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Endometrial cancer is the most prevalent gynecologic malignancy with a high risk of recurrence. Local recurrence occurs in 7–20% of patients with treated stage I cancer within 3 years after primary treatment. In this study, we found significantly elevated mRNA expression levels of the oncoprotein KRAS, along with two replicative stress markers, ATR and CHEK1, in samples of endometrial carcinomas of endometrium (ECE) from patients with relapse. In contrast, mRNA expression levels of the studied genes were low and uniform in samples from patients without relapse. Elevated levels of KRAS protein and the phosphorylated form of ATR/CHEK1 were distinguishing features of recurrent ECE. A strong positive correlation was found between elevated mRNA and protein levels of the studied molecules. Elevated KRAS protein levels are characteristic of poorly differentiated (G3) endometrial carcinomas with deep myometrial invasion in patients without recurrence. In contrast, in patients with recurrence, higher protein levels of KRAS, pATR and pCHEK1 were observed in samples of G1-2 endometrial carcinomas, with statistically significant differences confirmed for pATR. High pCHEK1 protein levels are associated with deep tumor invasion in the myometrium among patients with recurrence. ROC analysis confirmed that evaluating the specificity and sensitivity of KRAS, pATR and pCHEK1 predicts recurrence development in patients with ECE. Our findings indicate that markers of replicative stress may play a significant role in ECE pathogenesis. Determining their levels in tumor samples after primary treatment could help define patients at high risk of recurrence and guide consequent courses of treatment. [ABSTRACT FROM AUTHOR]

For comparative purposes, a quantitative estimation of antioxidant activity of phenolic compounds of different classes was conducted by way of the polarography method, via the ADP-Fe2+ model of the induced ascorbate-dependent lipid peroxidation of rat liver micro-somes within an in-vitro system. As a result, it was recognized that the antioxidant properties of phenolic compounds depend on the nature and chemical structure of several substances. In respect of such activity, leaders in the classes of investigated polyphenolic compounds are: Propyl gallate = Gallotannin (Phenolcarboxylic acids and their derivatives) > Quercetin = Myricetin (Flavonols) > Luteolin (Flavo n) = Mangiferin (Xanthones) > Kaempferol (Flavonols) = Catechin (Flavans). Thus, the assessment of the inhibition ability of the lipid peroxidation of microsomes by phenolic compounds can be used as an accessible test for the preliminary quantitative estimation of their antioxidant properties. [ABSTRACT FROM AUTHOR]

Once you have missed the first button ..., you'll never manage to button up Johann Wolfgang von Goethe Formate oxidation is a final step of methanol oxidation in methylotrophic prokaryotes and is important for detoxification of formate in other organisms. The structural mechanism of the formate dehydrogenase (FDH) of Pseudomonas sp. 101 has been studied for about 30 years. In the active center of FDH, the oxidation of formic acid into carbon dioxide in a NAD+-dependent way takes place. Residues that form the active center of that enzyme, as well as those that form the so-called substrate channel, are engaged in the catalytic cycle. Our study allowed to characterize a new residue, Tyr102, involved in the work of the enzyme. This residue is located in the outer neck of the substrate channel (at the beginning of the path of the substrate to the active center) and acts as a "button" which connects two enzyme domains into an active, "buttoned up" conformation. Our study of the kinetic parameters of mutant enzymes has shown that Tyr102Phe substitution leads to an approximately 80-fold increase of the Michaelis constant relative to the native enzyme, unlike Phe311Trp and Phe311Tyr substitution of neighboring residue Phe311. Our analysis of the Tyr102Phe mutant in the open conformation by X-ray crystallography has shown that its overall fold remains almost the same as that of the native enzyme. Molecular dynamics simulations of the ternary complexes of the native FDH enzyme and its Tyr102Phe mutant showed that Tyr102Phe substitution results in the loss of an interdomain hydrogen bond between the Tyr102 and Gln313 residues, which, in turn, destabilizes the closed conformation and affects the isolation of the FDH active site from water molecules. Our structural investigations have shown that Tyr102Phe replacement also leads to the destruction of interdomain contacts of Phe102 with Phe311, Pro312 residues, and decreases the stability of the Leu103-Val127 beta bridge. Phylogenetic analysis also confirmed the importance of the Tyr102 residue for enzymes from the FDH family, in which it is absolutely conserved. [Display omitted] • Tyr102 is strongly conserved in the FDH family. • Tyr102Phe substitution leads to an 80-fold decrease in the Michaelis constant. • Tyr102Phe substitution decreases stability of the Leu103-Val127 beta bridge. • Tyr102Phe substitution decreases interdomain contacts. • Tyr102 is necessary for the correct transition of FDH into the closed state. [ABSTRACT FROM AUTHOR]

Marker frequency analysis of the Escherichia coli recB mutant chromosome has revealed a deficit of DNA in a specific zone of the terminus, centred on the dif/TerC region. Using fluorescence microscopy of a marked chromosomal site, we show that the dif region is lost after replication completion, at the time of cell division, in one daughter cell only, and that the phenomenon is transmitted to progeny. Analysis by marker frequency and microscopy shows that the position of DNA loss is not defined by the replication fork merging point since it still occurs in the dif/TerC region when the replication fork trap is displaced in strains harbouring ectopic Ter sites. Terminus DNA loss in the recB mutant is also independent of dimer resolution by XerCD at dif and of Topo IV action close to dif. It occurs in the terminus region, at the point of inversion of the GC skew, which is also the point of convergence of specific sequence motifs like KOPS and Chi sites, regardless of whether the convergence of GC skew is at dif (wild-type) or a newly created sequence. In the absence of FtsK-driven DNA translocation, terminus DNA loss is less precisely targeted to the KOPS convergence sequence, but occurs at a similar frequency and follows the same pattern as in FtsK+ cells. Importantly, using ftsIts, ftsAts division mutants and cephalexin treated cells, we show that DNA loss of the dif region in the recB mutant is decreased by the inactivation of cell division. We propose that it results from septum-induced chromosome breakage, and largely contributes to the low viability of the recB mutant. [ABSTRACT FROM AUTHOR]

Conventional photodynamic treatment strategies are based on the principle of activating molecular oxygen in situ by light, mediated by a photosensitizer, which leads to the generation of reactive oxygen species and thereby causes cell death. A diarylethene-derived peptidomimetic is presented that is suitable for photodynamic cancer therapy without any involvement of oxygen. This light-sensitive molecule is not a mediator but is itself the cytotoxic agent. As a derivative of the cyclic amphiphilic peptide gramicidin S, the peptidomimetic exists in two thermally stable photoforms that are interconvertible by light of different wavelengths. The isomer generated by visible light shows much stronger toxicity against tumor cells than the UV-generated isomer. First in vivo applications are demonstrated on a tumor animal model to illustrate how the peptidomimetic can be administered in the less toxic form and then activated locally in a solid tumor by visible light. [ABSTRACT FROM AUTHOR]

The absorption and photoluminescence spectra of the solutions and crystals of ADP in the presence of dopant molecules (pH 3.5) and/or anion (pH 5.2) of salicylic acid and Tl + cation are studied. Dissociation of salicylic acid at the first stage is accompanied with the formation of salicylate complexes with thallium phototautomer. It is shown that the dopants are incorporated into the crystal, irrespectively of one another, in accordance with their distribution coefficients. The influence of the process of the impurity co-doping on the growth kinetics of the prismatic (100) ADP faces depends on the stoichiometry of the solution. The neutral H 2 Sal dopant monomers (pH 3.5) increase σ d and diminish the growth rate. The HSal − dopant monoanions (pH 5.2) reduce the amount of σ d and raise the growth rate. Tl + ions in the solution increase σ d and decrease the growth rate irrespectively of the pH. The influence of the HSal − /Tl + co-dopant (pH 5.2) on σ d is almost 1.5 times lower than the one of the H 2 Sal/Tl + co-dopant (pH 3.5); both co-dopants reduce the growth rate. The crystal growth is realized via moving macrosteps. [ABSTRACT FROM AUTHOR]

A novel series of compounds containing a polar, non-flat 2-imidazoline core was designed based on the SAR information available for aromatic azole cyclooxygenase-2 inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300 nM) comparable to clinically used Celecoxib and was shown to be more selective. The series represents the first example of selective COX-2 inhibitors built around a distinctly polar core, contradicting an earlier accepted view that a lipophilic scaffold is required for high inhibitor potency. The lead compound demonstrated very good oral bioavailability in mice, slow metabolic degradation, modest distribution into the brain and a remarkable anti-inflammatory efficacy in carrageenan-induced mouse paw edema model. A foundation has therefore been laid for a chemically novel series of COX-2 inhibitors that has a potential for diverse therapeutic applications in inflammatory disease area. [ABSTRACT FROM AUTHOR]

Abstract: Lithium dihydrogen phosphate (LiH2PO4, LDP) single crystals were grown from aqueous solutions of orthophosphoric acid. The influence of the concentration of the acid in the mother liquor on the solubility of LDP crystals and the conditions of their crystallization, was studied. The change of LDP solubility with the rise of the temperature was found to be not higher than 5mass%, irrespective of the acid concentration. The solubility diminished with the increase of the acid concentration in the mother liquor. The conditions of the growth of LDP crystals were analyzed from the viewpoint of the method of creation of the solution supersaturation, e.g. change of the acid concentration or evaporation of the solvent. The latter method is most optimal for the growth of LDP crystals from aqueous solutions of orthophosphoric acid. The habitus of the crystals was established to change with the rise of the acid concentration in the solution: the growth of the faces of the pyramid {11 } and the dome {01 } is suppressed, whereas the face of the pedestal {00 } continues to grow. The model of the influence of hydrogen bonds on the habitus of the crystals was considered. [Copyright &y& Elsevier]