State dependent dissociation of HERG channel inhibitors

BACKGROUND AND PURPOSE: Inhibition of HERG channels prolongs the ventricular action potential and the QT interval with the risk of torsade de pointes arrhythmias and sudden cardiac death. Many drugs induce greater inhibition of HERG channels when the cell membrane is depolarized frequently. The dependence of inhibition on the pulsing rate may yield different IC(50) values at different frequencies and thus affect the quantification of HERG channel block. We systematically compared the kinetics of HERG channel inhibition and recovery from block by 8 blockers at different frequencies. EXPERIMENTAL APPROACH: HERG channels were expressed heterologously in Xenopus oocytes and currents were measured with the two-electrode voltage clamp technique. KEY RESULTS: Frequency-dependent block was observed for amiodarone, cisapride, droperidol and haloperidol (group 1) whereas bepridil, domperidone, E-4031 and terfenadine (group 2) induced similar pulse-dependent block at all frequencies. With the group 1 compounds, HERG channels recovered from block in the presence of drug (recovery being voltage-dependent). No substantial recovery from block was observed with the second group of compounds. Washing out of bepridil, domperidone, E-4031 and terfenadine was substantially augmented by frequent pulsing. Mutation D540K in the HERG channel (which exhibits reopening at negative voltages) facilitated recovery from block by these compounds at −140 mV. CONCLUSION AND IMPLICATIONS: Drug molecules dissociate at different rates from open and closed HERG channels (‘use-dependent' dissociation). Our data suggest that apparently ‘trapped' drugs (group 2) dissociated from the open channel state whereas group 1 compounds dissociated from open and resting states

Stromal and Tumor Glioma-Derived Cells with Similar Characteristics have Differences in α-Smooth Muscle Actin Expression and Localization

Gliomas are solid brain tumors composed of tumor cells and recruited heterogenic stromal components. The study of the interactions between the perivascular niche and its surrounding cells is of great value in unraveling mechanisms of drug resistance in malignant gliomas. In this study, we isolated the stromal diploid cell population from oligodendroglioma and a mixed population of tumor aneuploid and stromal diploid cells from astrocytoma specimens. The stromal cells expressed neural stem/progenitor and mesenchymal markers showing the same discordant phenotype that is typical for glioma cells. Moreover, some of the stromal cells expressed CD133. For the first time, we demonstrated that this type of stromal cells had the typical myofibroblastic phenotype as the α-SMA+ cells formed α-SMA fibers and exhibited the specific function to deposit extracellular matrix (ECM) proteins at least in vitro. Immunofluorescent analysis showed diffuse or focal α-SMA staining in the cytoplasm of the astrocytoma-derived, A172, T98G, and U251MG glioma cells. We could suggest that α-SMA may be one of the main molecules, bearing protective functions. Possible mechanisms and consequences of α-SMA disruptions in gliomas are discussed

DDAO Controlled Synthesis of Organo-Modified Silica Nanoparticles with Encapsulated Fluorescent Boron Dipyrrins and Study of Their Uptake by Cancerous Cells

The design of cargo carriers with high biocompatibility, unique morphological characteristics, and capability of strong bonding of fluorescent dye is highly important for the development of a platform for smart imaging and diagnostics. In this paper, BODIPY-doped silica nanoparticles were prepared through a "one-pot" soft-template method using a sol-gel process. Several sol-gel precursors have been used in sol-gel synthesis in the presence of soft-template to obtain the silica-based materials with the most appropriate morphological features for the immobilization of BODIPY molecules. Obtained silica particles have been shown to be non-cytotoxic and can be effectively internalized into the cervical cancer cell line (HeLa). The described method of synthesis allows us to obtain silica-based carriers with an immobilized fluorescent dye that provide the possibility for real-time imaging and detection of these carriers

Hybrid inorganic-organic capsules for efficient intracellular delivery of novel siRNAs against influenza A (H1N1) virus infection

This work was supported by ARUK project grant 21210 ‘Sustained and Controllable Local Delivery of Anti-inflammatory Therapeutics with Nanoengineered Microcapsules’. The work was also supported in part by Russian Foundation of Basic Research grants No. 16-33-50153 mol_nr, No. 16-33-00966 mol_a, Russian Science Foundation grant No. 15-15-00170 and Russian Governmental Program ‘‘Nauka’’, No. 1.1658.2016, 4002

ХАРАКТЕРИСТИКА ГИБРИДОВ МЕЖДУ ALLIUM СЕРА L. И ALLIUM NUTANS L. ПО БИОХИМИЧЕСКОМУ СОСТАВУ

Wild species of Allium L. genus are not only a harbor of resistance to biotic factors such as pathogens and pests and abiotic factor such as drought, cold and freezing, but also have the biochemical composition differed from cultural species. Crosses between wild and cultured species in Allium genus are usually performed to develop breeding forms with improved content of biochemically valuable compounds. Hybrids F1 obtained from combination Allium сера x Allium nutans, where varieties ‘Stuttgarter Riesen’ and ‘Strigunovskiy’ served as parental forms from A.cepa were studied. Biochemical contents and morphological descriptions of obtained plants were also given in the article. NO3, К+, ascorbic acid, dry matter and total watersoluble antioxidants were analyzed in the plants. Increased content of NO3- was found in accession N13 F1 of A. cepa x A. nutans combination that was higher than in other accessions, including control plants. The accession N15 had a much higher content of Cl- and K+ in leaves than in other accessions. The content of ascorbic acid in all hybrids was 2-3 times less than in control accessions and varied from 15.8 to 28.6 mg%. All hybrid accessions had less dry matter content than in control accessions, achieving 9.3 to 11.7%, in control plants, 12.7. The lowest antioxidant content, 15.3 mg/g (conc. in ascorbic acid units), was found out in accession N3, but the highest antioxidant content 37.3 mg/g (conc. in ascorbic acid units) was in accession N16; it was twice higher than in control plants. The obtained hybrid F1 plants from combination A. cepa x A. nutans can be then selected for their best biochemical composition.Дикорастущие виды рода Allium L. являются источниками не только устойчивости к биотическим (болезням, вредителям) и абиотическим факторам окружающей среды (морозо-, зимостойкость, засухоустойчивость), но также отличаются по биохимическим показателям от культурного вида лука. Проведение скрещиваний с участием дикорастущих видов лука может увеличить содержание биохимических веществ у гибридов в сравнении с культурными. Во ВНИИССОК проводили скрещивания между дикорастущими и культурными видами рода Allium L. Для создания исходных форм для селекции с более высоким содержанием ценных биохимических веществ. Изучали растения межвидовых гибридов лука F1 в комбинации скрещивания A. cepa x A. nutans и растения родительских видов: Allium cepa L. (сорта лука репчатого – Штутгартер ризен, Стригуновский) и Allium nutans L. В работе представлена морфологическая характеристика растений межвидовых гибридов лука F1 Allium сера x Allium nutans и дана биохимическая оценка межвидовых гибридов лука. У растений определяли содержание NO3-, К+, аскорбиновой кислоты, сухого вещества, суммарного содержания водорастворимых антиоксидантов. Повышенное содержание NO3-наблюдалось у №13 F1 A. cepa x A. nutans в сравнении с другими вариантами и стандартом. У №15 F1 A. cepa x A. nutans содержание K+ в листьях значительно превышало накопление этих элементов у растений других вариантов. Содержание аскорбиновой кислоты у всех гибридов A. cepa x A. nutans было меньшим, по сравнению с контролем в два-три раза и варьировало от 15,8 до 28,6 мг%. Все гибридные растения также уступали растениям стандарта по содержанию сухого вещества (9,3-11,7%, в стандарте – 12,7%). Самыми низким содержанием антиоксидантов характеризовался образец №3 – 15,3 мг/г (ЕАК), самые высокие значения были получены в варианте №16 – 37,3 мг/г (ЕАК), превосходящие стандарт в два раза. У полученных растений F1 A. cepa x A. nutans через индивидуальный отбор целесообразно направленно отбирать формы, лучшие по биохимическому составу

Physicochemical properties of pore residues predict activation gating of CaV1.2: A correlation mutation analysis

Single point mutations in pore-forming S6 segments of calcium channels may transform a high-voltage-activated into a low-voltage-activated channel, and resulting disturbances in calcium entry may cause channelopathies (Hemara-Wahanui et al., Proc Natl Acad Sci U S A 102(21):7553–7558, 16). Here we ask the question how physicochemical properties of amino acid residues in gating-sensitive positions on S6 segments determine the threshold of channel activation of CaV1.2. Leucine in segment IS6 (L434) and a newly identified activation determinant in segment IIIS6 (G1193) were mutated to a variety of amino acids. The induced leftward shifts of the activation curves and decelerated current activation and deactivation suggest a destabilization of the closed and a stabilisation of the open channel state by most mutations. A selection of 17 physicochemical parameters (descriptors) was calculated for these residues and examined for correlation with the shifts of the midpoints of the activation curve (ΔVact). ΔVact correlated with local side-chain flexibility in position L434 (IS6), with the polar accessible surface area of the side chain in position G1193 (IIIS6) and with hydrophobicity in position I781 (IIS6). Combined descriptor analysis for positions I781 and G1193 revealed that additional amino acid properties may contribute to conformational changes during the gating process. The identified physicochemical properties in the analysed gating-sensitive positions (accessible surface area, side-chain flexibility, and hydrophobicity) predict the shifts of the activation curves of CaV1.2

Диагностика и лечение рака ротоглотки в реальной клинической практике в Республике Башкортостан: анализ за 2020 год

Introduction. Th e growing incidence of oropharyngeal cancer is driven by an increase in frequency of HPV-associated oropharyngeal cancer. Th e morbidity pattern of oropharyngeal cancer is area-specific.Aim. To analyze the oropharyngeal cancer diagnosis and treatment in the Republic of Bashkortostan for 2020.Materials and methods. Th e authors carried out a 2020 retrospective analysis of the diagnosis and treatment results of patients with oropharyngeal cancer. 79 patients were identified with this diagnosis. 84.8% (67/79) among them were males and 15.2% females (12/79). Th e mean age of the patients was 59.1 years. Th e site of primary tumor was on the oropharynx lateral wall in 37.8% cases (30/79), in the tongue root area — 24.1% (19/79), in the tonsils area — 17.7% (14/79), on the soft palate — 16.5% (13/79), on the oropharynx posterior wall — 3.8% (3/79).Results. Examination of tumor morphological types revealed squamous cell carcinoma (SCC) with various degrees of differentiation in 92.4% cases (73/79), adenocarcinoma of minor salivary gland — in 6.3% (5/79) and sarcoma in 1.2% (1/79). 57.5% of 73 patients with SCC (42/73) underwent protein (p16) immunohistochemistry, while 42.5% of the patients (31/73) did not. According to a surrogate marker for HPV, the following results were obtained for 42 patients: p16-positive in 23.8% cases (10/42), p16-negative in 76.2% (32/42). Stage distribution according to TNM-7: stage I — 11.4% (9/79), stage II — 17.7% (14/79), stage III — 36.7% (29/79), stage IV — 46.8% (37/79). Stage distribution according to TNM-8 (patients who underwent p16 immunohistochemistry): stage I — 11.9% (5/42), stage II — 23.8% (10/42), stage III — 19% (8/42), stage IV — 45.2% (19/42). In 2020, 72% of patients (57/79) received definitive treatment, 10.1% (8/79) — palliative care, 15.2% (12/79) — supportive care, and 2.5% (2/79) refused medical treatment.Discussion. Th e various types of radiation therapy were used as the main defi nitive treatment for patients with oropharyngeal cancer in 69.2% cases (45/65). Only 18.5% of patients (12/65) underwent surgery, 58.3% of which (7/12) received post-surgery radiation therapy.Conclusion. 57.5% of patients (42/73) were detected with HPV status, 23.8% (10/42) revealed surrogate markers for HPV association. 69.2% of patients (45/65) received radiation therapy as the definitive treatment. 18.5% of patients (12/65) underwent surgery, 58.3% of which (7/12) received postsurgery radiation therapy.Введение. Современная тенденция роста заболеваемости раком ротоглотки обусловлена ростом ВПЧ-ассоциированной формы рака ротоглотки. Структура данной заболеваемости имеет территориальные особенности.Цель исследования. Провести анализ диагностики и лечения рака ротоглотки в Республике Башкортостан за 2020 год.Материалы и методы. Выполнен ретроспективный анализ результатов диагностики и лечения пациентов с диагнозом «рак ротоглотки» за 2020 год. Данный диагноз был установлен 79 пациентам. Доля пациентов мужского пола составила 84,8 % (67/79), женского пола — 15,2 % (12/79). Средний возраст пациентов — 59,1 года. Первичная опухоль локализовалась на боковой стенке ротоглотки в 37,8 % (30/79), в области корня языка — 24,1 % (19/79), в области миндалин — 17,7 % (14/79), мягкого неба — 16,5 % (13/79), на задней стенке ротоглотки — 3,8 % (3/79) случаев. Результаты. При анализе морфологических форм опухоли в 92,4 % (73/79) случаев это плоскоклеточный рак (ПКР) различной степени дифференцировки, в 6,3 % (5/79) — аденокарциномы из малых слюнных желез, в 1,2 % (1/79) — саркома. Из 73 пациентов с ПКР ротоглотки иммуногистохимическое исследование на белок р16 было выполнено 57,5 % (42/73) пациентов, 42,5 % (31/73) пациентов не проведено. У 42 пациентов по данным суррогатного маркера ВПЧ-ассоциации получены следующие результаты: р16-положительный результат у 23,8 % (10/42), р16-отрицательный результат у 76,2 % (32/42). Распределение по стадиям в соответствии TNM- 7: 1-я стадия — 11,4 % (9/79), 2-я стадия — 17,7 % (14/79), 3-я стадия — 36,7 % (29/79), 4-я стадия — 46,8 % (37/79). Распределение по стадиям в соответствии TNM-8 (пациентам, которым выполнено исследование ИГХ на р16): 1-я стадия — 11,9 % (5/42), 2-я стадия — 23,8 % (10/42), 3-я стадия — 19 % (8/42), 4-я стадия — 45,2 % (19/42). За 2020 год радикальное лечение проведено 72 % (57/79), паллиативное лечение — 10,1 % (8/79), симптоматическая терапия — 15,2 % (12/79), от лечения отказались 2,5 % (2/79) пациентов.Обсуждение. Основным радикальным методом лечения пациентов с раком ротоглотки была лучевая терапия в различных вариантах — 69,2 % (45/65) случаев. Хирургическое лечение проведено только 18,5 % (12/65) пациентов, из них 58,3 % (7/12) проведена послеоперационная лучевая терапия.Заключение. Определение ВПЧ-статуса было выполнено у 57,5 % (42/73), и у 23,8 % (10/42) пациентов выявлены суррогатные маркеры ВПЧ-ассоциации. 69,2 % (45/65) пациентов в качестве основного радикального лечения была проведена лучевая терапия в различных вариантах. 18,5 % (12/65) пациентов было проведено хирургическое лечение, из них 58,3 % (7/12) проведена послеоперационная лучевая терапия

Hubungan Proses Belajar Daring Masa Pandemi Covid-19 dengan Prestasi Belajar IPA Siswa Kelas X SMA Negeri 2 Tondano

This study aims to determine the relationship between the online learning process during the Covid-19 pandemic and the science learning achievement of class X SMA Negeri 2 Tondano students. The online learning process is a teaching and learning process that is carried out online and interactively by utilizing information and communication technology, such as computer media with the internet as the delivery and recipient of the material. The research design used is correlational, with data collection techniques in the form of questions (statements) questionnaires and the average value of report cards using 20 students as samples. Tests carried out to prove the hypothesis were carried out by simple linear regression analysis, Pearson Product Moment correlation and t-test. The results of the regression equation obtained are Y = 0.2634x + 68.519 with a correlation value of r = 0.693 in the level of strong relationship, and the results from the t-test are tcount = 4.080 and ttable = 2.100, meaning tcount > ttable at = 0,05, the correlation between variables X and Y is significant, meaning that there is a strong and significant relationship between the online learning process during the Covid-19 pandemic and the science learning achievement of class X SMA Negeri 2 Tondano students