Association between the Prevalence of Somatic Mutations in PIK3CA Gene in Tumors and Clinical and Morphological Characteristics of Breast Cancer Patients.

The presence of activating somatic mutations in codons 542 and 545 of exon 9 (p.E542K c.1624G>A and p.E545K c.1633G>A) and in codon 1047 of exon 20 (p.H1047R c.3140A>G and p.H1047L c.3140A>T) of PIK3CA gene encoding catalytic p110α-subunit of phosphatidylinositol-3-kinase was studied in tumors of 473 breast cancer patients by multiplex allele-specific real-time PCR. Fifty-eight (12.3%) different mutations were found. An increase in the frequency of PIK3CA gene mutations with disease progression (from 2.4 to 28.7% with tumor progression from I-IIa to III-IV stage; p=0.0001) and a trend towards its increase in the tumors with unfavorable prognostic characteristics (high histological grade, triple negative phenotype) were demonstrated. The presence of the studied PIK3CA gene mutations in tumors significantly reduces relapse-free survival in the total group and in stage III cancer patients.

Regulatory Proteins of Epithelial-Mesenchymal Transition and Some Components of VEGF Signaling Pathway in Breast Cancer.

Immunohistochemical method was used to assay for Snail family regulatory proteins of epithelial-mesenchymal transition, their NF-κB coactivator, and the components of VEGF signaling pathway (VEGF and its receptors VEGFR1 and VEGFR2) in 157 specimens of breast tumors. Most tumors did not express SNAI1, while 65% tumors demonstrated mid- or high-level SNAI2 expression. There were significant correlations between the expression of SNAI1, SNAI2, and their NF-κB co-activator. Correlation was also detected between expression of Snail and VEGFR1 protein families in the tumors. In addition, the study revealed tumoral co-expression of SNAI2 and VEGFR2. The data attest to coordinated activation of regulatory proteins of epithelial-mesenchymal transition and the major components of VEGF signaling pathway in breast tumors.

Molecular markers of tumors.

The main biologically significant molecular markers of human tumors are discussed on the basis of modern published data and author's findings of many-year studies: steroid hormone receptors, growth factors and underlying signal proteins, tumor-associated proteases, and angiogenesis markers. Methodological aspects, progress in preclinical studies, international recommendations on the use of these parameters for prediction of the disease course and prescription of effective therapy are analyzed. Latest data on the potentialities and limitations of modern highly productive technologies (microchips) as an alternative to studies of individual molecular markers are presented.

Vascular endothelial growth factor in the serum of breast cancer patients.

Here we present the results of comparative immunoenzyme assay of the initial serum levels of VEGF in breast cancer patients (stages T1N0M0 and T2N0M0) and apparently healthy women (controls). It was found that VEGF concentrations in the serum of patients with breast cancer stages T1N0M0 and T2N0M0 significantly surpassed the control levels. Increased levels of VEGF surpassing the threshold values were more often observed in patients with T2N0M0 breast cancer compared to patients with T1N0M0 tumor. At the same time, this marker cannot be used in the diagnostics of this disease because in only 21.4% patients serum level of VEGF surpassed the upper boundary for this growth factor observed in the serum of control women. Serum concentration of VEGF in patients with stages T1N0M0 and T2N0M0 breast cancer did not depend on patient's age and reproductive function and receptor status of the primary tumor (estrogen and progesterone receptors), but was closely associated with tumor histogenesis and differentiation degree. Significantly higher levels of VEGF were observed in patients with lobular infiltrative breast carcinoma compared to patients with ductal tumors and in patients with low-differentiated tumors compared to highly and moderately differentiated tumors. High initial concentrations of VEGF (>300 pg/ml) were more often detected in patients with T2N0M0 breast cancer developing relapses within the first 3 years of follow-up compared to patients without relapses during the corresponding period (p=0.001). These findings suggest that serum level of VEGF in patients with T2N0M0 breast cancer before treatment can be used as an additional marker in parallel with standard clinical and morphological signs of the disease for more precise prognosis of early relapse (during the first 3 years of follow-up).

Cancer and soluble FAS.

A test system developed by the authors was used to measure serum concentrations of soluble Fas in patients with malignant and benign tumors of different location and morphology. Relationships between soluble Fas levels and the main clinical and morphological characteristics of cancer were evaluated. It is proven that the concentrations and incidence of detection of soluble Fas in the sera of patients with tumors are significantly higher than in normal subjects. No appreciable differences in the concentrations of soluble Fas were detected in malignant and benign tumors of the mammary gland, bones, ovaries, and adrenals. In thyroid cancer, soluble Fas levels were higher than in benign and hyperplastic processes in this organ. High level of soluble Fas is associated with late stages of the disease (ovarian cancer, cancer of the corpus uteri, adrenocortical and colorectal cancer) and with poor differentiation of the tumor (ovarian cancer and cancer of the corpus uteri), with local metastases (colorectal and adrenocortical cancer), and with tumor invasion into the myometrial tissue, intestinal wall, and adjacent tissues (cancer of the corpus uteri and colorectal cancer). A significantly high level of soluble Fas was detected in colorectal and adrenocortical cancer in the presence of at least 2 local metastases. Soluble Fas levels depended on tumor histogenesis in malignant and benign ovarian tumors. High concentration of soluble Fas was detected in large tumors in patients with ovarian cancer, cancer of the corpus uteri, colorectal cancer, thyroid cancer and adenoma, and in adrenocortical cancer. Initially high levels of soluble Fas are characteristic of patients whose tumors are little sensitive to nonadjuvant radiotherapy. The overall 5-year survival of patients with low levels of soluble Fas is better in osteosarcoma, cancer of the corpus uteri, ovarian and adrenocortical cancer.

[The influence of the Soviet antimalarial preparation dabequin on the hemostatic system and on the anticoagulant effect of heparin]. / Issledovanie vliianiia otechestvennogo protivomaliariinoi preparaty dabekhina na sistemu gemostaza i antikoaguliantnyi éffekt geparina.

In experiments on rabbits and experiments in vitro dabechin was shown to decrease the blood coagulation status and to change the anticoagulant effect of heparin. The latter depends on the route and duration of administration of the antimalarial drug. Injections of heparin in the period of the maximal blood content of dabechin decrease the specific action of the anticoagulant. A prolonged oral administration of dabechin enhances the anticoagulant effect of heparin. During in vitro experiments the ability of dabechin to neutralize heparin with a simultaneous decrease of its specific action was shown.

[Orthostatic tolerance and the status of central and peripheral hemodynamics during 7-day "dry" immersion in persons with neurocirculatory asthenia of the hypertensive type]. / Issledovanie ortostaticheskoi ustoichivosti i sostoianiia tsentra'lnoi i perifericheskoi hemodinamiki v rezhime 7-sutochnoi "sukhoi" immersii u lits s neirotsirkuliatornoi distoniei.

Eleven healthy male volunteers, aged 45-55 years, with neurocirculatory dystonia of the hypertensive type were exposed to 7-day dry immersion. The following parameters were measured: central and peripheral hemodynamics (by the method of rheography), linear blood flow velocity, and orthostatic tolerance before and after immersion. During an acute period of adaptation to immersion the test subjects developed: centralization of blood filling of the head and lungs, decrease of stroke volume and cardiac output, increase of linear blood flow velocity in forearm arteries and its decrease in leg arteries, drastic decline of orthostatic tolerance.

[Comparative evaluation of the anticoagulant activity of the sodium and calcium salts of heparin, isolated from swine intestinal mucosa]. / Sravnitel'naia otsenka antikoaguliantnoi aktivnosti natrievoi i kal'tsievoi solei heparina, vydelennogo iz slizistoi obolochki kishechnika svinei.

During in vitro experiments it was shown that at intravenous administration to rabbits and dogs in a dose of 100 IU/kg the anticoagulant effect of mucosal heparin sodium was greater than that of heparin calcium. At subcutaneous administration to rabbits in a dose of 750 IU/kg calcium heparin exhibited a stable and even anticoagulant effect for 12 hours. Mucosal sodium heparin administered subcutaneously caused marked peaks of hypocoagulation and rebound effect. At subcutaneous injection sodium heparin action duration was 10 hours.

[Effect of delagil on the blood coagulation system and the interrelation with heparin]. / Vliianie delagila na sistemu svertyvaniia krovi i vzaimootnosheniia s geparinom.

Experiments on rabbits have demonstrated the ability of delagil to slightly increase the time of whole blood coagulation upon a single parenteral injection. On the contrary, prolonged administration of the drug per os and intramuscularly was accompanied by an insignificant enhancement of hemocoagulation. Delagil changed the effect of heparin administered after it. Heparin injection at the height of blood delagil content was accompanied by a decrease in specific activity of the anticoagulant. Prolonged administration of delagil potentiated the anticoagulation effect of heparin and prevented the development of the "return effect". In experiments made in vitro, delagil was found to be capable of inhibiting blood coagulation and forming complexes with heparin, which was accompanied by the loss of the anticoagulant activity of the latter. Interaction of the antimalarial agent with heparin in blood plasma and buffer medium is governed by exponential dependence.

[Influence of nonachlazin, riboxin and isoptin on the blood coagulation system and the anticoagulant effect of heparin]. / Vliianie nonakhlazina, riboksina i izoptina na sistemu svertyvaniia krovi i antikoaguliantnyi éffekt geparina.

Nonachlazin binds in vitro heparin in blood plasma and aqueous medium. This interaction complies with logarithmic dependence. Isoptin increases in vitro plasma susceptibility to heparin, reduces the period of whole blood coagulation and thrombin time. Riboxin does not produce in vitro any effect on the blood coagulation parameters and heparin susceptibility. Single and chronic adminstration of the drugs exerts no effect on blood coagulation. Prolonged use of riboxin promotes the increased level of endogenous heparin. Both single and chronic administration of the drugs potentiates the anticoagulant action of heparin.