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

One Voice, Ancient and Resigned

While we know, or at least can imagine, what Gower looked like in his old age, it is hard to imagine or hear his voice. And yet, given what we know about his old age and visual impairments, his voice necessarily was important to his old age and continuing revisions of his texts. In this article, I attempt to reconstruct from some of his later poetry what that voice might have sounded like, at least in-text, and piece together how later authors heard that voice of old age

Women in the Sphere of Masculinity: The Double-Edged Sword of Women’s Integration in the Military

Too many women together are not a good thing anywhere, especially not in the military.2 Noa is one of numerous women who have managed to cross traditional gender lines in the Israeli military in the last decade, assigned to positions that typically had been reserved for men.3 The inclusion of those women in traditional masculine spheres was the result of legal changes initiated by women and feminist groups in the 1990s.4 Those changes were designed to promote greater gender equality in the military by opening prestigious combat units to women soldiers.5 Hence, Noa and all other women whose military experiences were documented in the film Company Jasmine were all facilitators of this vision of gender equality. For some women, having the equal opportunity to serve as their male counterparts proves to be a meaningful experience that raises their confidence and allows for individual achievements in areas traditionally inaccessible to women.11 This article focuses on these seemingly contradictory findings regarding women\u27s growing integration in the military, using the Israeli experience of gender integration in the IDF as a case study for exploring the ongoing feminist debate on women\u27s military service

Spartan Daily, May 10, 2007

Volume 128, Issue 56https://scholarworks.sjsu.edu/spartandaily/10370/thumbnail.jp

Regulated Intramembrane Proteolysis of the Virulence Activator TCPP in Vibrio cholerae.

In Vibrio cholerae, direct activation of genes that encode cholera toxin (CT) and toxin-coregulated pilus (TCP) requires the ToxT transcription activator, whose expression is regulated by a complex of membrane regulatory proteins including ToxR and TcpP. TcpP, with a cytoplasmic domain similar to that found in OmpR and a periplasmic domain that may respond to specific environmental signals, is degraded in a two-step proteolytic pathway known as regulated intramembrane proteolysis (RIP), which eliminates the expression of CT and TCP. Under specific conditions, degradation is inhibited by another membrane-bound periplasmic protein, TcpH. I applied forward and reverse genetic approaches to determine the site-1 protease of TcpP. Through these analyses, I found that a C-terminal protease called Tsp catalyzes TcpP degradation to a truncated yet still active species that we termed TcpP*, which is the substrate for the previously identified site-2 protease, YaeL. Moreover, my results indicate a role of TcpH in protecting full-length TcpP from spurious degradation by YaeL. I investigate the possibility of RIP regulating steady-state levels of TcpH and present evidence that TcpP confers stability to TcpH. Furthermore, in vivo studies in infant mice suggest that YaeL, but not Tsp, is required for intestinal colonization. These results expand our knowledge about RIP and the unorthodox mechanism of gene activation by membrane-bound transcription factors.PhDMicrobiology and ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113400/1/teoh_1.pd

The Elephant in the Room and Me

Panel: Writing in a Culture in Conflic