Biological Activity and Probable Mechanisms of Action of Derivatives of Tryptanthrin and Mostotrin Alkaloids.

The alkaloid tryptanthrin and its water-soluble derivative mostotrin exhibit high antimicrobial and antitumor activity. To develop more active and less toxic preparations, syntheses and testing of the biological activities of a number of new and/or little-studied analogs were performed. Some of them have been shown to have higher cytotoxicity against tumor and microbial cells than tryptanthrin and mostotrin. Thus, 8-fluorotryptanthrin effectively inhibits the proliferation of various tumor cell lines, namely: K-562/4, HCT-116 and HCT-116p53ko at lower concentrations than tryptanthrin, and 2,8-difluorostotrin exhibits a stronger antimicrobial effect against pathogenic bacteria S. aureus ATCC 29213 than mostotrin. It has been established that the antiproliferative properties of 8-fluorotryptanthrin and 8-fluoromostotrin are associated with their ability in nanomolar concentrations to inhibit the cell cycle of tumor cells at the stage of transition from the G1 phase to the S phase. The data obtained indicate the prospects for further in-depth studies of their antitumor properties.

[Risk factors for the early development of septic shock in patients with severe COVID-19].

AIM: In a retrospective study, we evaluated factors associated with the early development of septic shock in patients with severe COVID-19. MATERIALS AND METHODS: We collected medical records of the intensive care unit patients submitted by the local COVID-19 hospitals across Russia to the Federal Center for the Critical Care at the Sechenov First Moscow State Medical University (Sechenov University). Septic shock in crticially ill patients requiring mechanical ventilation was defined as a need in vasopressors to maintain blood pressure. RESULTS: We studied 1078 patients with severe COVID-19 who were admitted to the intensive care units for respiratory support. There were 611 males and 467 females. The mean age was 61.013.7 years. Five hundred twenty five medical records (48.7%) were received from the Moscow hospitals, 159 (14.7%) from the Moscow region, and 394 (36.5%) from the hospitals located in 58 regions of the Russian Federation. In 613 (56.9%) patients, diagnosis of SARS-CoV-2 infection was confirmed by PCR, and in the other cases it was established on the basis of the clinical picture and the results of the chest CT scan. Septic shock developed in 214 (19.9%) of 1078 patients. In the logistic regression model, the risk of septic shock in patients older than 50 years was higher than in patients of a younger age (OR 2.34; 95% CI 1.533.67; p0.0001). In patients with more severe SARS-CoV-2 infection, there was an increase in the prevalence of cardiovascular diseases, including coronary heart disease and atrial fibrillation, type 2 diabetes and malignant tumors. The risk of septic shock in patients with three or more concomitant diseases was higher than in patients without any concomitant chronic diseases (OR 1.76; 95% CI 1.762.70). CONCLUSION: The risk of septic shock in patients with acute respiratory distress syndrome induced by SARS-CoV-2 is higher in patients older than 50 years with concomitant diseases, although a severe course of the disease is also possible in younger patients without any concomitant disorders.

Mechanisms of Antiviral Activity of the Polyphenol Complex from Seagrass of the Zosteraceae Family against Tick-Borne Encephalitis Virus.

Antiviral activity of the polyphenol complex from seagrass of the Zosteraceae family against highly pathogenic strain of the tick-borne encephalitis virus was studied on passaged culture of porcine embryo kidney cells. The antiviral effect of the test compound manifested in a decrease in the infectious titer of the virus and depended on the concentration and application schemes. Polyphenol complex in a concentration of 100 µg/ml suppressed accumulation of the pathogen in the cell culture: pretreatment of the virus reduced its titer by 4 log, pretreatment of cells by 1.4 log, and application of the compound 1 h after cell infection by 2.8 log. Antiviral action of the test compound is determined by direct inactivation of the virus and inhibition of virus replication at the early stage, which attests to potential of this compound in the treatment of tick-borne encephalitis.

The role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia: literature review and own experience.

AIM: The analysis of experience of nelarabine use in refractory/relapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. MATERIALS AND METHODS: All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was ad- ministered as intravenous infusion at a dose of 650 mg/m2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. RESULTS: From 2009 to 2017, 54 patients with refractory/relapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34±8% vs 8±8%, p=0,05). In patients after allo-HSCT EFS, OS and CIR were 51±10%, 50±10% and 39,1±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. CONCLUSION: The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established dur- ing controlled clinical trials.

Antioxidants as Potential Antiviral Agents for Flavivirus Infections.

The review considers potential opportunities of certain antioxidants as antiviral agents for flavivirus infections. Currently flavivirus infections represent a significant public health problem for various regions of the world, since they result in high morbidity and mortality. Oxidative stress induced by viruses, including the flaviviruses, not only interferes with the body's important metabolic processes, but also regulates replication of the virus. A broad spectrum of antiviral activity of the natural phenolic antioxidants, i.e. rosmarinic acid and luteolin as components of the polyphenol complex isolated from the seagrass family Zsteraceae is decribed. The antiviral activity of rosmarinic acid and luteolin is shown to be due to their high antioxidant, antiinflammatory and neuroprotective potential. Particular attention is paid to the analysis of the activity of the polyphenol complex and its components against the tickborne encephalitis virus. The antiviral properties of the compounds with a broad spectrum of the biological action provide an oppor- tunity to consider them as promising candidates for combined therapy of tick-borne encephalitis.

[THE ROLE OF INTESTINE ISCHEMIA IN METABOLIC DISORDERS DURING THE AORTIC CLAMPING ABOVE THE CELIAC TRUNK.]

THE AIM: To identify the role of the intestine in the development of metabolic disorders with operations in the thoracoabdominal aorta developing after clamping of the aorta above the celiac trunk Materials and methods. The study was conducted in pigs (n = 6) with similar body weight (m = 35-39 kg). After the intoduction of animal anesthesia, surgery was performed by access to the visceral veins (upper and lower mesenteric kidney, liver spleen andfemur), from which the Blood samples to determine the concentration of lactate, glucose, as well as indicators of acid-base status. Then placing the clamp on the aorta above the level of discharge of the celiac trunk. Blood sampling and laboratory diagnosis carried out twice: before clamping the aorta and blood flow before the start after 60 minutes of ischemia. Histological study intestinal tissue also conducted. RESULTS: It is shown that the aorta cross-clamping develops pronounced metabolic disorders, manifested in the form of increased levels of lactate and glucose concentrations in all investigated parts of the splanchnic region. The most pronounced increase in lactate after clamping the aorta was observed in the blood samples flowing from the intestine. The results of histological studies show that intestinal hypoperfusion leads to severe pathological changes, that is a predisposing factor leading to the translocation of bacterial agents into the systemic circulation, to the process of expression of systemic inflammatory response and a powerful oxidative stress. CONCLUSION: Our experimental data show that when aortic clamping above the celiac trunk (ischemia mesenteric region) the greatest quantitative contribution to metabolic disorders the body of the animal created in a pathophysiological situation contributes to intestinal hypoperfusion. In this regard, one of the main tactics of the anaesthetist in the perioperative period should be the protection of the intestine against ischemia and its consequences.

[CLINICAL ASPECTS OF THE BLOOD LACTATE DYNAMICS DURING OPERATIONS ON THE HEART AND THE AORTA IN CONDITIONS OF CARDIOPULMONARY BYPASS.]

BACKGROUND: The frequency and the causes for the development of hyperlactatemia during operations on the heart and aorta in conditions of cardiopulmonary bypass (CB) is not adequately described in the literature. THE AIM: To study the clinical significance of the lactate dynamics in arterial blood depending on the source ofpathology, stages of operation, basic parameters of cardiopulmonary bypass, the characteristics of the post-perfusion period, and to identify ways to prevent the development of intraoperative hyperlactatemia in surgical interventions on the heart and aorta. MATERIALS AND METHODS: 420 adult cardiac surgery patients operated on the heart and ascending aorta were examined. All patients were operated on under balanced General anesthesia, CB in hypothermic or normothermic mode. Lactate level in arterial blood and the frequency of hyperlactatemia were analyzed at the following stages of operation: after induction of anesthesia, prebypass period, during CB, in the postbypass period and at the time of admission of the patient in the ICU. During CB we analyzed the duration of the CB, the degree of hemodilution, calculated value of oxygen delivery. Oxygen consumption was recorded in the current mode, the monitor CDI-500. Hyperlactatemia was considered the concentration of lactate above 3 mmol/L. RESULTS: Preperfusion period in all groups of cardiac surgery patients was characterized by a normal level of blood lactate in the absolute majority ofpatients, the frequency of hyperlactatemia did not exceed 1%. Hemodynamic stability was achieved without the use of catecholamines by optimizing volemia and heart rate. While CB showed a trend of increasing lactate on average in comparison with the previous period in patients operated on the heart. Duration CB less than 3 hours was not a factor in the development of hyperlactatemia, provided that oxygen delivery in all patients during perfusion exceeded 300 ml/min/m2, hematocrit ofperfusate at the end of CB was at 25-27% in most patients. To maintain it at a large hemodilution the ultrafiltration hemoconcentration was used. The frequency of hyperlactatemia was 3%. A significant increase in lactate concentration at the end of the CB to 3.39k1,3 mmol/l (range of 2.1-7.2 mmol/l) on the background of metabolic acidosis found only in patients with circulatory arrest due to receipt of blood products of anaerobic glycolysis after the resumption of the CB. They have frequency of hyperlactatemia risen to 29%. The lac- tate average value at admission ofpatients in the ICU with application of 50-60% ofpatients in dopamine/dobutrex at a dose of 5 mcg/kg/min and reaching the targets of transfusion therapy was slightly higher in the baseline period and corresponded to the upper level of normal values. Only during operations on the aortic arch under conditions of circulatory arrest, the concentration of lactate at the end of the operation was 3,4+1,1 mmol/l with a tendency to decrease in comparison with the period of the CB. From 88 to 93% patients during operations on the heart and ascending aorta without circulatory arrest and 64% ofpatients after operations on the aortic arch with circulatory arrest were admitted to the ICU with a normal lactate level in arterial blood Conclusion. The duration ofperfusion less than 3 hours in the conditions of these indicators preservation is not a risk factor for the development of hyperlactatemia. In postbypass period during operations on the heart and aorta without circulatory arrest about 90% ofpatients transferred to the intensive care unit (ICU) with normal values of lactate. During operations on the aortic arch with circulatory arrest about 60% ofpatients have normal levels of lactate at admission from the operating room to the ICU.

[Study of Antioxidant and Membranotropic Activities of Quinazoline Alkaloid Tryptanthrin Using Different Model Systems].

A comparative study of antioxidant (radical-interceptor) properties of tryptanthrin (quinazoline alkaloid shows a high anti-inflammatory activity and it is found in many types of different families of higher plants and microorganisms, including the human microbiome) in the systems of 2,2'-azo-bis(2-methylpropionamidin)dihydrochloride-luminol and hemoglobin-hydrogen peroxide-luminol has been conducted and the influence on the permeability of planar bilayer lipid membranes is evaluated. Trolox was used as a reference antioxidant, and ascorbic acid and dihydroquercetin were taken as standards. Tryptanthrin exhibits very weak antioxidant activity, being markedly inferior to the reference standard and antioxidants while testing antioxidant activity in both studied systems. By the efficacy of antioxidative action the substrates in the systems studied can be arranged in the following order: dihydroquercetin > trolox > ascorbic acid > tryptanthrin. Antioxidant potential of tryptanthrin is approximately 1000 and 3000 times lower than that of trolox and bioflavonoid dihydroquercetine, respectively. Tryptanthrin causes no significant changes in the permeability of planar bilayer membranes in a dose range of 0.5 to. 10 µg/ml. Our data show that tryptanthrin displays no significant radical-interceptor and membranotropic activities. It can be assumed that the observed high anti-inflammatory activity of tryptanthrin is not related to the neutralizing effect against reactive oxygen species and the influence on the permeability of cell membranes. The anticipated mechanisms of biological activity of tryptanthrin are discussed.

[THE COMPARISON OF RESULTS OF DETECTION OF MINIMAL RESIDUAL DISEASE IN PERIPHERAL BLOOD AND MARROW IN CHILDREN OF THE FIRST YEAR OF LIFE WITH ACUTE LYMPHOBLASTIC LEUCOSIS].

The occurrence of minimal residual disease is an important prognostic factor under acute lymphoblastic leucosis in children and adults. In overwhelming majority of research studies bone marrow is used to detect minimal residual disease. The comparative characteristic of detection of minimal residual disease in peripheral blood and bone marrow was carried out. The prognostic role of occurrence of minimal residual disease in peripheral blood and bone marrow under therapy according protocol MLL-Baby was evaluated. The analysis embraced 142 pair samples from 53 patients with acute lymphoblastic leucosis and various displacements of gene MLL younger than 365 days. The minimal residual disease was detected by force of identification of chimeric transcripts using polymerase chain reaction in real-time mode in 7 sequential points of observation established by protocol of therapy. The comparability of results of qualitative detection of minimal residual disease in bone marrow and peripheral blood amounted to 84.5%. At that, in all 22 (15.5%) discordant samples minimal residual disease was detected only in bone marrow. Despite of high level of comparability of results of detection of minimal residual disease in peripheral blood and bone marrow the occurrence of minimal residual disease in peripheral blood at various stages of therapy demonstrated no independent prognostic significance. The established differences had no relationship with sensitivity of method determined by value of absolute expression of gene ABL. Most likely, these differences reflected real distribution of tumor cells. The results of study demonstrated that application of peripheral blood instead of bone marrow for monitoring of minimal residual disease under acute lymphoblastic leucosis in children of first year of life is inappropriate. At the same time, retention of minimal residual disease in TH4 in bone marrow was an independent and prognostic unfavorable factor under therapy of acute lymphoblastic leucosis of children of first year of life according protocol MLL-Baby (OO=7.326, confidence interval 2.378-22.565).

[Prognostic value of bone marrow lesions in children with neuroblastoma detected by flow cytometry].

The purpose of the study was to evaluate the prognostic value of the detection of tumor cells in the bone marrow (BM) in children with neuroblastoma (NB) by flow cytometry. The detection of tumor cells was performed in BM of 51 patients with NB (24 boys and 27 girls) aged from 6 days to 15 years (median--1 year 3 months). Flow cytometry allowed determining NB cells in BM in a much larger number of cases than cytomorphology (49.0% and 29.4% of patients, respectively). Patients, in whom NB cells were not detected in BM by flow cytometry, had significantly better event-free and overall survival rates as well as progression free survival (83.5%, 87.7% and 86,8%, respectively) compared with those in whom immunophenotyping revealed the tumor cells (28.0%, 35.87% and 34,3%, respectively). The prognostic value of the detection of BM lesion by flow cytometry was also confirmed in selected groups of patients with other criteria of stratification. Therefore the detection of tumor cells in BM by flow cytometry could potentially be considered in conjunction with other factors in choosing treatment strategy in patients with NB.

[Prognostic value of the determination of bone marrow lesion in patients with neuroblastoma based on the gene PHOX2B and TH expression].

Bone marrow (BM) involvement in neuroblastoma patients is commonly detected by cytomorphology and associated with poor outcome. Molecular techniques, flow cytometry and immunocytochemistry were offered to detect low number of tumor cells in BM due to high value of analytical sensitivity, while prognostic significance of results, obtained with these methods is unclear. PHOX2B and/or TH genes expression was selected as molecular marker of BM involvement. It was determined in 411 BM samples obtained from 75 neuroblastoma patients. 263 BM samples were taken at the time of primary diagnosis, 80 during treatment and 68 before autologous stem cells (ASC) apheresis. Prognostic significance of BM involvement was defined using 5-year (in some groups 4-year) overall (OS), event free (EFS) and progression free (PFS) survival. 24 patients (32.0%) were positive for PHOX2B and/or TH expression in the BM at the time of primary diagnosis. They had decreased survival rates: EFS achieved 0.49+/-0.12, OS - 0.57+/-0.12, PFS - 0.54+/-0.12, comparing with 0.75+/-0.07, 0.80+/-0.07 and 0.77+/-0.07, respectively, in patients with negative BM, p=0.014, p=0.029 and p=0.033. The trend to decreased OS and PFS was detected in case of minimal residual disease presence at the end of the induction chemotherapy (OS and PFS both are 0.22+/-0.19 vs. 0.70+/-0.18 and 0.43+/-0.22, correspondingly, p=0.121, p=0.130). Detection of PHOX2B and/or TH genes expression in the BM before ASC harvesting led to significant decreasing of EFS and OS (0.00 vs. 0.59+/-0.14 and 0.75+/-0.13, respectively, p=0.021 and p=0.016).

[Antioxidative and membranotropic activities of rosmarinic acid].

The metabolic damages and inflammatory diseases are closely connected with high increase of the contents of the reactive oxygen species (ROS) and lipid peroxidation products in organism. In connection with this natural antioxidants are actively used for efficient fight with oxidative stress. In current work we have estimated an antioxidative potential of rosmarinic acid (RA), which is broadly wide-spread amongst plants and possesses the useful spectrum of biological activities. It has been shown that RA noticeably exceeded known antioxidants in test on antioxidant activities in Hb-H2O2-luminol and 2,2'-azo bis (2-methylpropionamidine) dihydrochloride-luminol systems, as well as on inhibition of linoleic acid peroxidation. On antioxidant activities the investigated substances can be arranged in the following order: RA > dihydroquercetin > trolox > ascorbic acid. RA molecules are localized mainly in the lipid bilayer of polar groups, but have no significant effect on its structural and functional properties: RA does not cause significant changes in permeability of planar bilayer membranes in a dose range of 0.5 to 10 microg/ml. Spontaneous incorporating of 1 mol% of RA into the lipid bilayer is sufficient for the complete prevention of lipid peroxidation. Thus, the antioxidant activity of RA is based on its ability to inhibit the initiation stage of free radical reactions of lipid peroxidation, largely caused by the formation of ROS. In this regard RA, as a powerful and effective inhibitor of ROS and lipid peroxidation, has great potential for wide use not only in medicine but also in the food industry to preserve the quality of perishable food products.

[Study of antioxidant and membrane activity of rosmarinic acid using different model systems].

Rosmarinic acid is found in many species of different families of higher plants and its chemical structure is phenol propanoid with various biological activity. In this paper, we conducted a comparative study of antioxidant (radical-scavenging) properties of rosmarinic acid in systems of 2,2'-azo-bis(2-methylpropionamidin)dihydrochloride-luminol and hemoglobin-hydrogen peroxide-lu- minol, determined its protective potential in preventing peroxidation of linoleic acid, and evaluated the effect on the permeability of planar bilayer lipid membranes. Linoleic acid peroxidation was assessed by iron-thiocyanate method. In these studies, trolox was used as a reference antioxidant, and ascorbic acid, and dihydroquercetin were taken as standards. Rosmarinic acid is significantly superior to trolox, ascorbic acid and dihydroquercetin in the tests for antioxidant activity in the systems studied, as well as in inhibition of linoleic acid peroxidation. According to their activity the investigated substances can be arranged in the following order: rosmarinic acid > dihydroquercetin trolox > ascorbic acid. Rosmarinic acid does not cause significant changes in the permeability of planar bilayer membranes in a dose range of 0.5 to 10 mkg/mL. Antioxidant activity of rosmarinic acid is due to the neutralization of reactive oxygen species and/or luminol radicals generated in model systems. The observed features of the antioxidant and membrane activity of rosmarinic acid, which may underlie the previously mentioned pharmacological effects are discussed.

[Elaboration of immune stimulating lipid-saponin subunit antigen carrier based on glycolipid monogalactosyldiacylglycerol from sea macrophytes and triterpene glycosides from Cucumaria japonica].

The ability of some triterpene glycosides of holothurians: holotoxin A1 from Apostichopus japonicus and a mixture of monosulphated triterpene glycosides from Cucumaria japonica called cucumarioside (CD) to form supramolecular complexes with cholesterol (Chol) and monogalactosyldiacylglycerol (MGDG) or phosphatidylcholine (PC) was studied. A transmission electron microscopy method was used to observe supramolecular lipid-saponin complexes formed by holotoxin A1 and CD with cholesterol in the presence of membrane lipids. The observed supramolecular complexes are tubular nanoparticles with a length of 100-300 nm, an external diameter of 10-16 nm and an internal diameter of 2-6 nm. The formation of tubular nanoparticles was more effective in the presence of MGDG than with PC. Nanoparticles forming in the presence of MGDG are shaped as a tubule, have a constant diameter and a strongly pronounced internal channel. In contrast, PC has no such properties; this lipid is unable to fully integrate in tubular nanoparticles. Based on electron-microscopy data the range of weight ratio of MGDG-Chol-CD was determined as a 1-10:2:3 that provided most effective formation of tubular nanoparticles. Different methods of incorporation of model antigens in complex MGDG-Chol-CD were studied. Influenza haemagglutinin and neuraminidase from commercial vaccine "Influvac" and pore forming protein YompF from Yersinia pseudotuberculosis were used as model antigens. From 54 to 72% of protein of "Influvac" vaccine and 88-92% of YompF were incorporated in supramolecular complexes depending on the method of incorporation. The loss of functional activity of haemagglutinin of vaccine "Influvac" was the result of applying ultrasonic disintegration for incorporation of this protein in complex MGDG-Chol-CD. YompF incorporation in MGDG-Chol-CD complex led to the increased diameter of tubular particles, in the same time incorporation of vaccine "Influvac" antigens produced the "cap" formation at the end of tubules. The possibility of a described supramolecular complex MGDG-Chol-CD to be a carrier for subunit bacterial and viral antigens is shown.

[Methods of detection and prognostic significance of genetic material increase of the short arm of chromosome 2 and a deletion of the short arm of chromosome 1 in patients with neuroblastoma].

MYCN gene amplification and 1p deletion in neuroblastoma patients are associated with poor prognosis and commonly used for patient's stratification into risk groups. MYCN copy number and 1p deletion status were analyzed with multiplex ligase-dependent probe amplification (MLPA), PCR and FISH. MYCN amplification was revealed in 21 patients (17.2%) simultaneously by MLPA and PCR. In 28 cases (23.0%) 2p gain was detected. 1p deletion was revealed in 28 patients (23.0%) while concordance between PCR and MLPA achieved 95.8%, PCR and FISH - 90.9%. Mean follow-up time achieved 42 months (ranged from 1 month to 13 years). Event-free survival and overall survival in MYCN-amplified patients as well as in patients with 1p deletion were significantly lower comparing with MYCN-negative patients or patients without 1p deletion.

[The standardization of diagnostic of paroxysmal night hemoglobinuria cytometry].

The flow cytometry becomes a more and more largely applied technique. However, the sufficient novelty of technique has no worked-out standards of diagnostic of many diseases. The lacking of external control of quality promotes development of large variety of approaches to diagnostic of diseases and impossibility to compare the study results from different laboratories. The paroxysmal night hemoglobinuria is an acquired clonal disease characterized by proliferation of stem cells with partial or total loss of expression of glykosylphosphosphatidyl inositol anchor needed to conjugate a number of surface proteins. The flow cytometry is a basic technique of detection and monitoring of clone of paroxysmal night hemoglobinuria. The article presents the results of paroxysmal night hemoglobinuria testing of 8 patients in 6 independent laboratories using flow cytometry by standard protocol recommended by the International society of clinical cytometrists (ICCS).

Validity of factorization of the high-energy photoelectron yield in above-threshold ionization of an atom by a short laser pulse.

An analytic description for the yield, P(p), of high-energy electrons ionized from an atom by a short (few-cycle) laser pulse is obtained quantum mechanically. Factorization of P(p) in terms of an electron wave packet and the cross section for elastic electron scattering (EES) is shown to occur only for an ultrashort pulse, while in general P(p) involves interference of EES amplitudes with laser-field-dependent momenta. The analytic predictions agree well with accurate numerical results.

[Localization of point mutations in the coding part of the VHL gene in clear cell renal cancer].

VHL gene is often inactivated in sporadic clear cell renal cancer (CCRC) due to somatic mutations, and it's germline mutations cause hereditary CCRC--von Hippel-Lindau syndrome. Localization of mutations in VHL, identification of new mutations and their influence on CCRC progression and sensitivity to targeted therapy are actual problems in modern oncogenetics. We have provided search and characterization of mutations in 248 primary CCRC using SSCP-analysis and sequencing. Somatic mutations were detected in 37.5% of samples, 72% of mutations were identified for the first time. New missense-mutations were analyzed by alignment programs and three-dimensional structure modeling. Mutation frequency was compared in different groups of patients in respect to stage, grade, and metastases. It was demonstrated that 39.1% samples with stage I harbor somatic mutations, however, no association with progression or metastases was found. We also have investigated localization of mutations in the VHL coding part and positions of missense-mutations and inframe deletions/insertions focusing on VHL critical sequences. VHL mutation analysis performed in this study improve the possibilities of laboratory diagnostics of familial and sporadic CCRC.

[Enhancing the immunogenic activity of influvac vaccine in the use of adjuvant TI complexes modified by echinochrome A].

The self-assembly of marine macrophyte glycolipids, holothurian saponin, and cholesterol gave rise to nanoscale morphological structures called tubular immunostimulating (TI) complexes. Whether the latter could be used on the basis of vaccine preparations containing the influenza virus subunit antigens was studied. There was an obvious increase in the immunogenicity of influenza virus hemagglutinin when the experimental animals were immunized with this antigen as part of TI complexes. It was shown that the adjuvant activity of the TI complex to influenza virus hemagglutinin could be enhanced by adding the known antioxidant echinochrome A from a sand-dollar (Echinarachnius parma) to the matrix of the TI complex.

[The TH, ELAVL4 and GD2 gene expression as diagnostic markers of bone marrow lesions in patients with neuroblastoma].

The bone marrow (BM) TH, ELAVL4 and GD2 genes expression was evaluated in 331 samples from 57 different stage neuroblastoma (NB) patients, 26 BM samples from patients without NB and samples from 2 NB cell lines (IMR-32, Kelly) by real-time PCR. BM samples were considered NB-positive if PHOX2B expression was found or tumor cells were detected in BM smears. TH expression was not revealed in normal BM and was significantly lower in NB-negative samples. Expression of PHOX2B, TH and GD2 remained stable throughout NB treatment, while ELAVL4 expression was down-modulated. ROC-analysis revealed similar initial and follow-up values of TH and PHOX2B in NB patients' bone marrow making it possible to be used for disease detection and monitoring. The test prediction value was 0.994 and 0.952, respectively. The additional test for TH didn't increase the test effectiveness in comparison with PHOX2B test. ELAVL4 and GD2 assessment didn't add diagnostic value for BM involvement monitoring in NB patients.