POLYFLUOROALKYL-2-(HET)ARYLHYDRAZONO-1,3-DICARBONYL COMPOUNDS IN INTRAMOLECULAR CYCLIZATION REACTIONS

This work was financially supported by the Program UB RAS (Grant number 18-3-3-13)

The heating rate influence on the elastic modulus temperature dependence of a corrosion-resistant nickel alloy

The temperature dependence of the elastic modulus of nickel-chromium-molybdenum alloy C4 was investigated by the method of dynamic mechanical analysis. At all heating rates, an abnormal increase in the elastic modulus is observed upon heating in the temperature range of 200-300 °C. It is shown that an increase in the heating rate shifts the beginning of the observed effect to the region of higher temperatures. The temperature anomaly in the elastic modulus of the C4 alloy is explained from the standpoint of the formation of a short-range order in a solid solution. The thermodynamically equilibrium temperature of the "disorder - short-range order" transition in C4 alloy is determined to be 205 °C. © Published under licence by IOP Publishing Ltd

QED cascades induced by circularly polarized laser fields

The results of Monte-Carlo simulations of electron-positron-photon cascades initiated by slow electrons in circularly polarized fields of ultra-high strength are presented and discussed. Our results confirm previous qualitative estimations [A.M. Fedotov, et al., PRL 105, 080402 (2010)] of the formation of cascades. This sort of cascades has revealed the new property of the restoration of energy and dynamical quantum parameter due to the acceleration of electrons and positrons by the field and may become a dominating feature of laser-matter interactions at ultra-high intensities. Our approach incorporates radiation friction acting on individual electrons and positrons.Comment: 13 pages, 10 figure

Properties of electrons scattered on a strong plane electromagnetic wave with a linear polarization: classical treatment

The relations among the components of the exit momenta of ultrarelativistic electrons scattered on a strong electromagnetic wave of a low (optical) frequency and linear polarization are established using the exact solutions to the equations of motion with radiation reaction included (the Landau-Lifshitz equation). It is found that the momentum components of the electrons traversed the electromagnetic wave depend weakly on the initial values of the momenta. These electrons are mostly scattered at the small angles to the direction of propagation of the electromagnetic wave. The maximum Lorentz factor of the electrons crossed the electromagnetic wave is proportional to the work done by the electromagnetic field and is independent of the initial momenta. The momentum component parallel to the electric field strength vector of the electromagnetic wave is determined only by the diameter of the laser beam measured in the units of the classical electron radius. As for the reflected electrons, they for the most part lose the energy, but remain relativistic. There is a reflection law for these electrons that relates the incident and the reflection angles and is independent of any parameters.Comment: 12 pp, 3 fig

Fulminant invasive group A streptococcal infection in children

Group A streptococcal infections dominate among invasive streptococcal infections, with the major causative agent, Streptococcus pyogenes, being quite stable in the environment and bearing a large number of chromosome encoded pathogenicity factors or transmitted by horizontal transfer through bacteriophages. Different genetic variants of S. pyogenes can have a different set of pathogenicity factors able to change during pathogen evolution and determine virulence level for specific isolate. With a short incubation period, the disease can proceed with developing invasive infection and toxic shock syndrome with unfavorable outcome within 7 days from disease onset. The purpose of this article is to increase the doctors’ alertness to early recognition and diagnosis, which directly affects adequate treatment in a timely manner and disease outcome. The data on streptococcal morbidity in Russia and worldwide, review of laboratory diagnostic methods and pathogen genetic typing are presented. The maximum number of cases of streptococcal septicemia in Russia was registered in 2022, which accounted for 69% of all cases during the 2014–2022 observation period. The article also describes two clinical cases of fulminant invasive group A streptococcal infection in children with symptoms of acute respiratory viral infections at the onset of the disease. The results of various laboratory diagnostics methods verifying the diagnosis are presented. The genetic characterization of microbial isolates was performed by deep DNA sequencing. In the biological material from patients (including autopsy in one case), S. pyogenes sequence type ST-28, serotypes emm-1.25 and emm-1.0 were identified. The increasing importance of invasive streptococcal infection for health care in Russia and other countries may be associated with a possible change in dominating S. pyogenes genetic variants. In this regard, the study on circulating S. pyogenes genotypes on an ongoing basis as part of surveillance of streptococcal infection and development of vaccine for specific prevention are required

Динамика распространенности бронхиальной астмы у детей в Новосибирске

Six-year dynamics of epidemiology of bronchial asthma was analyzed in Novosibirsk according to a common standardized protocol of the "International Study of Asthma and Allergic Diseases in Children" (ISAAC) programme. The pathology spread was studied using a total surveying among first-form and eight-form pupils (the survey involved 7291 pupils 1996, 6631 ones in 1999 and 6943 children in 2002). The results showed stable spread of bronchial asthma symptoms among the senior and junior pupils and prevalence of mild asthma with rare exacerbations in both the groups. A progredient growth of severe asthma attack rate was noted in eight-form pupils. An increase in frequency of combined upper and lower airway pathologies was registered with reduction in skin atopy rate. A problem of underestimating of the pathology was discussed.Исследована 6-летняя динамика эпидемиологии бронхиальной астмы по единым стандартизованным протоколам программы "Международное исследование астмы и аллергических заболеваний у детей" (ISAAC) в Новосибирске. Изучение распространенности патологии проводилось при сплошном анкетировании учеников 1-х и 8-х классов (7291 школьник в 1996 г., 6631 — в 1999 г. и 6943 — в 2002 г.). В динамике выявлены стабильная распространенность симптомов бронхиальной астмы у старших и младших школьников, сохранение преобладания легких редко рецидивировавших форм патологии в обеих возрастных группах. Отмечен прогредиентный рост тяжелых приступов удушья у восьмиклассников. В популяции школьников зарегистрировано увеличение сочетанного поражения верхних и нижних отделов респираторного тракта с сокращением частоты кожных форм атопии. Отражена проблема гиподиагностики патологии

Резистентность клеток рака молочной железы к полностью трансретиноевой кислоте ассоциирована со снижением базального уровня экспрессии ядерного рецептора RARα и индукции экспрессии цитохромов CYP26A1 и CYP26В1

Introduction. Retinoic acid (RA) is a key regulator of cell differentiation and a critical player in such systemic processes in the body as embryonic development, immune system cell maturation and functioning, tissue remodeling and several others. This compound displays an antitumor activity due to its ability to stimulate differentiation, induce apoptosis  and inhibit proliferation of malignant cells. The rapid acquisition of resistance to RA and its analogues by solid tumor cells is one of the main problems limiting the widespread use of retinoids in the therapy of malignant neoplasms. The mechanisms of RA-resistance are still poorly understood.The study objective – assessment of the relationship between the basal expression level of the nuclear RARα receptor and the RA-induced expression of the cytochromes CYP26A1and CYP26B1 with the resistance of breast cancer cells to the action of all-trans-retinoic acid.Materials and methods. Cell lines were cultured, the sensitivity of breast cancer cells to the action of fully trans-retinoic acid, RNA isolation, reverse transcription reaction and real-time polymerase chain reaction were analyzed).Results. In present study, using an experimental model represented by 9 breast cancer cell lines with different level of sensitivity to RA, we showed that the expression of the RA nuclear receptor RARα, as well as the level of mRNA induction of CYP26A1 and CYP26B1 cytochromes in response to RA treatment correlate with RA-sensitivity.Conclusion. Thus, a decrease of RARα expression as well as the reduced ability to catabolize RA are factors associated with RA-resistance of breast cancer cells.Введение. Ретиноевая кислота (РК) является одним из ключевых регуляторов дифференцировки клеток и важнейшим участником таких системных процессов в организме, как эмбриональное развитие, созревание и функционирование клеток иммунной системы, ремоделирование тканей и ряд других. Это соединение обладает противоопухолевой активностью благодаря своей способности стимулировать дифференцировку, индуцировать апоптоз и подавлять пролиферацию клеток злокачественных новообразований. Быстрое приобретение резистентности к РК и ее аналогам клетками солидных опухолей является одной из основных проблем, ограничивающих широкое применение естественных и синтетических ретиноидов в терапии злокачественных новообразований. Механизмы развития данной резистентности остаются до сих пор малопонятными.Цель исследования – оценка связи уровня базальной экспрессии ядерного рецептора RARα и РК-индуцированной экспрессии цитохромов CYP26A1 и CYP26B1 с резистентностью клеток рака молочной железы к действию полностью трансретиноевой кислоты.Материалы и методы. Проведены культивирование клеточных линий, анализ чувствительности клеток рака молочной железы к действию полностью трансретиноевой кислоты, выделение РНК, обратная транскрипция и полимеразная цепная реакция в реальном времени.Результаты. В данной работе с использованием экспериментальной модели, включающей 9 линий клеток рака молочной железы, различающихся по уровню чувствительности к РК, мы показали, что экспрессия матричной РНК гена ядерного рецептора РК, RARα, а также уровень индукции матричной РНК генов цитохромов CYP26A1 и CYP26В1 в ответ на обработку РК коррелируют с РК-чувствительностью клеток.Заключение. Таким образом, снижение экспрессии RARα и способности катаболизировать РК являются факторами, ассоциированными с РК-резистентностью клеток рака молочной железы

Феномен подавления ДНК-метилтрансферазы 3А при формировании резистентного фенотипа в клетках рака молочной железы

Introduction. Rearrangement of molecular pathways and activation of bypass signaling determine the progression of tumor cell resistance to various drugs. Study of the common features of resistant formation mechanisms is essential for breast and other cancer beneficial treatments.Materials and methods. The present work was performed on estrogen receptor α ERα-positive (ERα – estrogen receptor α) McF-7 breast cancer cells, established sublines resistant to the mTOR inhibitor rapamycin or antiestrogen tamoxifen, and ERα-negative MDA-MB-231 breast cancer cells. Methods used include MTT test, transient transfection, immunoblotting, real-time polymerase chain reaction and methylation analysis by bisulfite pyrosequencing.Results. We have shown that the resistance of breast cancer cells to targeted and hormonal drugs is associated with the suppression of DNA methyltransferase 3A (DNMT3A) and respective changes in DNA methylation; DNMT3A knockdown results in the partial resistance to both drugs demonstrating the pivotal role of DNMT3A suppression in the progression of cell resistance.Conclusion. Totally, the results obtained highlight the possible mechanism of tumor cell resistance to targeting/hormonal drugs based on the deregulation of DNMTs expression and demonstrate  direct connection between DNMT3A suppression and resistance progression.Введение. Переключение сигнальных путей и активация параллельных сигнальных каскадов относятся к ключевым факторам, определяющим развитие резистентности опухолевых клеток, и изучение механизмов подобной реаранжировки является одной из актуальных задач современной онкологии.Материалы и методы. Настоящая работа выполнена на ERα-положительных  (ERα – эстрогеновый рецептор α) клетках рака молочной железы MCF-7 и полученных из них сублиниях, устойчивых к ингибитору mTOR рапамицину или антиэстрогену тамоксифену, а также на ERα-отрицательных клетках рака молочной железы MDA-MB-231. Используемые методы включают тест МТТ, транзиторную трансфекцию, иммуноблоттинг, полимеразную цепную реакцию в реальном времени и анализ метилирования с помощью бисульфитного пиросеквенирования.Результаты. Мы показали, что резистентность клеток рака молочной железы к таргетным и гормональным препаратам связана с подавлением ДНК-метилтрансферазы 3А (DNMT3A) и соответствующими изменениями в метилировании ДНК. Нокдаун DNMT3A приводит к частичной резистентности к обоим препаратам, что демонстрирует ключевую роль подавления DNMT3A в развитии резистентности опухолевых клеток.Заключение. В целом, полученные результаты свидетельствуют о возможном механизме формирования устойчивости опухолевых клеток к таргетным/гормональным препаратам, основанном на дерегуляции экспрессии DNMT, и демонстрируют прямую связь между подавлением DNMT3A и развитием резистентности

Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals

4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of N. gonorrhoeae bacteria at MIC 0.9 μg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking. © 2022 by the authors.FFSN-2021-0005; Russian Foundation for Basic Research, РФФИ: 20-03-00312; Russian Science Foundation, RSF: 21-13-00390This work was financially supported by the Russian Science Foundation (grant No 21-13-00390 for V.I.S.): the synthesis and analysis of compounds, antimicrobial evaluation, cytotoxicity, analgesic and anti-inflammatory activity, mechanism of analgesia, molecular docking; by the Russian Foundation for Basic Research (grant No 20-03-00312 for Y.V.B.): esterase profile of compounds; antioxidant activity in ABTS and FRAP tests were performed in the frame of IPAC RAS State Targets Project FFSN-2021-0005