[Organization of maxillofacial and dental care for the wounded of the Voronezh front (July 1942 - July 1943)]. / Organizatsiya chelyustno-litsevoi i stomatologicheskoi pomoshchi ranenym Voronezhskogo fronta (iyul' 1942 g. ­ iyul' 1943 g.).

The article is devoted to the history of the formation of the system of assistance to maxillofacial wounded soldiers of the Voronezh Front during the battles for Voronezh in 1942-1943. The difficulties and achievements in the implementation of phased assistance to the wounded in the face, as well as the improvement of the organizational structure of surgical and dental care for soldiers and officers of the front are reflected.

Selected trends in head and neck cancer epidemiology in Slovakia - an international comparison.

BACKGROUND: Head-and-neck malignant neoplasms (diagnosis group C00-C14, according to ICD-10) form a heterogeneous group of diseases with close anatomical localization. The incidence is twice to three times higher in men than in women and is increasing worldwide. OBJECTIVE: The aim of our analysis was to estimate changes of incidence and mortality rates of head-and-neck malignancies associated with anatomical topographic regions over the time as well as to compare these indicators in different selected countries of the world. Secondary endpoints included the assessment of patients' age distribution, clinical stages of newly diagnosed cases, and point prevalence of the disease in the Slovak Republic (SR). MATERIAL AND METHODS: The data base for the calculations was obtained from national databases and outputs of the National Cancer Registry (NCR) of the SR (with summary data available from the National Epidemiological Portal of Malignant Tumors, which analyzed data from 1984-2003 and was available until 2009, the remaining data were obtained from annual analyses of the NCR of the SR and the National Centre for Health Information (NCZI)), from the Statistical Office of the SR, and from the IARC WHO global database outputs on incidence, mortality, prevalence and survival of the patients. Incidence and mortality data in the SR were available up to 2012 (including) and up to 2021 (including), respectively. A log-linear joinpoint regression model was used to analyze the development of incidence and mortality rates over time by using Joinpoint Regression Program software. To achieve maximum precision in the estimated total surviving population of patients with head and neck malignant neoplasms, a model was developed to calculate the point (overall) prevalence based on absolute numbers of long-term registered national counts of newly diagnosed patients, mortality from the disease, overall mortality, and survival probability. The representation of clinical stages of head and neck carcinoma in the SR was compiled from available national data (2000-2012) and from predictions and does not consider changes in TNM classifications over the time. RESULTS: The age-adjusted (to the world standard population, ASR-W) incidence rate and the age-adjusted (ASR-W) mortality rate of head-and-neck malignant tumors in the SR have shown a significantly decreasing tendency in men since 1990; however, in women both of these indicators have shown a significant increasing tendency, especially the significantly growing incidence since 2004. In 2012, the overall age-adjusted incidence and mortality rate of head-and-neck cancers in the SR were significantly higher in males (ASR-W incidence 22.6/100,000 and ASR-W mortality 15.26/100,000) compared to females (ASR-W incidence 4.21/100,000 and ASR-W mortality 1.52/100,000). More than 75% of newly diagnosed cases are already in advanced and metastatic clinical stages, which is the most unfavourable survival factor. The absolute prevalence of these patients in the SR was estimated to be N = 9,395 in the year 2021. CONCLUSION: It is necessary to get a current and well evaluated epidemiological overviews to be able to plan preventive and intervention programs in oncology.

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MicroRNAs epigenetically regulate physiological and pathological processes. Previously, we found that miR-204-5p is expressed at low levels in melanoma cells, and an increase in its level leads to a change in proliferation, migration, and invasion of these cancer cells. Now, using bioinformatics analysis, it has been shown that the target of miR-204-5p is FOXC1 transcription factor, which is implicated in carcinogenesis. Using the luciferase reporter assay, it was found that miR-204-5p suppresses expression of the FOXC1 gene by binding to its 3' non-coding region. Transfection of small interfering RNA (siRNA) targeting FOXC1 into melanoma cells caused a decrease in miR-204-5p levels, which is consistent with the generally accepted concept of feedback regulation of miRNA expression by target genes. According to the results of the MTT test and fluorescence microscopy, the proliferation level of melanoma cells under the influence of siRNA to FOXC1 decreased 72 h after transfection. Changes in the ratio of cells by cell cycle phase were analyzed using flow cytometry. Regulatory relationships between FOXC1 and miR-204-5p, and an inhibitory effect of FOXC1 knockdown on melanoma cell proliferation were revealed. Based on the results, it can be assumed that miR-204-5p regulates proliferation of melanoma cells by affecting FOXC1 expression.

Relaxed functional constraints on triplicate α-globin gene in the bank vole suggest a different evolutionary history from other rodents.

Gene duplication plays an important role in the origin of evolutionary novelties, but the mechanisms responsible for the retention and functional divergence of the duplicated copy are not fully understood. The α-globin genes provide an example of a gene family with different numbers of gene duplicates among rodents. Whereas Rattus and Peromyscus each have three adult α-globin genes (HBA-T1, HBA-T2 and HBA-T3), Mus has only two copies. High rates of amino acid evolution in the independently derived HBA-T3 genes of Peromyscus and Rattus have been attributed to positive selection. Using RACE PCR, reverse transcription-PCR (RT-PCR) and RNA-seq, we show that another rodent, the bank vole Clethrionomys glareolus, possesses three transcriptionally active α-globin genes. The bank vole HBA-T3 gene is distinguished from each HBA-T1 and HBA-T2 by 20 amino acids and is transcribed 23- and 4-fold lower than HBA-T1 and HBA-T2, respectively. Polypeptides corresponding to all three genes are detected by electrophoresis, demonstrating that the translated products of HBA-T3 are present in adult erythrocytes. Patterns of codon substitution and the presence of low-frequency null alleles suggest a postduplication relaxation of purifying selection on bank vole HBA-T3.

Association of CYP2C9*2 with bosentan-induced liver injury.

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (ß = 2.16, P = 0.024; ß = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

Functional characterization of ABCC2 promoter polymorphisms and allele-specific expression.

Multidrug resistance protein 2 (MRP2, ABCC2) is an efflux membrane transporter highly expressed in liver, kidney and intestine with important physiological and pharmacological roles. The goal of this study was to investigate the functional significance of promoter region polymorphisms in ABCC2 and potential allele-specific expression. Twelve polymorphisms in the 1.6 kb region upstream of the translation start site were identified by resequencing 247 DNA samples from ethnically diverse individuals. Luciferase reporter gene assays showed that ABCC2 -24C>T both alone and as part of a common haplotype (-24C>T/-1019A>G/-1549G>A) increased promoter function 35% compared with the reference sequence (P<0.0001). No other common variants or haplotypes affected ABCC2 promoter activity. Allele-specific expression was also investigated as a mechanism to explain reported associations of the synonymous ABCC2 3972C>T variant with pharmacokinetic phenotypes. In Caucasian liver samples (n=41) heterozygous for the 3972C>T polymorphism, the 3972C allele was preferentially transcribed relative to the 3972T allele (P<0.0001). This allelic imbalance was particularly apparent in samples with haplotypes containing two or three promoter/untranslated region variants (-1549G>A, -1019A>G and -24C>T). The observed allelic imbalance was not associated with hepatic or renal ABCC2 mRNA expression. Additional mechanisms will need to be explored to account for the interindividual variation in ABCC2 expression and MRP2 function.

Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping.

ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.

[Calcium-regulated photoproteins of marine coelenterates].

Ca(2+)-regulated photoproteins are bioluminescent proteins responsible for bioluminescence of marine coelenterates. The photoprotein molecule is a stable enzyme-substrate complex consisting of a single polypeptide chain and an oxygen "pre-activated" substrate, 2-hydroperoxycoelenterazine, which is tightly but non-covalently bound with a protein. The bioluminescence is triggered by calcium ions and originates from an oxidative decarboxylation of a protein bound substrate. The review provides current data on the photoproteins structure, the mechanism of bioluminescent reaction, the function of some amino acid residues of an active site in the catalysis and the formation of the emitter, as well as on applications of these proteins in a bioluminescent analysis.

[An experimental study of the effect of immunomodulators on the immune response to the anatoxin components of adsorbed DPT vaccine against a background of poisoning]. / Izuchenie v éksperimente vliianiia immunomoduliatorov na immunnyi otvet k anaktosinnym komponentam AKDS na fone intoksikatsii.

An experiment of rabbits subjected to artificial lead intoxication revealed that after the immunization of the animals with adsorbed DPT vaccine myelopid and thymoptin exhibited practically the same immunomodulating activity with respect to antibody response to diphtheria and tetanus toxoids, exceeding that of rabbits without intoxication. Still the immunomodulators used in this experiment did not completely compensate the negative effect of intoxication on antibody response to the toxoids. For the first time after immunization with adsorbed DPT toxoid lymphocytes capable of binding diphtheria toxoid were detected and the specific features of their dynamics in comparison with the activity of antitoxin were established. Myelopid and thymoptin were found to modulate immune response, evaluated by the content of antigen-binding lymphocytes, the injection of thymoptin completely compensating the negative effect of intoxication.

Obelin mRNA--a new tool for studies of translation in cell-free systems.

Obelin mRNA obtained in vitro with the aid of SP6 RNA polymerase was translated in a wheat germ cell-free system. Only the polypeptide with a molecular mass of about 20 kDa was synthesized. The activation of apoobelin with a synthetic coelenterazine revealed a luminescence activity initiated by calcium. The specific activity was 3.6 +/- 0.4 x 10(15)photons per mg of the in vitro synthesized obelin (k=6.9s(-1)). The luminescence of the obelin was in a good correlation with the protein concentration calculated by the incorporation of [14C]Leu. The determination of the amount of de novo synthesized obelin based on measurement of its luminescence is one-thousand times more sensitive than the approach based on the incorporation of labeled amino acid. Thus, obelin mRNA has some advantages for evaluating the efficiency of cell-free translation when compared with standard methods.

Insertion of short hepatitis virus A amino acid sequences into poliovirus antigenic determinants results in viable progeny.

In an infectious poliovirus cDNA construct, the determinant encoding antigenic epitope N-Ag1 (in a loop located between two beta-strands in poly-peptide VP1) was altered by site-directed mutagenesis, to be partially similar with the determinants for presumptive epitopes in polypeptides VP1 or VP3 of hepatitis A virus (HAV). The modified constructs proved to be infectious. However, another construct, in which the same locus encoded a 'nonsense' and a relatively hydrophobic amino acid sequence, exhibited no infectivity. These data showed the feasibility of the insertion of foreign sequences in a specific antigenically active locus of the poliovirus icosahedron, and suggest some limitations with respect to the sequences to be 'transplanted'.

[Reduction of the functional activity of the calcium pump of the sarcoplasmic reticulum of skeletal muscles in response to cold]. / Snizhenie funktsional'noi aktivnosti kal'tsievogo nasosa sarkoplazmaticheskogo retikuluma skeletnykh myshts pod vliianiem kholoda.

Fragments of sarcoplasmic reticulum (SR) from the white skeletal muscles of rat in cooling (1.5 day; -9 to +2 degrees C) revealed a decreased activity of the Ca2+-pump and rate of Ca2+ accumulation. The SR from rats adapted to cold for 2 and 4 weeks, revealed the same decreased functional ability. The Ca/ATP ratio was unchanged in all experiments.

Effect of cloxazepine on mitochondria.

Cloxazepine is a neuroleptic drug synthesized at the Research Chemical Pharmaceutical Institute, Sofia. Chemically it represents 2-chloro-11 (4-methyl-1-piperazinyl)-dibenz (1,4)-oxazepine succinate. The effect of cloxazepine on respiration and phosphorylation of isolated brain mitochondria as well as on the swelling of rat liver mitochondria was examined. It has been demonstrated that the drug is a very poor inhibitor of the respiratory chain, acting mainly on its substrate end. At concentration of 0.5 mM it causes a 50 per cent inhibition of the soluble mitochondrial ATPase. It has a marked membrane action: it uncouples oxidative phosphorylation and causes swelling of the mitochondria. The results show that pharmacological action of cloxazepine is not connected with influence on the energy metabolism but with membrane action of the drug.

[Effect of stenopril on the oxidative phosphorylation processes in rat mitochondria]. / Vliianie na stenopril vurkhu protsesite na okislitelno fosforilirane na mitokhondrii ot plukh.

The author examined the influence of the preparation stenopryl on the processes of oxidative prosphorilation in the liver and cerebral mitochondria of a rat in view of clarifying some aspects of its pharmacobiochemical mechanism. The results from the experiments in vitro revealed that stenopryl inhibited the processes of oxidative phosphorilation in comparatively high concentrations. The lower concentrations of the preparation did not induce changes. Stenopryl used in vitro, raised ATP-ase activity in liver mitochondria. The data on the experiments in vivo with a dose of 20 mg/kg of stenopryl showed that the preparation did not affect the oxidative processes, when two substrates of oxidation were used, but inhibited phosphorilation when sodium succinate was used. ATP-ase activity during treatment in vivo was not altered.

[Effect of methaqualone on the respiration, phosphorylation and ATPase activity of rat brain mitochondria]. / Vliianie na metakvalona vurkhu dishaneto, fosforiliraneto i ATF-aznata aktivnost na mozuchni mitokhondrii ot plukh.

The authors examined the influence of the preparation metaqualone on some aspects of adrenergic metabolism-respiration, phosphorilation and ATP-ase activity of brain mitochondria of a rat in order to discover pharmacobiochemical mechanism of action. The experimental data showed that administration of metaqualon in a dose of 70 mg per kg of body weight intraperitonealy, induced a lowering of phosphorilating activity in a substrate succinate. This fact gave a foundation to suppose that in shorted respiratory chain the effect of metaqualone on the aerobic resynthesis of ATP was at a level succinat-dehydrogenase complexes. Metaqulaon induced changes in the energetic metabolism, influencing mainly of the mechanisms of the synthesis of ATP without substantial effect on the electrone transport.