description of binding of a ligand to nucleic acid allows one to describe not only the kinetics of changes in the number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. A general analysis of absorption isotherms and the kinetics of ligand binding with nucleic acids allows one to determine the rate constants of formation and decomposition of the ligand-nucleic acid complex. A comparison of the results obtained with the case of low fillings is conducted.

[Effects of spatial-imagery task performance on the heart rate variability].

Effects of the efficiency of spatial task performance on the autonomic heart control were studied. Dynamic changes in autonomic balance diagnosed on the heart rate variability during maze-model task performance (the type of spatial-imagery activity) showed that the type of heart rate regulation depended on the performance efficiency. The results suggest that in subjects with low performance efficiency, problems in performance are associated with negative emotions that produce the emotional psychogenic stress. In subjects with high efficiency, the autonomic contour of the heart rate regulation prevailed. This was presumable associated with the adequacy of the maze-model task.

Regulation of parathyroid hormone-related peptide by estradiol: effect on tumor growth and metastasis in vitro and in vivo.

We evaluated the capacity of estradiol (E(2)) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E(2) caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E(2) tamoxifen. E(2) also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E(2) production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.

[Study of complexes of ethidium bromide with DNA by differential pulse voltammetry].

The interaction of ethidium bromide with calf thymus DNA was investigated by the method of differential pulse voltammetry. It was found that ethidium bromide binds with DNA in several ways. Corresponding values of the constants and the number of binding sites were determined. The intercalation, semi-intercalation, and electrostatic mechanisms of interaction were shown. The results obtained are in good agreement with the data obtained by spectroscopic (absorption and fluorimetric) methods.

[The study of interhemispheric asymmetry in spatial-perceptive problem solving]. / Issledovanie mezhpolusharnoi asimmetrii mozga pri reshenii zadachi prostranstvenno-obraznogo profilia.

Features of brain interhemispheric asymmetry during solving the spatial figurative task (maze model) were studied in men and women with different intelligence quotients (IQ). It was shown that during task solving the rate of information processing was higher in the right brain hemisphere, and amplitude characteristics of the event-related potentials were higher in the left hemisphere. No gender and IQ differences in the character of interhemispheric interaction were found during the realization of the maze-model task. The results testify that the character of hemispheric interaction depends om the task rype rather than gender and intelligence level.

[Circulating immune complexes in ischemic and hemorrhagic strokes]. / Tsirkuliruiushchie immunnye kompleksy pri ishemicheskom i gemorragicheskom insul'takh.

The study aimed at determination of circulating immune complexes (CIC) levels in a serum of patients with ischemic and hemorrhagic strokes, isolation of the complexes and their antigen composition identification. Spectrophotometric assay, polyethylene glycol precipitation and SDS PAG electrophoresis were used. Comparing to controls, significantly elevated levels of both small and big CIC were detected in the serum of the patients with ischemic stroke, while in the patients with hemorrhage stroke only the level of small CIC was elevated. The antigen CIC composition was specific for each stroke form and for control group either. Being compared to literature data, the results obtained revealed a specificity of the antigen CIC composition in ischemic and hemorrhagic strokes.

[Role of the right brain hemisphere in training for the operator work]. / Issledovanie roli pravogo polyshariia v protsesse obucheniia operatorskomu trudu.

Functional state of the human right brain hemisphere was studied during simulation of 4-hour operator's training work with a computer in novel conditions. Participants of the experiments differed in the degree of extraversion and baseline level of cortical activity. The obtained results suggest that the role of the right hemisphere in the process of simulated activity consists in reception and primary processing of information. This hemisphere is not involved in the correction of cortical activation to the optimal level of activity, which is necessary for the efficient performance of a task.

[Functional state of the autonomic nervous system according to the data of heart activity during performance of a computerized visual-spatial task]. / Funktsional'noe sostoianie vegetativnoi nervnoi sistemy po pokazateliam serdechnoi deiatel'nosti pri vypolnenii zritel'no-prostranstvennoi zadachi na komp'iutere.

The influence of the performance of a computerized visio-spatial task on the state of the autonomic nervous system of PC operators was studied. Statistical characteristics of the operator's heart rhythm during the 3-hour period of work on a computer were analyzed using Baevsky's method of variational pulsometry. The operators were classified in three groups by the character of their reaction to loading. It was suggested that the visio-spatial task performance on a computer could act as a stress factor only on a certain category of people.

[Effect of mechanical stress on lon mutant strain of Escherichia coli K-12]. / Vliianie mekhanicheskikh kolebanii na zhiznedeiatel'nost' lon-mutantnogo shtamma Escherichia coli K-12.

It was found that, depending on their frequency, mechanical vibrations (MVs) can either stimulate (4 Hz) or inhibit (50 Hz) the growth and the division of the lon mutant of Escherichia coli K-12. Similar effects were observed when the MV-treated nutrient medium was inoculated with untreated mutant cells. MVs enhanced the motility of mutant cells and the fragmentation of filament cells always present in the populations of lon mutants.

[The surface membrane potential in a fluctuating medium]. / Poverkhnostnyi potentsial membrany v fluktuiruiushchei srede.

Fluctuations of the surface membrane potential due to adsorbtion and desorbtion of ions when environmental fluctuations generate a fluctuation in the number of adsorbtion sites were investigated. The correlation functions of surface charge density, surface potential and the spectral density of surface potential fluctuations were calculated. The characteristic features of these fluctuations were determined.

A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo.

Urokinase plasminogen activator (uPA) plays an important role in the progression of several malignancies including breast cancer. We have identified a noncompetitive antagonist of the uPA-uPAR interaction derived from a nonreceptor binding region of uPA (amino acids 136-143). This 8-mer capped peptide (A6) inhibited breast cancer cell invasion and endothelial cell migration in a dose-dependent manner in vitro without altering cell doubling time. Intraperitoneal administration of A6 resulted in a significant inhibition of tumor growth and suppressed the development of lymph node metastases in several models of breast cancer cell growth and metastasis. Large areas of tumor necrosis and extensive positive staining by TUNEL were observed on histological and immunohistochemical analysis of experimental tumor sections from A6-treated animals. A6 treatment also resulted in a decrease in factor VIII-positive tumor microvessel hot-spots. These results identify a new epitope in uPA that is involved in the uPA-uPAR interaction and indicate that an antagonist based on this epitope is able to inhibit tumor progression by modulating the tumor microenvironment in the absence of direct cytotoxic effects in vivo.