Consensus as a method for evaluating the reproducibility of gastric intraepithelial neoplasia/dysplasia: possibility of using in the process of continuing professional education of pathologists

The reproducibility of the Modified Vienna classification of gastrointestinal neoplasia on the gastric mucosal biopsies was evaluated by using the kappa statistic. The work of a group of pathologists-experts was organized in the remote access mode with a demonstration of 26 cases (98 microphotographs) and an evaluation of the diagnostic category of gastric intraepithelial neoplasia/dysplasia. Different levels of agreement between the opinions of the participating experts have been established in depending on the diagnostic difficulty level. The kappa level ranged from 0.2 (poor agreement) to 0.66 (good agreement) and was depending from the chosen method of correction of the result. , This circumstance contributed to the formation of opinion that the diagnoses indefinite neoplasia/dysplasia-low and high grade neoplasia/dysplasia were the most difficult decisions. Possible reasons which reduce the level of consistency of pathologists are discussed.Методами каппа-статистики проведена оценка воспроизводимости Модифицированной Венской классификации неоплазий пищеварительного тракта на материале биопсий слизистой оболочки желудка. В дистанционном режиме организована работа группы патологоанатомов-экспертов с демонстрацией 26 наблюдений (98 фотографий) с оценкой диагностической категории интраэпителиальной неоплазии/дисплазии слизистой оболочки желудка. Установлены различные уровни совпадения мнения участвовавших экспертов в зависимости от сложности диагностической задачи. Уровень каппа колебался от 0,2 (плохое согласие) до 0,66 (хорошее согласие) в зависимости от выбранного метода коррекции результата, что способствовало формированию мнения о наиболее сложных с точки зрения согласованного мнения диагностических категориях, находящихся в ряду неопределенная неоплазия/ дисплазия – неоплазия/дисплазия низкой и высокой степени. обсуждаются возможные причины, снижающие уровень согласованности патологоанатомов-экспертов

Molecular and cellular basis in prediction of gastric cancer: a multidisciplinary research experience

A self-review of the results of multidisciplinary studies on the development of a predictive system for intestinal type gastric cancer (adenocarcinoma) is present. The authors' studies carried out in 2007-2017 in light of recent concepts of prediction and prevention of gastric cancer are discussed. The predictive model for gastric cancer is proposed. This includes an evaluation of inflammatory cytokine genes nucleotide polymorphisms, aberrant expression of microRNA, detection of tissue patterns of gastric atrophy and intestinal metaplasia (metaplastic atrophy), principles and possibilities of pathomorphological monitoring.Представлен самообзор результатов мультидисциплинарных исследований по разработке предиктивной системы в отношении рака желудка кишечного типа (аденокарциномы). Обсуждаются исследования авторов, выполненные в 2007-2017 годах в аспекте современных концепций предикции и превенции рака желудка. Предложена модель предикции рака желудка, включающая оценку нуклеотидных замен в генах воспалительных цитокинов, аберрантную экспрессию микроРНК, детекцию тканевых паттернов атрофии и метапластической атрофии слизистой оболочки желудка, принципы и возможности патоморфологического мониторинга

The role of the allosteric B site in the fumarase reaction

The role of a malate binding site in a concavity external to the more deeply situated active site has been a major mystery of the fumarase reaction. The malate, within 12 Å of the active site, was bound by hydrogen bonds to two main-chain amides and to two basic residues, H129 and R126. Mutation of the His of this so-called B site of Escherichia coli fumarase had little effect on the overall initial rate kinetics of the enzyme, which has obscured an understanding of the critical role of the site. Contrary to the WT enzyme, which is rate-limited in the recycling of free enzyme isoforms that follows product release, the enzyme with both basic residues modified is rate-limited in the product release step itself. A loss of complexity in the mutated, but still functional, step is indicated by a greatly reduced sensitivity of its rate to changes in temperature. Unlike the inhibition by glycerol shown with normal enzyme and attributed to a viscogenic effect on the recycling rate, the product-release step of the B-site mutants is accelerated by glycerol, suggestive of a structural effect on the 12-Å space between the A and B sites. It is proposed that the “extra” malate represents a stage in the transfer of substrate and product between the solvent and the “buried” active site of the enzyme

Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors

Dynamic nuclear polarization of 13C-labeled cell substrates has been shown to massively increase their sensitivity to detection in NMR experiments. The sensitivity gain is sufficiently large that if these polarized molecules are injected intravenously, their spatial distribution and subsequent conversion into other cell metabolites can be imaged. We have used this method to image the conversion of fumarate to malate in a murine lymphoma tumor in vivo after i.v. injection of hyperpolarized [1,4-13C2]fumarate. In isolated lymphoma cells, the rate of labeled malate production was unaffected by coadministration of succinate, which competes with fumarate for transport into the cell. There was, however, a correlation with the percentage of cells that had lost plasma membrane integrity, suggesting that the production of labeled malate from fumarate is a sensitive marker of cellular necrosis. Twenty-four hours after treating implanted lymphoma tumors with etoposide, at which point there were significant levels of tumor cell necrosis, there was a 2.4-fold increase in hyperpolarized [1,4-13C2]malate production compared with the untreated tumors. Therefore, the formation of hyperpolarized 13C-labeled malate from [1,4-13C2]fumarate appears to be a sensitive marker of tumor cell death in vivo and could be used to detect the early response of tumors to treatment. Given that fumarate is an endogenous molecule, this technique has the potential to be used clinically