Inactivation of Epigenetic Regulators due to Mutations in Solid Tumors.

Main factors involved in carcinogenesis are associated with somatic mutations in oncogenes and tumor suppressor genes representing changes in the DNA nucleotide sequence. Epigenetic changes, such as aberrant DNA methylation, modifications of histone proteins, and chromatin remodeling, are equally important in the development of human neoplasms. From this perspective, mutations in the genes encoding key participants of epigenetic regulation are of particular interest including enzymes that methylate/demethylate DNA, enzymes that covalently attach or remove regulatory signals from histones, components of nucleosome remodeling multiprotein complexes, auxiliary proteins and cofactors of the above-mentioned molecules. This review describes both germline and somatic mutations in the key epigenetic regulators with emphasis on the latter ones in the solid human tumors, as well as considers functional consequences of these mutations on the cellular level. In addition, clinical associations of the somatic mutations in epigenetic regulators are presented, as well as DNA diagnostics of hereditary cancer syndromes due to germline mutations in the SMARC proteins and chemotherapy drugs directly affecting the altered epigenetic mechanisms for treatment of patients with solid neoplasms. The review is intended for a wide range of molecular biologists, geneticists, oncologists, and associated specialists.

[Allelic imbalance of loci 17p13.1 (TP53), 1p36.1 (RUNX3), 16p22 (CDH1) and microsatellite instability in gastric cancer].

We examined allelic imbalance (AI) on loci 17p13.1 (TP53), 1p36.1 (RUNX) and 16p22 (CDHI) and microsatellite instability (MI) with BAT26 in 78 patients with gastric cancer. We have shown a significant difference in the frequency of allelic imbalance of the studied loci among different types of gastric cancer. Frequency of AI in 16p22.1 (CDH1) (p = 0.023), 17p13.1 (TP53) (p = 0.038), microsatellite instability (p = 0.047) and AD two and more loci in a single sample (p = 0.0176) was significantly higher in the intestinal type of gastric cancer than in the diffuse type. We have shown, that, frequency of AI in 16p22.1 (CDH1), and AD two and more loci in a single sample, was higher in thetumors with high or moderate type of tumor cells differentiation (p = 0.0414, p = 0.0057 respectively). We found no significant differences in the groups with metastases in regional lymph nodes, different tumor stage, localization of tumors and the generalization process.

[The systems of molecular genetic markers under cancer of stomach].

The study was organized to investigate the anomalous methylation of genes NA?1, RASSF1A, MLH1, N33, DAPK, the expression of genes hTERT. metalloproteinase MMP7, MMP9, survivin. COX-2, p53. The activity of telomerase in 106 samples of stomach tumors taken through intra-operation way and 53 samples of stomach tumors taken through endoscopic way and 50 samples of biopsy taken from patients with chronic calculous cholecystitis (comparison group) was analyzed too. These changes can be used as additional markers both in diagnostic of cancer of stomach and dynamic monitoring of operated patients.

[Detection of telomerase activity in gastric cancer].

Telomerase activity (TA) was examined in gastric adenocarcinomas and gastric lymphoma using a modified TRAP assay. TA was present in 16 of 18 (89%) gastric adenocarcinomas and in gastric lymphoma, whereas no TA was detected in normal tissue. Almost all samples had "high" and "very high" TA levels. Telomerase is undoubtedly associated with the process of malignant transformation and therefore can be an important marker for diagnostics of gastric cancer.

[Puncture hystobiopsy with tissue telomerase activity measurement in preoperative thyroid nodes diagnostics].

Demonstrated, that puncture thyroid hystobiopsy is safe and informative method of preoperative thyroid nodes diagnostics. Telomerase activity in tissue samples was significantly higher in case of malignant thyroid disease, although a positive correlation of telomerase activity was also with the amount of lymphocytes in bioptates. Combination of thyroid hystobiopsy with tissue telomerase activity measurement proved to be an effective means of preoperative diagnostic of patients with nodular goiter.

[Methodology of harmonizing hygienic standards for water substances, and its application to improving sanitary water legislation].

The article deals with methodology of harmonizing hygienic standards in order to correct and improve Russian sanitary water legislation. This methodology allows drawing on the world experience in the field of water hygiene, which is profitable in terms of cost-effectiveness and can contribute greatly to the national legislation.

[Classification of hazards of water pollutants].

The paper considers materials on the substantiation of criteria, indices, and their gradation for a new variant of the hygienic classification of hazards of water-contaminating substances. Emphasis is placed on the significance of a ratio of the maximally inactive concentrations (MIC) in terms of the toxicological sign of harmfulness to the threshold concentrations (TC) in terms of their effects on the organoleptic properties of water and on the general sanitary regime of water reservoirs. Only two types of late effects of substances, which are of individual significance for classification, such as carcinogenicity and reproductive effects, are identified. It is stated that a class of hazard may be toughened for high-stable substances, but neither the stability nor any other indices of the potential hazard of substances is the ground for reducing their hygienic standards in water.

[An evaluation of the efficacy of rehabilitating elderly patients with ischemic heart disease at the sanatorium stage bu using a 2-component method of studying myocardial contractile capacity]. / Otsenka éffektivnosti reabilitatsii bol'nykh ishemicheskoi bolezn'iu serdtsa pozhilogo vozrasta na sanatornom étape pri pomoshchi dvukhkomponentnogo metoda issledovaniia sokratitel'noi sposobnosti miokarda.

A proposed technique determining myocardial contractility is noninvasive and two-component. It involves measurement of the ratio left ventricular contraction force/rate, calculated from tetrapolar rheography findings. The technique provides more complete data on efficacy of the coronary patients' aftertreatment at health resorts. The overloading with the latter factors may appear unfavorable for the elderly patients due to aggravating myocardial contractility and cardiac arterial consistency derangement.

[Blood endorphin levels in myocardial infarction]. / Endorfiny krovi pri infarkte miokarda.

Blood gamma-endorphin concentrations were repeatedly measured, using an original radioimmunoassay, in patients with myocardial infarction. In the early days of acute myocardial infarction, high levels of this opioid peptide were observed, then plasma gamma-endorphin concentration gradually decreased by the time of discharge. In patients with grave complications, gamma-endorphin level was significantly lower, as compared to patients with uncomplicated infarction.

[Optimizing the exercise schedules of late middle-aged patients with chronic forms of ischemic heart disease]. / Optimizatsiia dvigatel'nogo rezhima bol'nykh pozhilogo vozrasta s khronicheskimi formami ishemicheskoi bolezni serdtsa.

The effects of different types of exercise on the results of bicycle ergometry were assessed in 83 coronary patients, aged 60 to 74 years, in the absence of heart failure, arterial hypertension, or medication, in conditions of a cardiovascular sanatorium. The patients were divided in 3 groups according to their training pulse rates, defined as follows: Training PR = resting PR + n X (threshold PR-resting PR), where n was equivalent to 0.5, 0.75, or 0.9, respectively. The best results were obtained in group 2 where n was 0.75, with a significant decrease in resting pulse rate and systolic arterial BP at the peak of exercise, the greatest increase in stress tolerance and total output at comparable physical stress levels. It is therefore concluded that exercise at such physical stress level was optimal for those patients.

[Use of phonotacho-oscillography in the diagnosis of neurocirculatory dystonia and hypertension]. / Primenenie fonotakhoostsillografii v diagnostike neirotsirkuliatornoi distonii i gipertonicheskoi bolezni.

A total of 95 persons were screened for the most informative phonotacho-oscillographic (PTOG) signs to differentiate between neurocirculatory dystonia and essential hypertension. They included 45 patients with stages I and II of essential hypertension, 22 patients with neurocirculatory dystonia and 28 healthy subjects (the control group). A new index alpha is offered, which represents the ratio of the products AM . Ti/Ai . Tm, where Ai is the amplitude of the initial portion, Am - the amplitude of the middle portion, Ti - the duration of the initial and Tm - the duration of the middle portion of the PTOG complex at the level of the maximum arterial pressure. The index alpha in healthy persons was 0.58 +/- 0.04; in the patients with neurocirculatory dystonia 1.02 +/- 0.06, and in the patients with essential hypertension 4.25 +/- 0.26. This index is offered for differential diagnosis between neurocirculatory dystonia and essential hypertension, especially during the functional test with nitroglycerin.

[Presystolic change in the length of the ischemic, border and distant myocardial areas in experimental coronary insufficiency and the action of inderal and metacin]. / Presistolocheskoe izmenenie dliny ishemicheskikh, pogranichnykh i otdalennykh uchastkov miokarda pri éksperimental'noi koronarnoi nedostatochnosti i deistvii inderala i metatsina.

Changes in the presystolic length in the phase of late diastole and in the size of active shortening in the phase of ejection were determined in the ischemic area and in areas of the myocardium bordering upon and in those remote from the focus of ischemia in acute experiments on the 20th and 60th seconds of reversible clamping of the coronary artery. Marked increase in the presystolic length and size of active shortening of the remote areas was noted by the 20th second. In the ischemic zone these values decreased. Due to the effect of a therapeutic dose of inderal, the intensifying reaction of the remote areas diminished markedly and the unfavourable effect of ischemia on the stretching and shortening functions of the ischemic zone became somewhat weaker. Metacin caused no such effect.

[Electrocardiologic diagnosis and the prognostic significance of blocks occurring in ischemic heart disease]. / Elektrokardiologicheskaia diagnostika i prognosticheskoe znachenie blokad, voznikshikh pri ishemicheskoi bolezni serdtsa.

A total of 280 patients with postinfarction and atherosclerotic cardiosclerosis and the bundle of His block were examined. The examination included recording of the ECG in 12 leads, the vectorcardiogram in the orthogonal system and after Frank and by the cube method, the cinecardiogram, polycardiogram, and radiocardiogram. It was established that bifascicular blocks of the left branch of the bundle of His are most unfavourable as regards the prognosis. The other types of blocks have no such effect and may rather be diagnostic signs indicating the localization and the extent of development of the necrotic or sclerotic process.

[Differentiated treatment and prevention of arrhythmias in myocardial infarct]. / Differentsirovannaia terapiia i profilaktika aritmii pri infarkte miokarda.

Monitoring and electrocardiographic observations were conducted in 900 patients during the acute and subacute periods of myocardial infarction. It was found that without preventive therapy arrhythmias develop in 85% of the patients, and with preventive antiarrhythmic treatment--in 75.5%. A combination of two and more types of arrhythmias was encountered in 42% of the cases. In the presence of routine therapy for myocardial infarction individual antiarrhythmic drugs displayed different efficacy. In supraventricular forms of arrhythmias the most effective drugs are Chinidin and Chinidin-Durules, Inderal and Hiluritmal, in ventricular forms--Lidokaine, Chinidin, Novocainamide, Inderal, Hiluritmal. A combined employment of these drugs against the background of potassium and magnesium salts administration, Inosie-F, water-soluble camphor and Cocarboxylase promoted the restoration of a normal sinus rhythm in 85% of the cases. When the drug therapy produced no antiarrhythmic effect and ventricular fibrillation developed, electroimpulse therapy was employed. In persistent atrioventricular blocks only cardiostimulation was effective.