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Purpose of the study - to assess the level of cognitive disorders in gerontological patients of the urological profile, depending on the use of sedation in the intraoperative period. A prospective cohort study was performed on 60 gerontological patients diagnosed with BPH II-III stages. Two groups were formed: conscious patients and patients using sedation. Operation - bipolar transurethral enucleation of the prostate (BTUEP). Determination of the depth of sedation with propofol was carried out according to the Ramsey sedation scale in the BIS-monitoring mode. Registration of cognitive status was carried out on the basis of the Montreal Cognitive Function Scale and the Hamilton Depression Scale. The level of cognitive functions of patients in both study groups before surgical treatment indicated the presence of mild impairments according to the Montreal Cognitive Function Scale and the Hamilton Depression Scale. In the group using sedation in patients, a statistically significant decrease (p<0,005) in the score for three items of the Hamilton depression scale was determined in comparison with the group with preserved consciousness in patients: average insomnia (χ2=5,07), working capacity and activity (χ2=4,17), mental anxiety (χ2=4,43). Anesthesia, including spinal anesthesia and sedation controlled by BIS-monitoring, in gerontological patients during BTUEP provides a positive effect on the cognitive functions of patients and reduces the manifestations of depressive symptoms according to the results of clinical interviews using the Montreal Cognitive Assessment Scale and the Hamilton Depression Scale.

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The aim of the study was to evaluate the effectiveness of the use of tranexamic acid in the prevention of intraoperative hemorrhagic complications in geriatric patients with bioply transurethral resection of the prostate (BTURP). The patients were divided into 2 groups by the envelope method. Patients of the first group (control group, n=42) did not receive tranexamic acid infusion. Patients of the second group (main group, n=42) received pre-intraoperative infusion of tranexamic acid at a dose of 2 mg/kg. All patients underwent BTURP on endoscopic equipment according to the standard technique under spinal anesthesia. The groups were compared according to the following criteria: the volume of intraoperative blood loss, the level of erythrocytes, platelets and hemoglobin, indicators of hemostasis, thromboelastography before and after surgery. It was established that the perioperative use of tranexamic acid allowed to significantly reduce the volume of blood loss in BTURP. The method of thromboelastography, due to quantitative and qualitative characteristics, is able to assess how the effectiveness of the use of a fibrinolysis inhibitor is achieved.

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The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.

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Phosphoinositide 3-kinase γ (PI3Kγ) consists of a catalytic subunit p110γ, which forms mutually exclusive dimers with one of the regulatory subunits called p101 and p84/p87(PIKAP). Recently, PI3Kγ emerged as being a potential oncogene because overexpression of the catalytic subunit p110γ or the regulatory subunit p101 leads to oncogenic cellular transformation and malignancy. However, the contribution of the individual subunits to tumor growth and metastasis and the mechanisms involved are not understood. We therefore individually knocked down the PI3Kγ subunits (p84, p101 and p110γ) in MDA-MB-231 cells, which reduced in vitro migration of the cell lines. Knockdown of p110γ or p101 inhibited apoptosis, Akt phosphorylation and lung colonization in SCID mice. Similarly, the knockdown of p110γ and p101 in murine epithelial carcinoma 4T1.2 cells inhibited primary tumor growth and spontaneous metastasis, as well as lung colonization. In contrast, knockdown of p84 in MDA-MB-231 cells enhanced Akt phosphorylation and lung colonization. These findings are the first to implicate differential functions of the two PI3Kγ regulatory subunits in the process of oncogenesis, and indicate that loss of p101 is sufficient to reduce in vivo tumor growth and metastasis to the same extent as that of p110γ.

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A system of differential equations describing, neglecting diffraction, the propagation of laser radiation in a medium with birefringence and cubic nonlinearity is derived. It is shown that the efficiency of depolarization compensation by means of a 90 degrees polarization rotator or a Faraday mirror decreases with increasing B-integral (nonlinear phase incursion). Comparison of the effectiveness of the considered method in the case of incident linear and circular polarization showed that for the circular polarization the optimal angle of polarization rotator is different from 90 degrees and the degree of polarization is less than for the linear one.

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The paper provides the results of studies of the impact of temperature on the structural and energetic state of drinking water and shows that the altered temperature conditions of water causes a change in its supramolecular structure and biological value.

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Chemokine receptors are essential mediators of the metastatic spread in various cancer types; however their precise function in the development of secondary tumors remains poorly understood. We report here a novel property of the chemokine receptors CXCR4 and CCR7 in inhibiting detachment-induced cell death--anoikis, which is believed to be one of the major blocks in the metastatic spread of various neoplasms. Activation of these chemokine receptors by their respective ligands, CXCL12 and CCL21 specifically reduced the sensitivity of metastatic breast cancer cells to anoikis by a distinct mechanism of selective regulation of pro-apoptotic Bmf and anti-apoptotic Bcl-xL proteins. Consequently, functional CXCR4 and CCR7 increased cell survival in the absence of correct ECM attachment both in vitro and in vivo. We also demonstrated that preventing chemokine-induced reduction in Bmf levels significantly attenuated breast cancer metastasis in an experimental mouse model. These results provide evidence for a previously unknown axis in malignant tumors, which connects chemokine receptors with deregulated apoptosis in the absence of the appropriate cell--ECM interaction and may offer novel targets for therapeutic intervention for the treatment of metastatic breast and potentially other tumors.

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Juvenile myelomonocytic leukemia (JMML) is a severe childhood malignancy. The autocrine production of GMCSF is believed to be responsible for the spontaneous proliferation of JMML cells. A nuclear factor-kappaB (NF-kappaB)/Rel binding site within the GM-CSF gene promoter, termed the kappaB element, plays an important role in controlling transcription from the GM-CSF gene. We investigated the effect of an oligonucleotide GM3, directed to form a DNA triple helix across this kappaB element, on growth and GM-CSF production by JMML cells. Treatment of these cells, either unstimulated or induced by TNFalpha, with GM3 led to a significant and specific inhibition of both GM-CSF production and spontaneous colony formation. This constitutes the first report linking specific triplex-mediated inhibition of gene transcription with a functional outcome; i.e., cell growth. We observed the constitutive presence of NF-kappaB/Rel proteins in the nucleus of JMML cells. The constitutive and TNFalpha-induced NF-kappaB/Rel complexes were identical and were composed mainly of p50 and c-Rel proteins. Treatment of the cells with a neutralizing anti-TNFalpha monoclonal antibody completely abrogated constitutive nuclear expression of NF-kappaB/Rel proteins. These results indicate that the aberrant, constitutive GM-CSF gene activation in JMML is maintained by TNFalpha-mediated activation of NF-kappaB/Rel proteins. Our findings identify the molecular basis for the autocrine TNFalpha activation of the GM-CSF gene in JMML and suggest potential novel and specific approaches for the treatment of this aggressive childhood leukemia.

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hemopoietic growth factor that is expressed in activated T cells, fibroblasts, macrophages, and endothelial cells. Although GM-CSF does not appear to be essential for normal hemopoiesis, overexpression of GM-CSF has been implicated in the pathogenesis of some diseases such as myeloid leukemia and chronic inflammation. An NF-kappaB/Rel binding site within the GM-CSF promoter, termed the kappaB element appears to be important for controlling expression in reporter gene assays in response to a number of stimuli in T cells. We investigated oligonucleotide-directed triple helix formation across this regulatory sequence as a potential tool to inhibit GM-CSF gene transcription. A 15-base oligonucleotide, GM3, was targeted to a purine-rich region in the GM-CSF proximal promoter, which overlaps the kappaB element. Gel mobility shift assays and DNase I footprinting demonstrated that GM3 formed a sequence-specific collinear triplex with its double-stranded DNA target. Triplex formation by GM3 blocked recombinant and nuclear NF-kappaB proteins binding to the GM-CSF element. GM3 also caused selective inhibition of the human T-cell lymphotrophic virus-1 Tax transactivator-induced luciferase activity from a reporter construct driven by the GM-CSF promoter in Jurkat T cells. Finally, GM3 greatly reduced the concentration of endogenous GM-CSF mRNA induced by different stimuli in Jurkat T cells but did not affect interleukin 3 mRNA levels in the same cells. We conclude that the kappaB element in the GM-CSF promoter plays a central role in the transcriptional activation of the endogenous GM-CSF gene. Colinear triplex formation acts as a selective transcriptional repressor of the GM-CSF gene and may have potential therapeutic application in cases of undesirable overexpression of this protein.

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The long-term effects of incubating freshly isolated, elicited guinea-pig peritoneal macrophages with the beta-adrenoceptor agonist isoprenaline and the selective inhibitor of phosphodiesterase (PDE) IV rolipram, on adenosine-3',5'-cyclic phosphate (cAMP)-specific PDE IV activity have been investigated. The level of cAMP PDE activity in macrophages was unaffected by long-term exposure of cells to rolipram alone. In contrast, in the presence of isoprenaline (10 microM), a concentration-related (0.05.50 microM) increase in cAMP PDE activity was observed in the cytosolic and particulate fractions. Incubation with isoprenaline alone did not affect macrophage cAMP PDE. cAMP PDE activities in homogenates of control cells and macrophages treated with isoprenaline (10 microM) and rolipram (5 microM) (3-fold activation) were inhibited by the selective PDE IV inhibitor, rolipram, with similar potencies (IC50: 2.3 microM). The increase in cAMP PDE activity in response to rolipram and isoprenaline was completely blocked by cyclohexamide (10 micrograms/ml). Incubating macrophages for 10 min with rolipram increased cAMP accumulation in the presence, but not in the absence, of isoprenaline (10 microM) over the same concentration range that induction of cAMP PDE activity was observed. cAMP levels remained elevated for at least 1 hr. Isoprenaline (10 microM) alone induced a transient elevation in cAMP levels that peaked at 2 min and had returned to basal levels by 10 min. Protein kinase A activity (PKA) was increased almost 10-fold (at 10 min) by exposing cells to rolipram plus isoprenaline and remained elevated for at least 4 hr. Isoprenaline alone induced a small (2-fold) increase in PKA activity and rolipram alone was without effect.

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A new type of acyclic nucleoside analogs is proposed, containing C5 hydroxyalkyl fragments, where the distance between 5'-hydroxyl group and the heterocyclic moiety corresponds to that in dideoxydidehydronucleosides (as confirmed by computer modelling). Condensation between 5-0-acetyl-1-bromo-2-pentene and persilylated heterocyclic bases (pyrimidines and guanine) or adenine sodium salt gives rise to the acyclic nucleosides (5a-d, 6a-d) with the yields ranging from 40% up to 85%. Deprotection by NH3/MeOH results in the desired nucleosides (1a-d, 2a-d) formation.

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Alkylation of 2,4-bis-O-(trimethylsilyl)uracil with hexafluoroacetone trifluoroacetylimine gave 5-(2-trifluoroacelylaminohexafluoroprop-2-yl)uracil, which was transformed by alkaline hydrolysis to 5-(2-aminohexafluoroprop-2-yl)uracil. The latter was glycosytated with 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-ribofyranosyl chloride by means of various modifications of the silyl method leading to the predominant formation of beta-deoxynucleoside; after deacylation 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil was obtained. Interaction of silylated 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)uracil with acylgalogenose gave anomeric O-substitutet deoxynucleosides, which were deblocked to give 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)-2'-deoxyuridine and corresponding alpha-anomer. Alkaline hydrolysis of N-trifluoroacetyl group in both individual anomers produced 1-(2-deoxy-alpha-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ur acil and the abovementioned beta-anomer. Of all compounds synthesised only 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil has a moderate inhibitory effect on replication of vaccinia virus in vitro.

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The interaction of lymphocytes from mouse lymph nodes with allogeneic stem cells was studied using exogenous colony formation inhibition test. Dual nature of the interaction was revealed: great amounts of lymphocytes inhibited, while small amounts stimulated colony formation. This dependence holds true for macro- and microcolonies as well as for erythrocyte and granuloid microcolonies in the bone marrow during fixation on day 8 and 11 after cell mixture transplantation.

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The effect of 2',5'-oligoisoadenylate on the activity of cyclic nucleotide (cAMP and cGMP) phosphodiesterase in cell (NIH 3T3) lysate was studied. It was shown that the activation of cAMP phosphodiesterase by 2',5'-oligoisoadenylate occurs via a non-competitive mechanism, i.e. the activator does not affect cAMP binding to phosphodiesterase but increases the rate constant of the reaction product (k2) formation. The kinetic parameters of this reaction, i.e. the values of activation constant, K alpha, and parameter beta characterizing the increase in the enzyme turnover number, were determined. 2'5'-Oligoisoadenylate was shown to cause specific activation of cAMP hydrolysis without affecting the activity of cGMP phosphodiesterase.

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