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

The Authorial Sublime: Text and Apotheosis

By definition, the sublime is unknowable, and therefore similarly unachievable. This essay, however, challenges the notion of sublimity as unattainable by comparing the literary criti-cisms of Roland Barthes and Hélène Cixous. In comparing their works and analyzing the dual significance each puts on the importance of “audience” as contributor, the very transformative characteristic of the sublime becomes apparent in the author. Writing is an uncanny act, and reading becomes a reimagining of what constitutes the sublime for and within each person who engages with a text. Roland ’s famous “The Death of the Author” elevates the author to a perpet-ual liveliness when read in conjunction with Hélène Cixous’s concepts of self, text, and the Third Body, therefore transcending the author from death to sublimity, even as the author’s works forever incur the uncanny responses of their perpetually-shifting audience and contextualization. Writing, thus, acts as a way by which one may surpass the limits of independent humanity and achieve the status of sublime

Teacher Perceptions of Factors Influencing Their Self-Efficacy with Using One-to-One Technology During Literacy Instruction

Teacher perceptions of factors that influence their own self-efficacy with using one-to-one technology during literacy instruction were examined through a multi-site, multi-subject case study. An initial survey was administered to determine the self-efficacy level of a group of participants from a school district that was implementing a one-to-one technology initiative. From this initial data set, four participants with varying levels of self-efficacy were invited to participate in the second, qualitative, phase of the data collection process to better understand factors they perceived to influence these levels. Results revealed that teachers perceived their self-efficacy of one-to-one technology use during literacy instruction to be influenced by several factors including the overall value they assigned to technology and the level of technical and moral support they received. Common themes emerged that indicate more can be done to improve teachers’ self-efficacy with one-to-one technology use, which may in turn increase district’s return on their technology investment

Transition a Squadron to Microsoft Teams

Over the past six weeks, I have embarked on a quest to increase my squadron\u27s productivity by addressing continuity, communication, and file storage. The method by which I addressed these issues is by transitioning the squadron to Microsoft Teams. The transition to Teams required planning, as we have four major sections of the squadron, all working different shifts because we operate 24/7. It required creativity, not only because of the 24/7 ops but also because utilizing Teams was different from the traditional way in which we would solve these sorts of problems. It also required me to get out of my comfort zone. I am an instructor, so teaching others was easy, but I am not technologically inclined, so tackling a project about technology required me to push myself. The project was an overall success, with room for improvement and growth in the future. We have transitioned roughly 90% of the squadron to utilizing Microsoft Teams for their shops and teams. We have created an easy way to communicate with each other and track goals, tasks, and projects. Overwhelmingly, the people utilizing the new system agree that it is a good move and valuable

Synthesis and NMR characterization of new tert-Butyl thiosemicarbazone compounds and corresponding palladium complexes

This work shows the synthesis and characterization of a series of tert-Butyl thiosemicarbazone compounds, based on the 4-tert-Butyl-3-thiosemicarbazide substrate. The corresponding palladium complexes of this series of ligands were obtained via a reaction with Palladium(II) Chloride. After synthesis and purification, the 1H NMR and 13C NMR spectra were obtained using a 500 MHz NMR spectrometer. Experimental data was observed using 2D NMR techniques, such as, HSQC (hetero-nuclear single quantum coherence) 1H-13C NMR and HSQC 1H-15N NMR to give evidence for the structures of these new compounds

An Analysis And Application Of The Major Psychological Concepts For The Religious Educator-Counselor

Since most of the psychological literature has been written for the professional psychologists and it requires the acquisition and retention of an abundance of technical terms, it was felt that it was impractical for the religious educator-counselor to be encumbered with such a task who is not necessarily a professional