Conjugates of 3,5-Bis(arylidene)-4-piperidone and Sesquiterpene Lactones Have an Antitumor Effect via Resetting the Metabolic Phenotype of Cancer Cells.

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

[Psychopathology of depressive-delusional states with religious content]. / Psikhopatologicheskie osobennosti depressivno-bredovykh sostoyanii s religioznym soderzhaniem.

OBJECTIVE: Identification of psychopathological characteristics of depressive-delusional states with religious content, development of a typology, determination of formation features, nosological assessment. MATERIAL AND METHODS: A total of 79 patients (47 female, 32 male, mean age 27±6.5 years) with depressive-delusional states with religious content within the affective and schizophrenia spectrum disorders were studied. Clinical-psychopathological, psychometric (PANSS, HDRS, S. Huber CRS) and statistical methods were used. RESULTS: Based on the psychopathological structure, specific mechanisms of development of delusions and themes of the religious experiences, three types of depressive-delusional states were identified: type 1 - with a predominance of depressive delusions congruent with affect and delusional ideas of guilt, sinfulness, abandonment of God (14 patients, 17.7%; 6 women, 8 men; mean age 28±4.5 years; HDRS score 33±5.6, the total PANSS score 71±5.3, the PANSS positive subscale score 15.8±3.7); type 2 - with the addition of incongruent delusional constructs, persecutory disorders and acute sensory delusions to the existing depressive religious delusion, with the phenomenon of confessional ambivalence (27 patients, 34.2%; 16 women, 11 men; mean age at attack manifestation 25±9 years; HDRS score 29.6±4.4, the total PANSS score 87±6.2, the PANSS positive subscale score 23.5±4.2); type 3 - depressive-paranoid states with a predominance of Kandinsky-Clerambault syndrome of religious content (38 cases, 48.1%; 20 women, 18 men; mean age at attack manifestation 23.4±2.5 years; HDRS score 32.7±3.7, the total PANSS score 102±7.3, the PANSS positive subscale score 32.5±4.5). CONCLUSION: The study of depressive-delusional states with religious content has shown their clinical-psychopathological heterogeneity. The religious experiences served as a pathoplastic factor, which essentially modified the clinical-psychopathological picture of the disease due to presence of the specific religious phenomena. The identified types of depressive-delusional disorders with religious content had different diagnostic value.

[REASONS FOR CITIZENS TO APPLY FOR PAID MEDICAL SERVICES ACCORDING TO SOCIOLOGICAL SURVEYS OF THE POPULATION].

An actual characteristic of the processes taking place in the Russian healthcare, especially during the ongoing transformation of the state healthcare system aimed at building a patient-oriented healthcare model, is the analysis of the reasons why citizens prefer medical care provided for a fee. The purpose of the study is to study the main reasons for the treatment of the population of the city of Moscow for medical services provided for a fee and their comparison with the reasons for applying for paid medical services (PMU) in other regions of the Russian Federation.The main materials of the study were the data of a sociological survey of visitors to the capital's medical organizations about the reasons for the population's application for obtaining PMU, as well as the results of sociological surveys on this topic in other regions of the Russian Federation. As a result, not only the main reasons for applying for medical services on a paid basis were identified, but also regional peculiarities of the prevalence of PMU.

Dynamic and thermodynamic models of adaptation.

The concept of biological adaptation was closely connected to some mathematical, engineering and physical ideas from the very beginning. Cannon in his "The wisdom of the body" (1932) systematically used the engineering vision of regulation. In 1938, Selye enriched this approach by the notion of adaptation energy. This term causes much debate when one takes it literally, as a physical quantity, i.e. a sort of energy. Selye did not use the language of mathematics systematically, but the formalization of his phenomenological theory in the spirit of thermodynamics was simple and led to verifiable predictions. In 1980s, the dynamics of correlation and variance in systems under adaptation to a load of environmental factors were studied and the universal effect in ensembles of systems under a load of similar factors was discovered: in a crisis, as a rule, even before the onset of obvious symptoms of stress, the correlation increases together with variance (and volatility). During 30 years, this effect has been supported by many observations of groups of humans, mice, trees, grassy plants, and on financial time series. In the last ten years, these results were supplemented by many new experiments, from gene networks in cardiology and oncology to dynamics of depression and clinical psychotherapy. Several systems of models were developed: the thermodynamic-like theory of adaptation of ensembles and several families of models of individual adaptation. Historically, the first group of models was based on Selye's concept of adaptation energy and used fitness estimates. Two other groups of models are based on the idea of hidden attractor bifurcation and on the advection-diffusion model for distribution of population in the space of physiological attributes. We explore this world of models and experiments, starting with classic works, with particular attention to the results of the last ten years and open questions.

[IMPROVEMENT OF ORGANIZATIONAL APPROACHES TO REGULAR MEDICAL CHECKUP SERVICE IN THE METROPOLITAN HEALTHCARE SYSTEM].

An adequate response to the challenges people face in the context of continuing urbanization, increasing life expectancy and, at the same time, falling birth rates, is to maximize the containment of chronic non-communicable diseases (NCDs) by high level of healthcare organization and medical services provided to the patients with such pathologies. Global economic losses caused by NCDs result in disability and early mortality among working population as well as in significant treatment costs increasing with the advancement of the disease. That is why outpatient care for NCD patients which includes behaviour factors monitoring is an urgent task for the world and Russian healthcare. In this regard, the goal of this study is to find organizational solutions to improve regular medical checkup service for NCD patients in the metropolitan healthcare system, relying on the data provided by medical organizations in the form of statistical observations. Thus, the results of correlation analysis have revealed a connection between the increased number of individuals in the second and third health groups and individuals scheduled for a regular medical checkup at the end of the year and its absence between the clinical examination results and the number of firstly diagnosed patients. It is also reported that the number of diseases registered for a regular medical checkup at the end of the reporting period (year) has increased, so patients with polymorbid conditions are supposed to prevail among the others on these days and require a special approach to their management. Taking into account the results obtained, possible ways for optimizing the organizational model of a regular medical checkup are the following: special hours (days) for such patients admission, permanent cooperation of a doctor (local general practitioner, GP, family doctor) and a health worker with a secondary medical education (to deal with organizational issues), etc.

[Laboratory errors for identification of the escherichia coli strains of the serological groups O6 and O25 as acute intestinal infections.]

Were studied the genes encoding the virulence factors of 221 strains: E. coli O6:H1 (194) and E. coli O25:H4 (27), isolated in 2014-2018 from stool samples of children and adults examined according to epidemic indications. Molecular methods included PCR with hybridization-fluorescence and electrophoresis detection of amplified products. The strains did not have virulence genes for diarrheagenic E. coli (DEC) pathogroups EPEC, ETEC, EIEC, EHEC, EAggEC, and belonged to the phylogenetic group B2. They contained from four to eight genes encoding virulence factors of ExPEC: E. coli O6:H1 - pap (68,6%), sfa (87,6%), fimH (96,4%), hly (62,4%), cnf (74,7%), iutA (97,9%), fyuA (95,9%), chu (100%); E. coli O25:H4 - pap (66,7%), afa (22,2%), fimH (100%), hly (44,4%), cnf (44,4%), iutA (100%) , fyuA (100%), chu (100%). The antimicrobial susceptibility testing to 6 classes of antimicrobials (beta-lactams, fluoroquinolones, aminoglycosides, nitrofurantoin, sulfanilamide, trimethoprim / sulfamethoxazole) according the EUCAST. 60,3% of E. coli O6:H1 were sensitive to antibiotics, E. coli O25:H4 remained sensitive to carbapenems and nitrofurans. Extended-spectrum cephalosporins resistance was due to the production ESBL (CTX-M). The 57,1% resistant strains of E. coli O6:H1 and 100% of E. coli O25:H4 strains belonged to the MDR phenotype. The XDR phenotype had one in five MDR strains of E. coli O6:H1 and E. coli O25:H4. All strains of E. coli O25:H4 belonged to ST131. Given the important role of E. coli in human pathology, detection of virulence genes should be performed to confirm the etiological significance of the isolated strain.

[Antimicrobial resistance and clinical significant resistance mechanisms of Salmonella isolated in 2014-2018 in St.Petersburg, Russia.]

The article presents the results of antimicrobial resistance monitoring of Salmonella isolated from children and adults with diarrhea in St. Petersburg in 2014-2018. In 746 isolates of 42 serovars more than 90,0% belonged to three: S. enteritidis (79,6%), S. typhimurium (6,8%) and S. infantis (3,8%). The antimicrobial susceptibility testing (according the EUCAST) to 7 classes of antimicrobials revealed the resistance in 78,6% of Salmonella. Low-level quinolone resistance (MIC of ciprofloxacin 0,12-0,5 mg/l) was detected in 63,3% isolates (S. enteritidis -71,0%, S. typhimurium - 15,7%, S. infantis - 89,3%) and was due to five kinds of single nucleotide substitutions in gyrA: Asp87Tyr - 36,1% of studied isolates (only S. infantis); Ser83Phe - 22,2% (only S. enteritidis); Asp87Asn - 19,4% (S. enteritidis, S. typhimurium, S. hadar, S. newport); Ser83Tyr -11,1% (S. enteritidis and S. infantis) and Asp87Gly - 8,3% (only S. enteritidis). Only in one S. kentucky isolate with high-level fluoroquinolone resistance (MIC of ciprofloxacin > 8,0 mg/l) two substitutions (Ser83Phe and Asp87Asn) were detected. Two Salmonella isolates (S. typhimurium and S. corvallis) had plasmid-mediated quinolone resistance (qnrS). Extended-spectrum cephalosporin resistance was found in 6 Salmonella serovars (1,6%). The bla-genes were detected: of genetic group CTX-M1 - in 10 isolates (serovars S. typhimurium, S. enteritidis, S. abony, S. coeln and S. virchow), CTX-M2 - in 2 S. typhimurium isolates, CTX-M9 - in three S. enteritidis isolates. In one S. typhimurium CTX-M1 and CTX-M2 were detected. The gene of CMY-2 (molecular class C cephalosporinase) was revealed in two isolates (S. newport and S. enteritidis). Our study showed that Salmonella (the main bacterial pathogen of acute diarrhea in children and adults) isolated in Saint-Petersburg had antimicrobial resistance to drugs of choice for salmonellosis treatment.

[The influence of laser radiation of the infrared range with a wavelength of 1270 nm on mice Balb/cNude]. / Vliianie lazernogo izlucheniia infrakrasnogo diapazona s dlinoi volny 1270 nm na myshei Balb/cNude.

BACKGROUND: The effects of low-intensity laser radiation (LILR) on the skin depend on the wavelength and density of the irradiation flux. Moreover, the vast receptor field of the skin facilitates the systemic influence of irradiation on the body. AIMS: The objective of the present study was to evaluate the effects of low-intensity laser irradiation (LIRI) of the infrared range with a wavelength of 1270 nm on the skin of mice Balb/cNude. MATERIAL AND METHODS: The study was carried out with the use of the linear immunodeficient mice Balb/c nude obtained from the animal house of the Pushchino branch of the Academicians M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Biorganic Chemistry. The animals were irradiated once with a fiber laser of stimulated Raman scattering with a wavelength (λ) of 1270 nm, a power of 1.96 mW during the 2 min exposure at an intensity of 10 mW/cm2, and an energy flux density of 1.2 J/cm2. The histological studies and morphometry of the skin autoptate were performed. In adition, the expression of microRNA-21, -31, -130a, -191, -200c, -205, -218 was determined in the skin. Reverse transcription and real-time PCR reactions with Taq-Man probes and primers were performed on the nucleic acid amplifier CFX96 ('BioRad', USA).MicroRNA-191 was chosen as the reference gene. The bioinformation analysis of signaling pathways involving the studied microRNAs was performed using the DJANA miRPath database v.3.0. RESULTS: A significant increase in the amount of keratinocytes of the basal layer was documented together with diffuse lymphoid-leukocyte infiltration of the interlobular connective tissue of the subcutaneous fat and endomysium after LILR. The pattern of microRNA expression was tissue-specific. An increase in the expression of micro-RNA-31 and-21 in the skin and a multidirectional change in miRNA-200 and -218 levels were shown. The bioinformation analysis showed that miR21 and miR31 were involved in the regulation of such signaling pathways as PI3K-Akt, Jak-STAT, MAPK, and mTOR of importance for carcinogenesis. Also, they have a signaling significance in the development of melanoma, kidney cancer, prostate cancer and malignant glioma. CONCLUSION: The data obtained in this study suggest activation of the tumor cell-specific and basic processes in the skin of immunodeficient Balb/cNude mice under the influence of low-intensity laser radiation with a wavelength of 1270 nm applied at a dose of 1.2 J/m2.

[Role of neutrophil dysfunction in the pathogenesis of systemic lupus erythematosus]. / Rol' disfunktsii neitrofilov v patogeneze sistemnoi krasnoi volchanki.

Neutrophil dysfunction plays a considerable role.in systemic lupus erythematosus (SLE) The protective function of neutrophils is carried out through various mechanisms: isolation of granular antimicrobial peptides (gAMP), microbial phagocytosis with subsequent degradation via reactive oxygen species inside the phagolysosomes; as well as bactericidal action due to the release of networks from chromatin and gAMP, also called neutrophil extracellular traps (NECTs). The development of neutropenia in SLE has multiple causes, including the formation of antibodies directly to leukocytes; that of neutralizing autoantibodies to the growth factors of neutrophils and cells - myeloid precursors; bone marrow suppression; involvement of neutrophils in the processes of apoptosis and NETosis. Neutrophils in SLE are characterized by reduced phagocytic ability and pathological oxidative activity. In SLE, there is a decrease in the ability to remove the products of neutrophil apoptosis, which is correlated with disease activity. SLE patients are noted to have a higher expression level of the genes specific for low-density granulocytes, an abnormal immature neutrophil population. The impaired processes of formation of NECTs and removal NETosis products play a substantial role in the pathogenesis of SLE. It is shown that the abnormal formation of NECTs also causes endothelial injury and increases the risk of thromboses. The design of novel drugs that act on the specific parts of the formation of NECTs or contribute to their removal from the extracellular environment can propel therapy for SLE and other autoimmune diseases to new heights. There is evidence for further investigations of neutrophil-mediated pathogenetic processes in SLE in order to identify potential therapeutic targets and to understand the mechanisms of action of drugs used in clinical practice.

Procedure for Purification of Recombinant preMsk1p from E. coli Determines Its Properties as a Factor of tRNA Import into Yeast Mitochondria.

Mitochondrial genomes of many eukaryotic organisms do not code for the full tRNA set necessary for organellar translation. Missing tRNA species are imported from the cytosol. In particular, one out of two cytosolic lysine tRNAs of the yeast Saccharomyces cerevisiae is partially internalized by mitochondria. The key protein factor of this process is the precursor of mitochondrial lysyl-tRNA synthetase, preMsk1p. In this work, we show that recombinant preMsk1p purified from E. coli in native conditions, when used in an in vitro tRNA import system, demonstrates some properties different from those shown by the renatured protein purified from E. coli in the denatured state. We also discuss the possible mechanistic reasons for this phenomenon.

[The ways of improvement of direct results of surgery of patients with rectal cancer].

The data of 1740 patients (during 20 years) with rectal cancer were analyzed. Planned operations were performed in 95.8% of patients. The adenocarcinoma was verified in all patients. Accompanying pathology was detected in 84.9% of patients and the pathology of cardiovascular system was more frequent (76.6%). Complicated course of tumourous process was revealed in 4.5% of patients (cases of bowel obstruction, the perifocal inflammation). The majority of patients had the II, III stage of the oncologic process. All operations were performed by conventional (open) way. The number of anterior resection of the rectum increased and the number of abdominoanal resection with bringing down reduced. The specific weight of sphincter preserving operations, which were completed by forming a colostomy decreased. The quantity of performed abdominoperineal extirpation was constant.

[Approaches to the improvement of forensic medical expertise in the cases of sexual crimes and doubtful gender status].

The authors analyzed the results of the forensic medical expertise of the cases of sexual assaults and covert sexual abuse. Special attention is given to the peculiarities of forensic-medical expertise in the cases of veneral diseases and HIV-infection, injuries to sexual organs in women and men. The specific approaches to the examination of corpses in the cases of atypical sexual behavior or a murder supposedly committed for sexual motives are considered.

Noncanonical functions of aminoacyl-tRNA synthetases.

Aminoacyl-tRNA synthetases, together with their main function of covalent binding of an amino acid to a corresponding tRNA, also perform many other functions. They take part in regulation of gene transcription, apoptosis, translation, and RNA splicing. Some of them function as cytokines or catalyze different reactions in living cells. Noncanonical functions can be mediated by additional domains of these proteins. On the other hand, some of the noncanonical functions are directly associated with the active center of the aminoacylation reaction. In this review we summarize recent data on the noncanonical functions of aminoacyl-tRNA synthetases and on the mechanisms of their action.

[Forensic medical expertise of injuries in the anorectal region and rectum related to the sexual assault].

Injuries to the anorectal region and rectum associated with sexual crimes require forensic medical assessment even though this issue remains to be poorly developed. The results of 84 forensic medical expertises are presented based on the materials obtained by examining both women and men who applied with complains of sexual abuse (anogenital penetration) to the Primorskoye territorial Bureau of forensic medical expertise during 5 years, from 2005 to 2009. The study has demonstrated correlation between dynamics of applications of the victims of either sex and the lack of a tendency toward a decrease in their frequency. The signs characteristic of acute injuries and chronic conditions are described. The causes of diagnostic errors during forensic medical expertise of sexual abuse are discussed.

[Forensic medical expertise of injuries in the anorectal region and rectum unrelated to attempts at sexual abuse].

The results of analysis of 46 commission forensic medical expertises are presented based on the materials concerning injuries and changes in the anorectal region and rectum unrelated to attempts at sexual abuse. The materials were collected and stored by the Primorskoye territorial Bureau of forensic medical expertise during 5 years, from 2005 to 2009. All injuries and changes were categorized into several groups in terms of their origin, viz. car accidents, inadequate medical care, insertion of foreign bodies, falls on sharp and protruding objects, gunshot wounds, chemical and thermal burns, sports training, etc. The occurrence of the injuries is illustrated by the examples from forensic medical practice. It is concluded that experts describing injuries and changes in the anorectal region and rectum must act in conformity with the order of the Russian Ministry of Health No 346 dated October 21, 2010) and use instrumental methods and terminology accepted in modern proctology. The severity of harm to health in subjects presenting with injuries and changes in the anorectal region and rectum should be evaluated in terms of both the degree of the threat to life and the outcome of the treatment with special reference to the duration of health impairment, severity of the trauma, and its consequences (anorectal dysfunction).

[Combined therapy and radiotherapy in stage-II Hodgkin disease].

The aim of the study was to raise efficacy of combined treatment of stage II Hodgkin's disease by optimization of fractionation and volume of irradiation. It included 179 patients with involvement of supradiaphragmatic lymph nodes treated in 1986-2006. It was found that multi-fractionation was followed by lower frequency of relapse as compared with standard regimens as well as rates of early ones. The most efficient dosage was 30-36 Gy as far as frequency, term of relapse occurrence and recurrence-free survival were concerned.

[Haponin (eIF1AD) interacts with glyceraldehyde 3-phosphate dehydrogenase in the CHO-K1 cell line].

Haponin (HLDF-alike protein) was previously identified from the human promyelocytic leukemia HL-60 cell line. For the functional study of this protein, we obtained recombinant haponin with an N-terminal hexahistidine tag using a baculovirus expression system. Antibodies against 6xHis-haponin were produced, and the expression of endogenous haponin was demonstrated in mammalian cell lines of different origin. Using affinity chromatography and immunoprecipitation methods, we have shown that in CHO-K1 cells haponin interacts with glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which is one of the vital glycolytic enzymes with a diverse set of noncanonical functions.

[Association study of the Val158Met polymorphism of the catechol-O-methyltransferase gene and alcoholism and heroin dependence: the role of a family history].

The aim of this study was to investigate the association the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene and predisposition to alcoholism and heroin dependence. The authors genotyped DNA samples from 964 Russian males (395 alcoholics, 243 heroin addicts and 326 healthy controls). The association between the Val158Met COMT polymorphism and alcoholism was found in males with high density of family history (two or more blood relatives with alcoholism within the family). In this group, the frequency of a L (Met) allele was significantly higher in comparison with controls (p=0,001), patients without family history (p=0,034) and patients with the mild density of family history (p=0,0005). The frequency of the HH (ValVal) genotype was reduced as well compared to the controls (p=0,003). In the group of heroin addicts with the mild density of family history, there was a trend to lower frequency of the HH genotype (p=0,058) compared to patients without family history. The results suggest that the functional Val158Met COMT polymorphism is one of the significant markers of genetic predisposition to addiction diseases.