ABT-737 promotes tBid mitochondrial accumulation to enhance TRAIL-induced apoptosis in glioblastoma cells

To search for novel strategies to enhance the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis pathways in glioblastoma, we used the B-cell lymphoma 2/Bcl2-like 2-inhibitor ABT-737. Here we report that ABT-737 and TRAIL cooperate to induce apoptosis in several glioblastoma cell lines in a highly synergistic manner (combination index <0.1). Interestingly, the concerted action of ABT-737 and TRAIL to trigger the accumulation of truncated Bid (tBid) at mitochondrial membranes is identified as a key underlying mechanism. ABT-737 and TRAIL cooperate to cleave BH3-interacting domain death agonist (Bid) into its active fragment tBid, leading to increased accumulation of tBid at mitochondrial membranes. Coinciding with tBid accumulation, the activation of Bcl2-associated X protein (Bax), loss of mitochondrial membrane potential, release of cytochrome-c and second mitochondria-derived activator of caspase (Smac) into the cytosol and caspase activation are strongly increased in cotreated cells. Of note, knockdown of Bid significantly decreases ABT-737- and TRAIL-mediated Bax activation and apoptosis. Also, caspase-3 silencing reduces ABT-737- and TRAIL-induced Bid cleavage and apoptosis, indicating that a caspase-3-driven, mitochondrial feedback loop contributes to Bid processing. Importantly, ABT-737 profoundly enhances TRAIL-triggered apoptosis in primary cultured glioblastoma cells derived from tumor material, underlining the clinical relevance. Also, ABT-737 acts in concert with TRAIL to suppress tumor growth in an in vivo glioblastoma model. In conclusion, the rational combination of ABT-737 and TRAIL cooperates to trigger tBid mitochondrial accumulation and apoptosis. This approach presents a promising strategy for targeting the apoptosis pathways in glioblastoma, which warrants further investigation

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

The Economic Impact of the Iraq War and Higher Military Spending

In order to get an approximation of the economic impact of the increase in U.S. military spending associated with the wars in Iraq and Afghanistan, CEPR commissioned the economic forecasting company Global Insight to run a simulation with its macroeconomic model. It produced a simulation of the impact of an increase in annual U.S. military spending equal to 1 percent of GDP, approximately the actual increase in spending compared with the pre-war budget. Global Insight's simulation shows higher military spending raises interest rates, which reduces net exports, housing construction and car sales, thereby slowing the economy and job creation

Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas

Platinum drug-resistance in ovarian cancers is a major factor contributing to chemotherapeutic resistance of recurrent disease. Members of the Bcl-2 family such as the anti-apoptotic protein Bcl-XL have been shown to play a role in this resistance. Consequently, concurrent inhibition of Bcl-XL in combination with standard chemotherapy may improve treatment outcomes for ovarian cancer patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-XL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo\ud experimental data, wherein tumor xenografts were established in mice and treated with ABT-737 and carboplatin on a fixed periodic schedule, alone or in combination, and tumor sizes recorded regularly. We show that the validated model can be used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the time of infusion of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin administered each week combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. We also investigate the potential of ABT-737 co-therapy with carboplatin to prevent or delay the onset of carboplatin-resistance under two scenarios. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, the model is used to identify drug delivery schedules that induce tumor remission with even low doses of combination therapy. When resistance is intrinsic, due to a pre-existing cohort of resistant cells, tumor remission is no longer feasible, but our model can be used to identify dosing strategies that extend disease-free survival periods. These results underscore the potential of our model to accelerate the development of novel therapeutics such as ABT-737, by predicting optimal treatment strategies when these drugs are given in combination with currently approved cancer medications

Experimental determination of position-estimate accuracy using back-azimuth signals from a microwave landing system

Flight tests using the Boeing 737 airplane to obtain position estimates with back azimuth signals from a microwave landing system (MLS) are discussed. The equations and logic used to generate a navigation position estimate in the MLS back azimuth signal environment are described. The error in the navigation position estimate is determined. A summary of the Boeing 737 position estimate update process is described. The navigation position estimate error calculated flight data and radar tracking information is analyzed. The position estimate error data using the MLS inputs are compared with error data obtained during dual distance measuring equipment updates

Pictorial Socratic dialogue and conceptual change

Counter-examples used in a Socratic dialogue aim to provoke reflection to effect conceptual changes. However, natural language forms of Socratic dialogues have their limitations. To address this problem, we propose an alternative form of Socratic dialogue called the pictorial Socratic dialogue. A Spring Balance System has been designed to provide a platform for the investigation of the effects of this pedagogy on conceptual changes. This system allows learners to run and observe an experiment. Qualitative Cartesian graphs are employed for learners to represent their solutions. Indirect and intelligent feedback is prescribed through two approaches in the pictorial Socratic dialogue which aim to provoke learners probe through the perceptual structural features of the problem and solution, into the deeper level of the simulation where Archimedes’ Principle governs

General discussion [Experiments on ion-pair formation in gas-phase polyatomic molecules]

A brief summary of experiments on ion-pair formation in gas-phase polyatomic molecules

Practice-based doctorates and questions of academic legitimacy

Over the last six years there has been a massive increase in the number of students studying for practice-based doctorates in Art and Design. It is now possible to do a practice-based PhD in over forty departments, although what is expected from doctoral students varies considerably across institutions. In 1997 the United Kingdom Council for Graduate Education (UKCGE) addressed the variance between practice-based doctorates in the report Practice-Based Doctorates in the Creative and Performing Arts and Design. This paper examines the recommendations made by the report and asks to what extent does it acknowledge art as a legitimate research practice within the university. The UKCGE report recommends that all practice-based PhDs have a substantial theoretical and contextualising element that will demonstrate general scholarly requirements and render the artwork accessible to judgement. I argue that this proposal is problematic on several counts; it draws a firm line between theory and practice, places academic research in opposition to practice generally and artwork specifically, maintains the stereotype of art as anti-intellectual and forgets the degree to which theory is itself a practice. In addition it suggests that art practice can only be legitimised as research when it is framed by a conventionally academic enquiry. I suggest that instead of trying to make art practice fit academic regulations it would be more productive to use the practice-based PhDs as a way of re-thinking academic conventions and scholarly requirements

A high resolution scheme for flows in open channels with arbitrary cross-section

The aim of this paper is to present a numerical scheme to simulate unsteady, one dimensional flows in open channels with arbitrary cross-section. This scheme is fully conservative of volume and momentum and preserves the non-negativity of the water depth. The finite difference method derived is semi-implicit in time and based on a space staggered grid. A high resolution technique, the flux limiter method, is implemented to control the accuracy of the proposed scheme. Our purpose is to achieve the precision and the stability of the method with respect to the regularity of the data. A few computational examples on classical test cases are given to illustrate the properties of the present method in terms of stability, accuracy and efficiency

Full-scale testing, production and cost analysis data for the advanced composite stabilizer for Boeing 737 aircraft, volume 2

The development, testing, production activities, and associated costs that were required to produce five-and-one-half advanced-composite stabilizer shipsets for Boeing 737 aircraft are defined and discussed