PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma.

BackgroundLeiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth.MethodsLMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds. The top 10 % of hits underwent secondary validation to determine their EC50 and immunoblots were performed to confirm selective drug action. The efficacy of combination drug therapy with doxorubicin (Dox) in vitro was analyzed using the Calcusyn program after treatment with one of three dosing schedules: concurrent treatment, initial treatment with a selective compound followed by Dox, or initial treatment with Dox followed by the selective compound. Single and combination drug therapy were then validated in vivo using LMS xenografts.ResultsCompounds that targeted PI3K/AKT/mTOR pathways (52 %) were most effective. EC50s were determined to validate these initial hits, and of the 11 confirmed hits, 10 targeted PI3K and/or mTOR pathways with EC50 values <1 μM. We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro. Immunoblots confirmed on-target effects of these compounds in the PI3K and/or mTOR pathways. We next investigated if there was synergy with these agents and first line chemotherapy doxorubicin (Dox), which would allow for earlier introduction into patient care. Only combined treatment of BEZ235 and Dox was synergistic in vitro. To validate these findings in pre-clinical models, leiomyosarcoma xenografts were treated with single agent and combination therapy. BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone.ConclusionsIn summary, this study supports further investigation into the use of PI3K and mTOR inhibitors alone and in combination with standard treatment in leiomyosarcoma patients

Part 3. A Novel Stereocontrolled, In Situ, Solution- and Solid-Phase, Aza Michael Approach for High-Throughput Generation of Tetrahydroaminoquinoline-Derived Natural-Product-like Architectures

With the goal of rapidly accessing tetrahydroquinoline-based natural-product-like polycyclic architectures, herein, we report an unprecedented, in situ, stereocontrolled Aza Michael approach in solution and on the solid phase. The mild reaction conditions required to reach the desired target are highly attractive for the use of this method in library generation. To our knowledge, this approach has not been used before, and it opens a novel route leading to a wide variety of tetrahydroquinoline-derived bridged tricyclic derivatives.NRC publication: Ye

Part 1. Modular Approach to Obtaining Diverse Tetrahydroquinoline-Derived Polycyclic Skeletons for Use in High-Throughput Generation of Natural-Product-like Chemical Probes

A practical synthesis of a tetrahydroaminoquinoline scaffold (12) was developed that used a stereocontrolled aza Michael as the key reaction. Three tetrahydroquinoline alkaloid-like, tricyclic derivatives 16, 18, and 19 with different medium to macrocyclic ring skeletons were obtained, using this scaffold as the starting material, in a modular manner. The macrocyclic compounds with an isolated olefin and an electron-deficient olefin were obtained by ring-closing metathesis approaches. Compounds 16 and 18 are unique and contain bridged 10- and 12-membered functionalized rings. The NMR studies of these compounds revealed interesting information on the conformation of the bicyclic scaffolds that was dependent on the nature and the size of the macrocyclic rings. Finally, this modular methodology, using compound 21 anchored onto the solid support, successfully led to the generation of different macrocyclic derivatives, 23, 25, and 27 in solid-phase synthesis. The solid-phase synthesis approach outlined in this article has the potential to generate tetrahydroquinolinebased tricyclic compounds containing different medium to macrocyclic architectures.NRC publication: Ye

Fluorinated musk fragrances : the CF2 group as a conformational bias influencing the odour of civetone and (R)-muscone

This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC). The authors acknowledge the EPSRC National Mass Spectrometry Facility (Swansea). M.Y. thanks the China Scholarship Council for financial support. D.O'H. thanks the Royal Society for a Wolfson Research Merit Award.The difluoromethylene (CF2) group has a strong tendency to adopt corner over edge locations in aliphatic macrocycles. In this study, the CF2 group has been introduced into musk relevant macrocyclic ketones. Nine civetone and five muscone analogues have been prepared by synthesis for structure and odour comparisons. X-ray studies indeed show that the CF2 groups influence ring structure and they give some insight into the preferred ring conformations, triggering a musk odour as determined in a professional perfumery environment. The historical conformational model of Bersuker and co-workers for musk fragrance generally holds, and structures that become distorted from this consensus, by the particular placement of the CF2 groups, lose their musk fragrance and become less pleasant.PostprintPeer reviewe

Environmental data logger

Tato bakalářská práce se zabývá návrhem a realizací záznamníku stavu prostředí pro vnitřní prostory a ukládání dat, které záznamník produkuje. Teoretická část se zaměřuje na popis internetu věcí (IoT), teorie k rozhraní I2C a dále na popis čidel a výběru desky pro dané řešení. V praktické části je popsán kód.This bachelor thesis focuses on design and realization of environmental data logger for indoor use. The theoretical section focuses on Internet of Things (IoT), theory of I2C bus, description of sensors and choice of a board for this implementation. Practical section of the thesis describes the code.Fakulta elektrotechniky a informatikyLogická i stylistická úroveň práce jsou na velmi dobré úrovni a odpovídají standardům bakalářské práce. Dle vedoucího práce student pracoval velmi systematicky, provedl velmi dobrý rozbor problematiky před jejím řešením, čímž si byl schopen vybrat pro sebe vyhovující a kvalitní řešení. Student dobře reagoval na dotazy komise. Komise navrhuje práci na ocenění za vynikající tvůrčí výsledky dle článku 3, písm. b) Stipendijního řádu Univerzity Pardubice.Dokončená práce s úspěšnou obhajobo

Antenna radiation pattern measurement system using UAV

Tato diplomová práce se zabývá návrhem, realizací a testováním aparatury pro měření vyzařovacích charakteristik antén ve vzdálené zóně s použitím bezpilotního prostředku kategorie mikro-UAV. Práce obsahuje teorii k měření antén, pravidla letového provozu mikro-UAV, chyby působící na měření, návrh zařízení, popis vytvořených programů, ukázku měření a výsledků.This master thesis focuses on the design, implementation, and testing of a micro-UAV unmanned vehicle based far field antenna test range measuring equipment. Theses covers antenna measurement theory, impact of micro-UAV flight rules, errors impact on measurement, equipment design, custom software description, proof of concept test results.Fakulta elektrotechniky a informatikyDiplomová práce se zabývá návrhem systému pro měření vyzařovacích charakteristik antén ve vzdálené zóně s použitím bezpilotního prostředku kategorie mikro UAV. Cíle diplomové práce byly naplněny, vznikl měřicí systém schopný provádět měření anténních systémů ve vzdálené zóně. Systém je schopen kromě samotného měření parametrů antén vyhodnotit nebo s použitím opakovaných měření v různých vzdálenostech značně eliminovat vliv prostředí. Systém má i potenciál dalšího rozvoje pro hodnocení reálného chování složitých radiotechnických systémů v provozu. Cíle diplomové práce byly splněny.Dokončená práce s úspěšnou obhajobo