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

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

Regional Chemotherapy Infusion Via the Bronchial Artery in Combined Treatment of Non-Small Cell Lung Cancer

Introduction. Chemotherapy in the form of endovascular infusion or its combination with radiotherapy is a method for treating non-small cell lung cancer (NSCLC), which raises heated discussions among specialists. This study is aimed at assessing the early results of combined treatment of NSCLC patients with selective chemotherapy infusion via the bronchial artery.Materials and methods. A retrospective analysis of treatment results for 24 patients with central pulmonary cancer hospitalized in the Shymkent Oncological Centre (Kazakhstan) during 2016–2019 was carried out. The average age of the patients was 46.4 ± 11.3 years. According to the histological study, 19 and 5 patients were diagnosed with squamous cell lung cancer and undifferentiated carcinoma, respectively. The patients were recognized as surgically incurable; three courses of neoadjuvant polychemotherapy via selective catheterization of the bronchial artery and regional intra-arterial administration of drugs were prescribed according to the DR scheme: Docetaxel 75 mg/m2 , Cisplatin 75 mg/m2 .Results and discussion. Upon completion of three courses of selective chemotherapy, 20 (83.3%) patients showed the possibility of surgical treatment: 15 patients underwent extended pulmonectomy, 5 patients underwent extendedcombined pulmonectomy with pericardial resection with intrapericardial, separate processing of the vessels of the lung root. After the surgical stage, all patients received radiation therapy to the mediastinal area at a single tumour dose of 2 Gy and a total radiation dose of 45–50 Gy. According to an analysis of the mortality and survival rates, 28-day mortality comprised 5% (1 patient, whose death occurred as a result of acute cardiovascular failure); one-year survival rate was 91.6%.Conclusions. Preliminary results of our study show that selective chemotherapy via the bronchial artery increases the frequency of surgical interventions and the overall survival of patients with inoperable pulmonary cancer

Регионарная химиоинфузия в бронхиальную артерию в комбинированном лечении больных с немелкоклеточным раком легкого

Introduction. Chemotherapy in the form of endovascular infusion or its combination with radiotherapy is a method for treating non-small cell lung cancer (NSCLC), which raises heated discussions among specialists. This study is aimed at assessing the early results of combined treatment of NSCLC patients with selective chemotherapy infusion via the bronchial artery.Materials and methods. A retrospective analysis of treatment results for 24 patients with central pulmonary cancer hospitalized in the Shymkent Oncological Centre (Kazakhstan) during 2016–2019 was carried out. The average age of the patients was 46.4 ± 11.3 years. According to the histological study, 19 and 5 patients were diagnosed with squamous cell lung cancer and undifferentiated carcinoma, respectively. The patients were recognized as surgically incurable; three courses of neoadjuvant polychemotherapy via selective catheterization of the bronchial artery and regional intra-arterial administration of drugs were prescribed according to the DR scheme: Docetaxel 75 mg/m2 , Cisplatin 75 mg/m2 .Results and discussion. Upon completion of three courses of selective chemotherapy, 20 (83.3%) patients showed the possibility of surgical treatment: 15 patients underwent extended pulmonectomy, 5 patients underwent extendedcombined pulmonectomy with pericardial resection with intrapericardial, separate processing of the vessels of the lung root. After the surgical stage, all patients received radiation therapy to the mediastinal area at a single tumour dose of 2 Gy and a total radiation dose of 45–50 Gy. According to an analysis of the mortality and survival rates, 28-day mortality comprised 5% (1 patient, whose death occurred as a result of acute cardiovascular failure); one-year survival rate was 91.6%.Conclusions. Preliminary results of our study show that selective chemotherapy via the bronchial artery increases the frequency of surgical interventions and the overall survival of patients with inoperable pulmonary cancer. Введение. На сегодняшний день химиотерапия в виде эндоваскулярной химиоинфузии или комбинации с лучевой терапией является дискуссионным методом в лечении немелкоклеточного рака легкого (НМРЛ). В этой связи целью настоящего исследования является оценка ранних результатов комбинированного лечения пациентов с НМРЛ селективной химиоинфузией в бронхиальную артерию.Материалы и методы. На базе онкологического центра г. Шымкент (Казахстан) проведен ретроспективный анализ результатов лечения 24  пациентов с  центральным раком легкого, госпитализированных в  период 2016– 2019  гг. Средний возраст пациентов составил 46,4 ± 11,3  года. По  данным гистологического исследования, у 19 пациентов верифицирован плоскоклеточный рак легкого, у 5 пациентов — недифференцированная карцинома. Пациенты были признаны хирургически инкурабельны, было назначено по три курса неоадъювантной полихимиотерапии с селективной катетеризацией бронхиальной артерии и регионарным внутриартериальным введением препаратов по схеме DР: Доцетаксел 75 мг/м2 , Цисплатин 75 мг/м2 .Результаты и обсуждение. По окончании трех курсов селективной химиотерапии у 20 (83,3%) пациентов отмечена возможность хирургического лечения: 15 пациентам была выполнена расширенная пульмонэктомия, 5 пациентам — расширенно-комбинированная пульмонэктомия с резекцией перикарда с интраперикардиальной, раздельной обработкой сосудов корня легкого. После хирургического этапа все больные получили лучевую терапию на область средостения РОД 2 Грей, СОД 45–50 Грей. Анализ летальности и выживаемости демонстрирует, что 28‑суточная летальность составила 5% (1 пациент), смерть наступила в результате развития острой сердечно-сосудистой недостаточности; однолетняя выживаемость составила 91,6%.Заключение. Таким образом, предварительные результаты нашего исследование показали, что селективная химиотерапия в  бронхиальную артерию увеличивает частоту хирургических вмешательств и  общую выживаемость пациентов с неоперабельным раком легкого.

Characterizing CO and NO y Sources and Relative Ambient Ratios in the Baltimore Area Using Ambient Measurements and Source Attribution Modeling.

Modeled source attribution information from the Community Multiscale Air Quality model was coupled with ambient data from the 2011 Deriving Information on Surface conditions from Column and Vertically Resolved Observations Relevant to Air Quality Baltimore field study. We assess source contributions and evaluate the utility of using aircraft measured CO and NO y relationships to constrain emission inventories. We derive ambient and modeled ΔCO:ΔNO y ratios that have previously been interpreted to represent CO:NO y ratios in emissions from local sources. Modeled and measured ΔCO:ΔNO y are similar; however, measured ΔCO:ΔNO y has much more daily variability than modeled values. Sector-based tagging shows that regional transport, on-road gasoline vehicles, and nonroad equipment are the major contributors to modeled CO mixing ratios in the Baltimore area. In addition to those sources, on-road diesel vehicles, soil emissions, and power plants also contribute substantially to modeled NO y in the area. The sector mix is important because emitted CO:NO x ratios vary by several orders of magnitude among the emission sources. The model-predicted gasoline/diesel split remains constant across all measurement locations in this study. Comparison of ΔCO:ΔNO y to emitted CO:NO y is challenged by ambient and modeled evidence that free tropospheric entrainment, and atmospheric processing elevates ambient ΔCO:ΔNO y above emitted ratios. Specifically, modeled ΔCO:ΔNO y from tagged mobile source emissions is enhanced 5-50% above the emitted ratios at times and locations of aircraft measurements. We also find a correlation between ambient formaldehyde concentrations and measured ΔCO:ΔNO y suggesting that secondary CO formation plays a role in these elevated ratios. This analysis suggests that ambient urban daytime ΔCO:ΔNO y values are not reflective of emitted ratios from individual sources