The SMAC mimetic LCL-161 selectively targets JAK2V617F mutant cells.

Background:Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo. Methods:To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2V617F-driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2V617F-driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis. Results:We found that JAK2V617F-mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2V617F-mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2V617F-driven MPN. Conclusion:LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN

The role of surface completion on the convexity context effect

In order to represent and interact with our environment, the visual system has to perceptually organize the retinal image into potential objects and their spatial relations. One aspect of perceptual organization is figure-ground segregation, the process of identifying which parts of a scene are figure and which are background. One tendency is for the visual system to assign convex regions as figure and concave regions as ground. Recently, this convexity bias was discovered to increase when the number of repeating figure-ground regions increases. It has been hypothesized that this convexity context effect (CCE) is caused by observers perceptually completing the concave regions into a single background behind the convex figures. If true, then the CCE should occur even when regions are made discontinuous by another surface that partially occludes them but should not occur when regions are discontinuous with no occluding surface to explain the discontinuity. The results of my project partially confirm these predictions in that partially occluded displays produced an equal magnitude CCE as unoccluded displays. However, discontinuous displays without an occluding surface also produced an equal magnitude CCE as unoccluded contiguous displays. Follow-up experiments will address this failure of our control condition

Women Rising from the Depths of Congolese History: The Mobilization and Politicization of the Women of the Congo

No abstract provided

DETERMINATION OF A FREE-PISTON STIRLING ENGINE-GENERATOR OPERATING CURVE FOR APPLICATIONS IN ENERGY EXTRACTION

Renewable energy generation faces challenges in energy storage, particularly in providing sustained load management between periods of excess generation, peak demand, and intermittency. Clean and dependable energy storage methods exist, but the need for higher efficiency energy extraction motivates the search for sophisticated methods. One such method is a Liquid Air Energy Storage (LAES) system paired with a Stirling engine. This thesis investigated the power output of a particular Free-Piston Stirling Engine-Generator (FPSEG) for potential use in energy extraction from the aforementioned system to power an islanded microgrid. A full FPSEG testing apparatus was constructed and several heating conditions were tested to obtain an operating curve for the studied FPSEG. Additionally, a basic numerical model was developed for the FPSEG working fluid. Data from these experiments were evaluated to show potential coupling capabilities with a LAES system.Office of Naval Research, Arlington, VA 2203-1995Ensign, United States NavyApproved for public release. Distribution is unlimited