3-ARYL-[1,2,4]TRIAZOLO[4,3-c]QUINAZOLINE DERIVATIVES: SYNTHESIS AND MODIFICATIONS

This work was supported by the Ministry of Science and Higher Education of Russian Federation, State Contract no FEUZ-2020-0058 (Н687.42Б.223/20)

SYNTHESIS OF (2-ARYLQUINAZOLIN-4-YL)HYDRAZONES OF 2-HYDROXYBENZALDEHYDES AS POTENTIAL PHOSPHOINOSITIDE 3-KINASE (IP3Kδ) AND CASEIN KINASE 2 (CK2) INHIBITORS

This work was supported by the Ministry of Science and Higher Education of Russian Federation, State Contract no FEUZ-2020-0058 (Н687.42Б.223/20)

2-AZINYL QUINAZOLINES: SYNTHESIS AND PHOTOPHYSICAL PROPERTIES

This work was supported by the Russian Scientific Foundation (project 22-23-00006)

The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma

The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care

Objectives of the Millimetron Space Observatory science program and technical capabilities of its realization

We present the scientific program of the Spectr-M project aimed at the creation and operation of the Millimetron Space Observatory (MSO) planned for launch in the late 2020s. The unique technical capabilities of the observatory will enable broadband observations of astronomical objects from 50 μm to 10 mm wavelengths with a record sensitivity (up to ~ 0.1 μJy) in the single-dish mode and with an unprecedented high angular resolution (~ 0.1 μas) in the ground-space very long baseline interferometer (SVLBI) regime. The program addresses fundamental priority issues of astrophysics and physics in general that can be solved only with the MSO capabilities: 1) the study of physical processes in the early Universe up to redshifts z ~ 2 × 106 through measuring μ-distortions of the cosmic microwave background (CMB) spectrum, and investigation of the structure and evolution of the Universe at redshifts z < 15 by measuring y-distortions of the CMB spectrum; 2) the investigation of the geometry of space-time around supermassive black holes (SMBHs) in the center of our Galaxy and M87 by imaging surrounding shadows, the study of plasma properties in the shadow formation regions, and the search for observational manifestations of wormholes; 3) the study of observational manifestations of the origin of life in the Universe - the search for water and biomarkers in the Galactic interstellar medium. Moreover, the technical capabilities of the MSO can help solve related problems, including the birth of the first galaxies and SMBHs (z ≳ 10), alternative approaches to measuring the Hubble constant, the physics of SMBHs in 'dusty' galactic nuclei, the study of protoplanetary disks and water transport in them, and the study of 'ocean worlds' in the Solar System

Gene therapy of mass pathologies

Описан комплекс исследований, которым позволяет пройти путь от идеи до экспериментального решения принципиальной возможности генной терапии массовых патологий, на примере инсулинзависимого сахарного диабета и атеросклероза. Произведен подбор и анализ регуляторных элементов, которые позволяют осуществлять экспрессию экзогенных генов независимо от состояния общей клеточной регуляции . На клетках различных тканей и организмов, а также in vivo показано экспрессию генетического материала , вводимого (как модельного гена бактериальной β-галактозидазы, так и генов инсулина и аполипопротеина высокой плотности Al, которые имеют отношение к вышеупомянутым патологий ) . Отмечено неправомерность экстраполяции результатов, полученных в культуре клеток, на животных; показано неоднозначность экспрессии рекомбинантных молекул в зависимости от генного окружения и типа клеток реципиентов. Как в культуре клеток, так и в организму обнаружено индивидуально– клеточную гетерогенность количественных характеристик экспрессии : введенного извне гена. Кроме того, отмечено индивидуально – организменном и возрастную гетерогенность экспрессии экзогенной информации. Сделан вывод о необходимости индивидуализации генной терапии массовых патологов .Описано комплекс досліджень, яким дозволяє пройти шлях від ідеї до експериментального вирішення принципової можливості генної терапії масових патологій, на прикладі інсулінзалежного цукрового діабету та атеросклерозу. Зроблено добір та аналіз регуляторних елементів, які дозволяють здійснювати експресію екзогенних генів незалежно від стану загальної клітинної регуляції. На клітинах різних тканин та організмів, а також in vivo показано експресію генетичного матеріалу, що вводиться (як модельного гена бактеріальної β-галактозидази, так і генів інсуліну та аполіпопротеїну високої щільності Al, які мають відношення до вищезгаданих патологїй). Відзначено неправомірність екстраполяції результатів, отриманих в культурі клітин, на тварин; показано неоднозначність експресії рекомбінантних молекул залежно від генного оточення і типу клітин реципієнтів. Як в культурі клітин, так і в організмові виявлено індивідуально-клітинну гетерогенність кількісних характеристик експресі: введеного ззовні гена. Крім того, відзначено індивідуально-організмову та вікову гетерогенність експресії екзогенної інформації. Зроблено висновок про необхідність індивідуалізації генної терапії масових патологів.The whole complex of investigations is described that allows to run the way from the idea to experimental realization of a fundamental possibility of gene therapy and its application to mass pathologies on the sample of insulin-dependent diabetes and atherosclerosis. The search and analysis were performed of such regulatory elements that would permit an expression irrespective of the state of a general cell regulation. Expression of the implanted gene material is shown on cells of different tissues and different organisms and also in vivo (both the model gene of β-galactosidase Escherichia coli and insulin- and apolipoprotein high density Al-coding genes related to above stated pathologies). It is concluded that the results obtained in the culture outside the organisms shouldn't be extrapolated on the animals, i. e. on the organism's level. The expression of recombinant molecules is shown to be ambiguous and depend on gene's surroundings and the type of recipient cells. Both in the culture and in the organism the individual cell heterogeneity is observed in the quantitative characteristics of the expression of gene implanted from outside. Besides, an individual organism and age heterogeneity with regard to the expression of the exogenous gene is reported. The conclusion is made about the necessity to individualize gene therapy of mass pathologies

Measurement of associated charm production induced by 400 GeV/c protons

An important input for the interpretation of the measurements of the SHiP ex- periment is a good knowledge of the differential charm production cross section, including cascade production. This is a proposal to measure the associated charm production cross section, employing the SPS 400 GeV/c proton beam and a replica of the first two interaction lengths of the SHiP target. The detection of the produc- tion and decay of charmed hadron in the target will be performed through nuclear emulsion films, employed in an Emulsion Cloud Chamber target structure. In order to measure charge and momentum of decay daughters, we intend to build a mag- netic spectrometer using silicon pixel, scintillating fibre and drift tube detectors. A muon tagger will be built using RPCs. An optimization run is scheduled in 2018, while the full measurement will be performed after the second LHC Long Shutdown

Objectives of the Millimetron Space Observatory Science Program and Technical Capabilities of Its Realization

We present the scientific program of the Spectr-M project aimed at the creation and operation of the Millimetron Space Observatory (MSO) planned for launch in the late 2020s. The unique technical capabilities of the observatory will enable broadband observations of astronomical objects from 50 μm to 10 mm wavelengths with a record sensitivity (up to ∼0.1 μJy) in the single-dish mode and with an unprecedented high angular resolution (∼0.1 μas) in the ground-space very long baseline interferometer (SVLBI) regime. The program addresses fundamental priority issues of astrophysics and physics in general that can be solved only with the MSO capabilities: 1) the study of physical processes in the early Universe up to redshifts z ∼ 2 106 through measuring μ-distortions of the cosmic microwave background (CMB) spectrum, and investigation of the structure and evolution of the Universe at redshifts z<15 by measuring y-distortions of the CMB spectrum; 2) the investigation of the geometry of space-time around supermassive black holes (SMBHs) in the center of our Galaxy and M87 by imaging surrounding shadows, the study of plasma properties in the shadow formation regions, and the search for observational manifestations of wormholes; 3) the study of observational manifestations of the origin of life in the Universe - the search for water and biomarkers in the Galactic interstellar medium. Moreover, the technical capabilities of the MSO can help solve related problems, including the birth of the first galaxies and SMBHs (z ⪆ 10), alternative approaches to measuring the Hubble constant, the physics of SMBHs in 'dusty' galactic nuclei, the study of protoplanetary disks and water transport in them, and the study of 'ocean worlds' in the Solar System. © 2021 Uspekhi Fizicheskikh Nauk, Russian Academy of Sciences and IOP Publishing.We appreciate the referees for their critical notes.Thestudy was partially supported by the project New Scientific Groups of LPI, no. 41-2020. AP thanks the RSF for its support (project 19-72-00064). AB is supported by RSF grant 18-12-00351 and by the State Target FEUZ-2020-0038. The work by IZ (Section 4) is supported by RFBR grant 18-02-00660. DV was supported by a grant from the Russian Government and Ministry of Higher Education and Science, 075-15-2020-780 (no. 13.1902.21.0039). The work by VSh (Section 4.4) was supported by a grant from the Russian Government for research by leading scientists under the program Studies of Stars with Exoplanets (agreement 075-15-2019-1875)

ICAR: endoscopic skull‐base surgery

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