[Morphological precursors of high-grade serous ovarian cancer]. / Morfologicheskie predshestvenniki seroznogo raka yaichnikov vysokoi stepeni zlokachestvennosti.

At the beginning of this century, there was a paradigm shift in understanding the histogenesis of high-grade serous carcinomas. The theory of the origin of these tumors from the ovarian surface epithelium was replaced by the concept of their origin from the secretory epithelium of the fallopian tubes. In recent years, researchers have put forward the hypothesis of the "escape" of the precursor of high-grade serous carcinomas. It allows looking at the carcinogenesis of these neoplasms as a natural history of tumor transformation of the serous epithelium without reference to a specific localization.

[Comparison of the efficiency of surgical excision methods for detecting extraprostatic extension and positive resection margin in prostate cancer]. / Sravnenie effektivnosti metodov vyrezki operatsionnogo materiala dlya vyyavleniya ekstraprostaticheskogo rasprostraneniya i polozhitel'nogo kraya rezektsii pri rake prostaty.

On the samples of 26 prostatectomies, the method of excision of the prostate gland according to Kim was tested. This method increased the number of blocks by 30.2% and increased the detectability of extraprostatic extension by 41.7% and positive surgical margin by 40.0% compared to the method of alternate prostate sections. Also, the method according to Kim reduced the number of blocks of prostate tissue by 34.3% compared to the method of complete prostate excision.

[Molecular genetic profile of seromucinous ovarian tumors]. / Molekulyarno-geneticheskii profil' seromutsinoznykh opukholei yaichnikov.

Seromucinous tumors belong to a group of ovarian epithelial tumors. They were originally described as tumors characterized by Müllerian endocervical differentiation. Molecular genetic studies have indicated these tumors as endometriosis-associated tumors due to the presence of ARID1 gene mutations. However, the histogenesis of these neoplasms is still unstudied.

[Hemoperitoneum as a predictor of the traumatic process complications in the injured persons with severe combined trauma].

Multifactorial analysis was conducted in 48 injured persons, who had suffered combined abdominal organs trauma, trauma severity score according to the AIS-90 scale more than 25 points, and died. There were elaborated theoretical aspects of prognostication of the injured person's death timing. There was established, that while hemoperitoneum volume enhancement by 200 ml (critical level of hemoperitoneum is considered 682 ml) the death timing becomes accelerated by 1.2 h.

Identification of phosphorylation sites in aminoglycoside phosphotransferase VIII from Streptomyces rimosus.

We demonstrate for the first time the role of phosphorylation in the regulation of activities of enzymes responsible for inactivation of aminoglycoside antibiotics. The aminoglycoside phosphotransferase VIII (APHVIII) from the actinobacterial strain Streptomyces rimosus ATCC 10970 is an enzyme regulated by protein kinases. Two serine residues in APHVIII are shown to be phosphorylated by protein kinases from extracts of the kanamycin-resistant strain S. rimosus 683 (a derivative of strain ATCC 10970). Using site-directed mutagenesis and molecular modeling, we have identified the Ser146 residue in the activation loop of the enzyme as the key site for Ca2+-dependent phosphorylation of APHVIII. Comparison of the kanamycin kinase activities of the unphosphorylated and phosphorylated forms of the initial and mutant APHVIII shows that the Ser146 modification leads to a 6-7-fold increase in the kanamycin kinase activity of APHVIII. Thus, Ser146 in the activation loop of APHVIII is crucial for the enzyme activity. The resistance of bacterial cells to kanamycin increases proportionally. From the practical viewpoint, our results increase prospects for creation of highly effective test systems for selecting inhibitors of human and bacterial serine/threonine protein kinases based on APHVIII constructs and corresponding human and bacterial serine/threonine protein kinases.

[Improved procedure of the search for poly(ADP-ribose) polymerase-1 potential inhibitors with use of molecular docking approach].

A search for poly(ADP-ribose) polymerase-1 inhibitors by virtual screening of a chemical compound database and a subsequent experimental verification of their activities have been done. It was shown that the most efficient method to predict inhibitory properties implies a combinatorial approach joining molecular docking capabilities with structural filtration. Among more than 300000 database chemicals 9 PARP1 inhibitors were revealed; the most active ones, namely: STK031481, STK056130, and STK265022,--displayed biological effect at a micro-molar concentration (IC50 = 2.0 microM, 1.0 microM and 2.6 microM, respectively).

Inhibition of SYK and cSrc kinases can protect bone and cartilage in preclinical models of osteoarthritis and rheumatoid arthritis.

The pathophysiology of osteoarthritis (OA) includes the destruction of subchondral bone tissue and inflammation of the synovium. Thus, an effective disease-modifying treatment should act on both of these pathogenetic components. It is known that cSrc kinase is involved in bone and cartilage remodeling, and SYK kinase is associated with the inflammatory component. Thus the aim of this study was to characterize the mechanism of action and efficacy of a small molecule multikinase inhibitor MT-SYK-03 targeting SYK and cSrc kinases among others in different in vitro and in vivo arthritis models. The selectivity of MT-SYK-03 kinase inhibition was assayed on a panel of 341 kinases. The compound was evaluated in a set of in vitro models of OA and in vivo OA and RA models: surgically-induced arthritis (SIA), monosodium iodoacetate-induced arthritis (MIA), collagen-induced arthritis (CIA), adjuvant-induced arthritis (AIA). MT-SYK-03 inhibited cSrc and SYK with IC50 of 14.2 and 23 nM respectively. Only five kinases were inhibited > 90% at 500 nM of MT-SYK-03. In in vitro OA models MT-SYK-03 reduced hypertrophic changes of chondrocytes, bone resorption, and inhibited SYK-mediated inflammatory signaling. MT-SYK-03 showed preferential distribution to joint and bone tissue (in rats) and revealed disease-modifying activity in vivo by halving the depth of cartilage erosion in rat SIA model, and increasing the pain threshold in rat MIA model. Chondroprotective and antiresorptive effects were shown in a monotherapy regime and in combination with methotrexate (MTX) in murine and rat CIA models; an immune-mediated inflammation in rat AIA model was decreased. The obtained preclinical data support inhibition of cSrc and SYK as a viable strategy for disease-modifying treatment of OA. A Phase 2 clinical study of MT-SYK-03 is to be started.

[Complex environmental and virological monitoring in the Primorye Territory in 2003-2006].

The paper presents the results of monitoring of viruses of Western Nile (WN), Japanese encephalitis (JE), tick-borne encephalitis (TBE), Geta, Influenza A, as well as avian paramicroviruses type I (virus of Newcastle disease (ND)) and type 6 (APMV-6) in the Primorye Territory in 2003-2006. Totally throughout the period, specific antibodies to the viruses were detected by neutralization test in wild birds (7.3%, WN; 8.0%, Geta; 0.7% Batai; 2.8%, Alpine hare (Lepus timidus); by hemagglutination-inhibition test in cattle (11.4% WN; 5.9%, JE; j 3.0%, TBE; 11.6%, Geta), horses (6.1, 6.8, 0, and 25.3%, respectively), and pigs (5.4, 1.5, 0, and 5.9%, respectively) by enzyme immunoassay (IgG) in human beings (0.8, 0.5, 6.8, and 3.2%, respectively. Reverse-transcription polymerase chain reaction (RT-PCR) was used to reveal RNA of the NP segment of influenza A virus in 57.9 and 65% of the cloacal swabs from wild and domestic birds, respectively; and the HA-segment of subtype HH was not detected in 2005. HA/H5 RNA was recorded in 5.5 and 6.7% of the swabs from wild and domestic birds, respectively; 6% of the specimens from domestic birds were M-segment positive in 2006. RNA of influenza A virus NA/H7 and RNA was not detected throughout the years. In 2004, the cloacal swabs 8 isolated influenza A strains: two H3N8 and two H4N8 strains from European teals (Anas crecca), two (H3N8 and H6N2) strains from Baikal teals (A. formosa), one (H10N4) strain from shovelers (A. clypeata), and one (H4N8) from garganeys (A. querquedula). In 2004, one ND virus strain was isolated from the cloacal swabs from European teals (A. crecca). RT-PCR revealed RNA of this virus in some 8 more cloacal swabs from black ducks (A. poecilorhyncha) (3 positive specimens), pheasants (Phasianus colchicus) (n = 2), garganeys (A. querquedula) (n = 1), gadwalls (A. strepera) (n = 1), and geese (Anser anser domesticus) (n = 1). Sequencing of the 374-member fragment of the ND virus F gene, which included a proteolytic cleavage site, could assign two samples to the weakly pathogenetic variants of genotype 1, one sample to highly pathogenic variants of genotype 3a, five to highly pathogenic ones of genotype 5b. Isolation of APMV-6 (2003) from common egrets (Egretta alba) and geese (Ans. anser domesticus) is first described.

PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation.

Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.

[Use of tindurine for treating toxoplasmic myocarditis in adults]. / Primenenie tindurina dlia lecheniia toksoplazmoznogo miokardita u vzroslykh bol'nykh.

To treat 50 patients with toxoplasmosis myocarditis the authors used tindurine (pyrimethamine). The drug was given in doses of 50 mg, twice, daily, for 5 days. The course of treatment consisted of 3-5 such cycles, with intervals of 7-10 days. The drug tolerance, side effects and efficacy of the first course of treatment were studied.

[Antibodies to polysaccharides of group A Streptococcus in the sera of patients with myocarditis]. / Antitela k polisakharidu streptokokka gruppy A v syvorotkakh bol'nykh miokarditami.

Antibodies to polysaccharide of streptococcus of group A (A-polysaccharide) were studied in the sera of 95 patients with myocarditis and 105 patients of the control group (congenital heart disease, angina pectoris of effort). In myocarditis patients were found in 51 (52.7%) out of 95 cases (group I); antibodies to A-polysaccharide were absent in 44 (46.3%) of cases (group II). In the control group antibodies were found in 32 (30.4%) out of 105 patients. The number of sera with high level of antibodies to A-polysaccharide is greater in the group of patients with myocarditis, than in the control group (50,98 and 37.5%, respectively). Determination of antibodies to A-polysaccharide can be used as one of the methods for aetiological diagnosis of myocarditis.

[Determination of antibodies to Streptococcus group A polysaccharide by an immunodiffusion method in human sera in various pathological processes of streptococcal etiology]. / Opredelenie antitel k polisakharidu streptokokka gruppy A metodom immunodiffuzii v syvorotkakh cheloveka pri razlichnykh patologicheskikh protsessakh streptokokkovoi étiologii.

A method for the assay of antibodies to the specific antigenic determinant of group A streptococcal polysaccharide (A-polysaccharide) in human sera was developed. The sera were tested in the precipitation test in agar gel with different doses of A-polysaccharide. The presence of a high level of the above-mentioned antibodies is indicative of infection caused by group A streptococcus, but not streptococci of other groups or by the L-forms of streptococci. In 87.5% of patients with primary rheumatism a high level of antibodies to the specific antigenic determinant of A-polysaccharide was detected during the first day of the disease, which confirms most convincingly the etiological role of group A streptococcus in rheumatism. Considerable differences in the level of antibodies to A-polysaccharide in the active and non-active phases of rheumatism have been established, which makes it possible to use the presence of a high level of these antibodies as an indicator of the rheumatic process activity. A considerable percentage of sera with a high level of antibodies to A-polysaccharide was also detected in erysipelas and acute glomerulonephritis patients.

[Toxoplasmosis-induced myocarditis]. / Toksoplazmoznye miokardity.

The clinical picture of myocarditis was studied in 72 patients with toxoplasmic infection and in 44 patients not suffering from this infection. Comparison of the clinical signs of myocarditis in these two groups showed that myocarditis of toxoplasmic etiology has no characteristic features. The only distinction between these two groups was the different frequency of various symptoms. In view of this, methods of laboratory diagnosis of toxoplasmosis acquire much significance.

[Adaptive reserves of the myocardium in patients with ischemic heart disease]. / Adaptatsionnye rezervy miokarda u bol'nykh ishemicheskoi bolezn'iu serdtsa.

Myocardial adaptive reserves and their relation to the function of the adrenocorticohypophyseal system were examined in 69 patients with coronary heart disease. To define the adaptation of the myocardium during exercise, the index of myocardial adaptation was used. The function of the adrenocorticohypophyseal system was judged from blood levels of somatotropic hormone and cortisol before, at the peak, and 2 hours after exercise testing. A substantial decrease in myocardial adaptive capacity was found in CHD patients as compared with healthy subjects. These abnormalities proved to be more marked in patients with clinical signs of severe coronary failure than in those with moderate coronary circulatory failure. It was concluded that the function of the adrenocorticohypophyseal system was one of the factors determining myocardial adaptation during exercise in patients with coronary heart disease.

[Antibodies to non-type-specific group A streptococcal cell wall antigens in human sera]. / Antitela k netipospetsificheskim belkovym antigenam kletochnoi stenki streptokokka gruppa A v syvorotkakh cheloveka.

The use of gel immunodiffusion for the determination of antibodies to nontype-specific cell-wall protein antigens of group A streptococcus allowed to eliminate reactions caused by antibodies to type-specific antigens, group polysaccharide and teichoic acid. Antibodies to nontype-specific antigens, and particularly to two such antigens, occurred more frequently in the blood sera of patients with rheumatism in the active phase than in patients with rheumatism in the inactive phase, erysipelas and with non-rheumatic cardiac diseases, and in donors. Antibodies to nontype-specific antigens occurred in the blood sera of patients with rheumatism in the inactive phase and with non-rheumatic cardiac diseases as frequently as in donors. The occurrence of these antibodies in the blood sera of erysipelas patients was significantly more frequent than in donors; but antibodies to two nontype-specific antigens occurred in erysipelas patients, in contrast to patients with rheumatism in the active phase, not more frequently than in donors. Patients with rheumatism and erysipelas seem to differ in their immune response to certain nontype-specific streptococcal antigens.