Laboratory biomarkers of an effective antitumor immune response. Clinical significance.

The modern checkpoint inhibitors block the programmed death-1 receptor and its ligand, cytotoxic T-lymphocyte-associated antigen 4 on tumor cells and lymphocytes, that induces cytotoxic reactions. Nowadays, there are no approved clinical and laboratory predictor markers of immune therapy efficacy, which would allow a more personalized approach to patient selection and treatment. The aim of this review is to analyze possible biomarkers of efficacy for treatment with checkpoint inhibitors according to the pathogenic mechanisms of drug action. The review revealed possible predictive biomarkers, that could be classified to 3 groups: biomarkers of high mutagenic potential of the tumor, biomarkers of high activity of adaptive immunity, biomarkers of low activity of the tumor microenvironment. The determination of the described markers before the start of therapy can be used to formulate a treatment regimen, in which the use of various immunomodulatory drugs, inhibitors of proinflammatory cytokines, angiogenic molecules, and probiotics can be considered.

[The influence of sinusoidal modulated currents on the fatty acid composition of plasma and blood erythrocytes in the patients presenting with chronic cholecystitis]. / Vliyanie sinusoidal'nykh modulirovannykh tokov na sostav zhirnykh kislot plazmy i eritrotsitov krovi u patsientov s khronicheskim kholetsistitom.

The objective of the present study was to evaluate the effectiveness of the treatment with sinusoidal modulated currents on lipid metabolism in the patients presenting with chronic cholecystitis in the state of remission. PATIENTS AND METHODS: The study included 25 patients with chronic non-calculosis cholecystitis in phase of remission and 20 healthy subjects (controls). We studied the serum lipid spectrum as well as the fatty acid composition of plasma and blood erythrocytes before and after therapy with sinusoidal modulated currents applied to the right-sided hypochondrium region. RESULTS AND DISCUSSION: The treatment of the patients with chronic cholecystitis in remission with the use of sinusoidal modulated currents produced moderate lipid-modulatory and membranotropic effects mediated through the activation of the processes of lipid metabolism that may result in the depletion of the pool of essential polyunsaturated fatty acids. CONCLUSION: The results of this study give evidence that it is advisable to treat the patients presenting with chronic cholecystitis by sinusoidal modulated currents in the combination with the oral intake of exogenous polyunsaturated fatty acids.

[Blood fatty acids in the development and correction of metabolic syndrome]. / Zhirnye kisloty krovi v formirovanii i korrektsii metabolicheskogo sindroma.

AIM: to investigate the composition of plasma fatty acids (FA) and red blood cells and the level of eicosanoids in patients with metabolic syndrome (MS) and to assess whether metabolic disturbances may be corrected during a cycle use of an ω-3 polyunsaturated fatty acid (PUFA). SUBJECTS AND METHODS: Examinations were made in 46 patients, including Group 1 (a control group) of 15 persons without MS components; Group 2 of 31 patients with MS, Group 3 of 16 MS patients who had taken an ω-3 PUFA for 6 months, and Group 4 of 15 MS patients who had received the drug for 12 months. The composition of plasma FA and red blood cells was analyzed on a gas-liquid chromatograph. An enzyme immunoassay was used to measure the serum levels of tumor necrosis factor-α (TNF-α) and eicosanoids (thromboxane B2, 6-keto-prostaglandin F1α, leukotriene B4). A biologically active additive from the king crab (Paralithodes camtschatica) hepatopancreas was used as a source of ω-3 PUFA. RESULTS: Having a higher proportion of linoleic and α-linolenic acids in the plasma, the patients were found to have decreased levels of ω-3 and ω-6 PUFAs (linoleic and α-linolenic, arachidonic, and eicosapentaenoic acids) and a larger proportion of Mead acid and saturated FAs (myristic and stearic acids) in the red blood cells, suggesting that that cellular blood FA transfer was impaired and FAs were absorbed by cells. Their serum samples showed the high levels of leukotriene B4, 6-keto-prostaglandin F1α, and thromboxane A2. The long-term (6- and 12-month) use of ω-3 PUFA from the king crab hepatopancreas had a positive impact in modifying the lipid FA composition of red blood cells and in eliminating deficiencies of physiologically important ω-3 and ω-6 PUFAs in the blood cells. CONCLUSION: The findings suggest that FAs and their metabolites play an important role in the pathogenesis of MS and that dietary ω-3 PUFA should be incorporated into a package of preventive and therapeutic measures for MS.

[Association of fatty acid metabolism with systemic inflammatory response in chronic respiratory diseases]. / Assotsiatsiia metabolizma zhirnykh kislot s sistemnoi vospalitel'noi reaktsiei pri khronicheskikh zabolevaniiakh organov dykhaniia.

We examined composition of plasma non-esterified fatty acids (NFAs), erythrocyte fatty acids, levels of eicosanoids in patients with asthma and chronic obstructive pulmonary disease (COPD) with different type of the inflammatory response. The results of our study show that asthma and COPD in remission are associated with changes in the composition NFAs of plasma, FA of erythrocytes, level eicosanoid despite the difference in the regulation of immunological mechanisms of systemic inflammation. These changes are characterized by excessive production of arachidonic acid (20:4n-6) and cyclooxygenase and lipoxygenase metabolites (thromboxane B2, leukotriene B4) and deficiency of their functional antagonist, eicosapentaenoic acid (20:5n-3). The recognized association between altered fatty acid composition and disorders of the immune mechanisms of regulation of systemic inflammation in COPD and asthma demonstrated the important role of fatty acids and their metabolites in persistence of inflammatory processes in diseases of the respiratory system in the condition of remission.

[Modification of fatty acid composition of polar and neutral lipids of blood and liver in rat in conditions of prolonged high-fat diet].

Studied the composition of fatty acids of polar and neutral lipids of plasma, erythrocytes and liver Wistar rats under prolonged high-fat diet. It was established that during long-term (90-180 days) in rats high-fat load is blocking the cells ligand-retseptor active capture polyunsaturated fatty acids (PUFAs) in the low-density lipoprotein (LDL). This is confirmed by the accumulation of blood in LDL cholesterol and lipid fractions, esterified n-3 and n-6 PUFA (triacylglycerides, sterols esters, phospholipids), while the deficit these same fatty acids in the lipids of erythrocytes. In the liver under the influence of prolonged high-fat diet increased pool monoenic (18:1 n-9) and polyunsaturated (20:5 n-3, 20:3 n-6, 22:5 n-3) fatty acids. These data suggest that prolonged exposure of rats high-fat diet contributes to compensatory de novo synthesis of fatty acids in the liver. However, due to violations of the receptor active transport of fatty acids synthesized in the liver fatty acids are not captured by cells of the peripheral organs. Identified data allow us to expand the understanding of the role of nutritional factors in the physiology and pathophysiology of the cell, modulation of lipid metabolism.

[Liver phospholipids composition and activity of glutathione redox-system in rats on prolonged high-fat diet].

We studied liver phospholipid composition and activity of the glutathione redox-system in rats on prolonged for 180 days high-fat diet. The adaptive response was formed from day 30 to day 90 of high-fat load and was associated with increased relative content of phosphatidylseryne and phosphatidylethanolamine homeostasis. Constant antioxidant activity of glutathione redox-system for 30 days period of high-fat load was achieved by stable glutathioneperoxidase activity, on 90th day--level of glutathione reductase increased. The detected fluctuations in phospholipid composition and activity of glutathione redox-system in liver tissue on 30-90th days of the experiment indicated the formation of a compensatory response to maintain cell integrity. On 180th day of high-fat load due to exhaustion of compensatory mechanisms in the glutathione antioxidant defense and intensification of lipid peroxidation the lipid matrix of cytomembrane underwent profound restructuring associated with decreased levels of phosphatidylinositol, phosphatidylethanolamine, increased proportion of apoptotic phospholipids (phosphatidylserine, sphingomyelin). Such phospholipids composition on the background of glutathione redox-system inhibition can determine apoptosis, necrosis and liver fibrogenesis. These results extend the knowledge about mechanisms of liver adaptation and disadaptation to nutritional stress.

[Quality of life of patients with locally advanced operated gastric cancer during the period of chemotherapy].

The comparative analysis of the main life quality parameters for patients with locally advanced operated gastric cancer was carried out using the EORTC QLQ-C30, STO-22 version 3.0. at stages of chemotherapeutic treatment. All patients (n = 47) have been divided into 2 groups depending on application of chemotherapy (cisplatin + 5-fluorouracil) prevention by hemo-immunostimulation ("Glutoxim"). The changes in functional state, symptoms and general health status of patients were evaluated. It is revealed that application of Glutoxim significantly improves functional state and insignificantly influences disease symptoms.

[Modification of the erythrocyte membrane lipids in rats under conditions of alimentary stress].

Erythrocyte phospholipids and lipid fatty acid composition was investigated at different stages of exposure to high-caloric diet in male Wistar rats. The revealed modification of erythrocyte lipids shows specific features of membrane response to stress factors of alimentary nature, in particular, cell protection compensatory mechanism initiation on the 90th day and their depletion by the 180th day of high-caloric diet.

[Combined application of magnetolaserotherapy and polyunsaturated fatty acids for the treatment of patients with hypertensive disease].

The authors report the results of combined treatment including application of magnetolaserotherapy and n-3 polyunsaturated fatty acids for the management of patients presenting with hypertensive disease. These data give evidence of the accumulation of atherogenic fractions of plasma lipids and pathological modification of the fatty acid composition in erythrocyte membranes. They suggest the appropriateness of lipid-correcting and membrane-protective treatment for patients presenting with hypertensive disease. It is concluded that the proposed combination of magnetolaserotherapy and polyunsaturated fatty acids may be instrumental in the normalization of the serum lipid profile and the correction of the cellular fatty acid composition.

Phospholipid composition of erythrocytes and glutathione redox system in rats during adaptation to cholesterol load.

We studied phospholipid composition of erythrocytes and the state of the glutathione redox system in rats during adaptation to cholesterol load for 180 days. The adaptive response is formed during the period from day 30 to day 90 of cholesterol load and is associated with increased relative content of phosphatidylethanolamine and phosphatidylinositol, activation of glutathione redox system enzymes (glutathione reductase and glutathione peroxidase), and enhanced production of glutathione.

[The composition of blood fatty acids and the level of oxylipins in patients with metabolic syndrome].

Gas liquid chromatography was used to analyze the composition of plasma free fatty acids (FA) and erythrocyte lipid FAs in patients with metabolic syndrome (MS) in various glucose-insulin homeostasis. The serum lipids of oxylipins were studied in patients with MS, by applying enzyme immunoassay. The patients with MS in the absence of glucose-insulin homeostatic disorders and those with significant insulin resistance (IR) were found to have accumulation of polyenic FA (18:2 omega6), 18:p omega3, 22:4 omega6) and a decreased pool of saturated FA (12:0, 14:0, 16:0, 17:0) in the plasma with simultaneous polyunsaturated FA (18:3 omega3, 20:4 omega6) with a preponderance of fatty FA (14:0, 18:0) in the red blood cells. The high serum concentrations of leukotriene B, and 6-keto-prostaglandine-F1a, were detectable in the examinees with MS. Increased thromboxane A2 synthesis was observed when the patients with MS developed IR. The findings suggest that there are impairments in the composition of plasma free FA and erythrocyte lipid FA and in the synthesis of oxylipins in patients with MS.

[The prevalence of concomitant diseases among in-patients on the subject of rheumatic gout].

The article contains the results of the study of rate, ratio and characteristics of concomitant diseases among in-patients with various clinical anatomic forms of rheumatic gout.

[The role of modification of fatty acid composition of erythrocyte lipids in pathogenesis of arterial hypertension].

We used liquid chromatography for analysis of fatty acids (FA) in lipids of erythrocytes of patients with hypertensive disease (HD) with normo- (group 1) and hyperlipidemia (group 2). Abnormalities of FA composition of erythrocyte lipids were revealed in both groups. In group 1 we found deficit of polyenic acids of omega-6 family, accumulation of Mead acid - prostanoid precursor with pronounced vasoconstrictor and pro inflammatory properties. In group 2 we noted more profound rearrangement of lipid matrix of erythrocyte membrane manifested as deficiency of omega-3 polyenic acids, accumulation of palmitinic and arachidonic acids. Preponderance of saturated FA in erythrocytes and deficiency of polyenic acids might evidence for pathology of their ligand-receptor transport into the cell. Blockade of active FA transport initiates formation of HD, promotes accumulation of atherogenic fractions of lipoproteins in blood. These results evidence for important pathogenetic role of FA in development of hypertension.

[The role of free and esterified fatty acids in pathogenesis of metabolic syndrome].

Patients with insulin resistance and those with metabolic syndrome (MS) in the absence of alteration of glucose-insulin homeostasis were found to have abnormal composition of plasma free fatty acids (FA) and lipid FA in erythrocytes. Patients with metabolic syndrome and different glucose-insulin homeostasis accumulated polyenic FA and lost saturated FA in plasma; saturated FA in their erythrocytes increased while polyunsaturated FA decreased. These findings suggest disturbed receptor-mediated active transport of FA and the predominance of passive absorption of free FA by cells as a cause of insulin resistance and hyperinsulinism.

[The composition of nonesterified fatty acids in patients with metabolic syndrome].

The blood composition of non-etherized fatty acids (NEFA) was studied in 22 patients with metabolic syndrome (MS) and 11 healthy individuals. The qualitative NEFA composition presented by 31 components of individual fatty acids was analyzed, by taking into account of glucose-insulin homeostatic changes in MS patients: those without insulin resistance (IR) (Group 1) and those with diagnosed IR (Group 2). MS patients with normal insulinemia were ascertained to have lower levels of lauric, myristic, palmitic, C24:0, C16:0i acids. With a decrease in the relative quantity of saturated NEFA, the levels of polyunsaturated fatty acids (FA) increased. The proportions of linoleic (C18:2 omega 6) and linolenic (C18:3 omega 3) acids doubled (p < 0.01), arachidonic acid (C20:4 omega 6) was observed to tend to rise. The cumulative FA index sigma omega 6 increased twofold. In Group 1, the integrated index of changes in the FA series (unsaturation index) was 41% higher than that in the control group (p < 0.05). In Group 2, the vector of changes in the relative quantity of NEFA was similar, but impairments were less marked than that in Group 1. The findings suggest that the development of insulin resistance is preceded by impaired blood cell transfer and absorption of NEFA.

[Taxonomic composition of bacteria associated with cultivated mollusks Crassostrea lugubris and Perna viridis and with the water of the Gulf of Nha Trang Lagoon, Vietnam].

One hundred and four strains of heterotrophic bacteria have been isolated and characterized from two species of bivalve mollusks cultivated in the Gulf of Nha Trang (Vietnam) and from the water of a mariculture farm. The isolates have been identified on the basis of morphological, physiological, biochemical, and chemotaxonomic properties, as well as by the content of G+C bases in DNA. In the microflora of mollusks, Vibrio alginolyticus was predominant; the pathogenic species V. harveyi and V. splendidus were found as well. Staphylococci and bacilli occupied the second place in abundance after vibrios. In addition, coryneforms and enterobacteria, as well as Pseudomonas spp. and Pseudoalteromonas spp., were revealed. The composition of the water microflora was more diverse as compared with the microflora of mollusks. In the water, Bacillus spp., Vibrio spp., and Pseudomonas spp. were predominant. Brevibacterium spp. and other coryneform bacteria, as well as enterobacteria, occurred in significant amounts. In addition, Pseudoalteromonas spp., Marinococcus sp., Halobacillus sp., Shewanella sp., Sulfitobacter sp., and bacteria of the CFB cluster were noticed. The presence of pathogenic and conditionally pathogenic bacterial species in the water and mollusks is probably the reason for the high death rate of cultivated animals at the mariculture farm.

[Feeding and growth of Japanese scallop inhabiting different bottom sediment types].

Two parts of the population of Japanese scallop Mizuhopecten yessoensis inhabiting sites with different bottom sediments in an open part of Peter the Great Bay of the Sea of Japan were compared. The scallops grew slower on muddy site compared to sandy site despite better food availability at muddy site. The food sources were determined using fatty acids as biomarkers. Analysis of the fatty acid composition of the scallops has identified diatom plankton, flagellates, and invertebrate larvae as the main scallop food sources. Benthic bacteria insignificantly contributed to the scallop diet. The food composition slightly varied in scallops on different sediment types. Most likely, low oxygen content in water, high resuspension of fine sediment particles rich in dead organic matter, and high content of contaminants accumulated in muddy sediments are the main factors of decelerated growth of scallops on muddy sites.

Characterization of unusual alkaliphilic gram-positive bacteria isolated from degraded brown alga thalluses.

Two orange-pigmented Gram-positive, aerobic bacteria were isolated from enrichment culture during degradation of brown alga Fucus evanescens thalluses. In this work, atomic force microscopy (AFM) has been used to study the cell morphology. The non-contact mode imaging revealed unusual irregular coccoid shape of cells, possessing a single flagellum. Bacteria produced carotenoid pigments, were chemo-organotrophic, alkaliphilic and halo-tolerant growing well on nutrient media containing up to 15% NaCl. Growth temperature ranged from 5 to 45 degrees C. The DNA base compositions were 48 mol% G + C and the level of DNA similarity of two strains was conspecific (98%). A comparative phylogenetic analysis of 16S rRNA gene sequences revealed that the strain KMM 3738 tightly clustered with recently described Planococcus maritimus (99.9% 16S rRNA gene sequence similarity). DNA-DNA hybridisation experiments revealed that DNA from the KMM 3738 showed 12-15% and 16-35% of genetic relatedness with the DNA of type strains of the genera Planomicrobium and Planococcus, respectively, and 87% with DNA from Planococcus maritimus, indicating that new isolates belong to the later species.

[Bacterial communities of brown and red algae from Peter the Great Bay, the Sea of Japan].

The structure of microbial communities of brown algae, red algae, and of the red alga Gracilaria verrucosa, healthy and affected with rotten thallus, were comparatively investigated; 61 strains of heterotrophic bacteria were isolated and characterized. Most of them were identified to the genus level, some Vibrio spp., to the species level according to their phenotypic properties and the fatty acid composition of cellular lipids. The composition of the microflora of two species of brown algae was different. In Chordaria flagelliformis, Pseudomonas spp. prevailed, and in Desmarestia viridis, Bacillus spp. The composition of the microflora of two red algae, G. verrucosa and Camphylaephora hyphaeoides, differed mainly in the ratio of prevailing groups of bacteria. The most abundant were bacteria of the CFB cluster and pseudoalteromonads. In addition, the following bacteria were found on the surface of the algae: Sulfitobacter spp., Halomonas spp., Acinetobacter sp., Planococcus sp., Arthrobacter sp., and Agromyces sp. From tissues of the affected G. verrucosa, only vibrios were isolated, both agarolytic and nonagarolytic. The existence of specific bacterial communities characteristic of different species of algae is suggested and the relation of Vibrio sp. to the pathological process in the tissues of G. verrucosa is supposed.