The human lactate dehydrogenase isoform A plays an important role in the anaerobic metabolism of tumour cells and therefore constitutes an attractive target in the oncology field. Full-atom models of lactate dehydrogenase A (in complex with NADH and in the apo form) have been generated to enable structure-based design of novel inhibitors competing with pyruvate and NADH. The structural criteria for the selection of potential inhibitors were established, and virtual screening of a library of low-molecular-weight compounds was performed. A potential inhibitor, STK381370, was identified whose docking pose was stabilized through additional interactions with the loop 96-111 providing for the transition from the open to the closed conformation.
The territory of Moscow increased significantly after the adjoining to the city the southwestern regions in 2012. Changing the status of these territories leads to changes in their economic, social and geographical position, functional structure and population of settlements, the configuration of transport, increase of housebuilding, land use change, raise of anthropogenic pressures on natural objects, etc. In view of those changes the Cartography and Geoinformatics department of the Lomonosov Moscow State University in 2013 launched a project aimed in creation a series of maps for integrated environmental and geographical land assessment of the new Moscow territories. It implies the development of informational support for a comprehensive assessment of natural and human-made environment, the intensity of land use and population occupancy and movements with the aid of geotechnology, including geoprocessing operations and remote sensing data, implemented in geographic information system (GIS) and online technologies.
Objectives. We examined the level of persistence (remaining on therapy) and compliance (taking the medication according to directions) and its impact on the effectiveness of therapy in patients with postmenopausal osteoporosis (PMO) treating with combination medication containing 70 mg alendronic acide and 2800 IU colecalciferol - Fosavance under the supervision of medical practitioners. Material and methods. The trial was performed in the form of 2-year prospective observational multicenter study that included 373 patients with PMO aged 40-88 years, initiated therapy with Fosavance under the supervision of 20 physicians had their medical practice in Moscow (18) or Moscow region (2). Patient compliance and persistence with therapy assessed every 6 months for 2 years, the effectiveness of treatment evaluated in 2 years on the dynamics of bone mineral density (BMD) and indicators of quality of life (QOL) by the SF-36 scale. Results. 70.2% of recruited in the study PMO patients prematurely stopped therapy with Fosavance, including 41% - in the first 6 months. Among the patients who dropped out, 42.7% were lost to follow by medical practitioners, 28.6% switched to another drug therapy, 19.1% had no money to buy medication. 22.5% from 111 women who continued treatment after 2 years were non-compliant due to the high cost of therapy (52%), optionality with the purchase of the drug at the pharmacy (28%) or taking pills (16%), or lack of medication in the pharmacy (4%). There were no statistically significant differences in BMD change in compliant (CP) and non-compliant patients (NCP) in lumbar spine, trochanter and total proximal femur in 2 years. But the increase in femoral neck BMD was higher in CP vs. NCP (Δ=1.97% [-1.41; 13.3] and Δ=-2.03 [-10.4 5.20], p=0.0267). CP had greater increase in QOL by SF-36 scoring at role-physical functioning (Δ=5 points [0; 25] at CP vs. Δ=0 points [-50; 0] at NCP, p=0.0195), role-emotional functioning (Δ=50 points [0; 84] and Δ=0 points [-100; 0] respectively, p=0.0001) and social functioning (Δ=13 points [-13; 25] and Δ=-13 points [-25; 0] respectively, p=0.0048). Conclusions. Low adherence to Fosavance negative impact on the effectiveness of treatment PMO and QOL. At the initiation of therapy it's requires close interaction between the doctor and the patient, maintaining patients on regular treatment motivation and selection of the drug taking into account convenience of the reception.
Human lactate dehydrogenase A plays an important role in the glucose metabolism of tumor cells and constitutes an attractive target for chemotherapy. Molecular fragments able to bind in the active site of this enzyme and form hydrogen bonds with the Arg168 guanidinium group, as well as additional interactions with the loop 96–111 in the closed conformation, have been identified by virtual screening of sulfonates and experimental testing of their inhibitory effect. The sulfo group can occupy a similar position as the carboxyl group of the substrate and its structural analogs, whereas the benzothiazole group attached via a linker can be located in the coenzyme (NADH) binding site. Thus, the value of merging individual structural elements of the inhibitor by a linker was demonstrated and ways of further structural modification for the design of more effective inhibitors of lactate dehydrogenase A were established.
Результаты. Качество жизни у больных ПМОП было статистически значимо хуже (p<0,05) по домену В по сравнению с группами «нормальная МПК» и «нормальная МПК + остеопения», по домену Ж -по сравнению с группами «остеопе-ния» и «нормальная МПК + остеопения», по домену Г и суммарному показателю качества жизни -по сравнению с груп-пой «нормальная МПК + остеопения». Обнаружена прямая корреляция между количеством субклинических КПП в целом и компрессионных переломов поясничных позвонков, с одной стороны, и суммой баллов по доменам А-Д и суммарным показателем качества жизни (p<0,05) -с другой. У больных ПМОП, имеющих как минимум один субклинический КПП, отмечалось статистически значимое (p<0,05) снижение качества жизни по сравнению с женщинами без КПП по доменам А-Д и общему показателю качества жизни. Заключение. Развитие ПМОП и субклинических КПП ассоциируется с ухудшением различных аспектов качества жизни у женщин в постменопаузе. Учитывая высокую диагностическую ценность опросника QUALEFFO-41, необходима его валидизация в Российской Федерации. Ключевые слова: остеопороз, постменопауза, QUALEFFO-41, качество жизни, компрессионный перелом позвонков. THE INFLUENCE OF POSTMENOPAUSAL OSTEOPOROSIS AND SUBCLINICAL VERTEBRAL FRACTURES ON POSTMENOPAUSAL WOMEN'S QUALITY OF LIFEMarchenkova L.A., Prokhorova E.A., Dreval' A.V., Polyakova E.Yu., Petukhova N.Yu., Vishnyakova M.V. Moscow Regional Research and Clinical Institute (MONIKI); 61/2 Shchepkina ul., Moscow, 129110, Russian FederationAim: To estimate the influence of postmenopausal osteoporosis (PMO) and subclinical vertebral fractures (SVF) on the quality of life of women in postmenopause. Materials and methods:This study was carried out in 508 postmenopausal women aged 37-88 years, a median -63 years [57; 70], who were divided into 3 groups depending on bone mineral density (BMD) level: PMO (n=362), osteopenia (n=78) and normal BMD (n=68). The quality of life was assessed by using the questionnaire of the European Osteoporosis Foundation -QUALEFFO-41 with 41 questions in the following seven domains: А -а pain, B -activities of daily living, C -jobs around the house, D -mobility, E -leisure, social activities, F -general health perception, G -mental functions, and total QUALEFFO score as well, where the highest score corresponded to the lowest quality of life.Results: The quality of life in patients with PMO for domain С was worse (p<0.05) as compared to that in groups "normal BMD" and "normal BMD + osteopenia"; for domain G -as compared to that of groups "osteopenia" and "normal BMD + osteopenia"; and for domain D and total QUALEFFO score -as compared to that in the group "normal BMD + osteopenia". A positive correlation (p<0.05) was found between the total number of SVF and the number of SVF in lumbar spine, and scores for domains А-E and total score of QUALEFFO-41 questionnaire. A statistically significant decrease of the quality of life (p<0.05) was noted in PMO patients who had at least one SVF as compared to women without SVF for domains А-E and a total QUALEFFO score. ...
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