Optimization of Turbine Rim Seals

Experiments are being conducted to gain an understanding of the physics of rim scale cavity ingestion in a turbine stage with the high-work, single-stage characteristics envisioned for Advanced Subsonic Transport (AST) aircraft gas turbine engines fo the early 21st century. Initial experimental measurements to be presented include time-averaged turbine rim cavity and main gas path static pressure measurements for rim seal coolant to main gas path mass flow ratios between 0 and 0.02. The ultimate objective of this work is develop improved rim seal design concepts for use in modern high-work, single sage turbines n order to minimize the use of secondary coolant flow. Toward this objective the time averaged and unsteady data to be obtained in these experiments will be used to 1) Quantify the impact of the rim cavity cooling air on the ingestion process. 2) Quantify the film cooling benefits of the rim cavity purge flow in the main gas path. 3) Quantify the impact of the cooling air on turbine efficiency. 4) Develop/evaluate both 3D CFD and analytical models of the ingestion/cooling process

GRADES: Gradient descent for similarity caching

A similarity cache can reply to a query for an object with similar objects stored locally. In some applications of similarity caches, queries and objects are naturally represented as points in a continuous space. Examples include 360° videos where user's head orientation - expressed in spherical coordinates - determines what part of the video needs to be retrieved, and recommendation systems where the objects are embedded in a finite-dimensional space with a distance metric to capture content dissimilarity. Existing similarity caching policies are simple modifications of classic policies like LRU, LFU, and qLRU and ignore the continuous nature of the space where objects are embedded. In this paper, we propose Grades, a new similarity caching policy that uses gradient descent to navigate the continuous space and find the optimal objects to store in the cache. We provide theoretical convergence guarantees and show Grades increases the similarity of the objects served by the cache in both applications mentioned above

GRADES: Gradient descent for similarity caching

International audienceA similarity cache can reply to a query for an object with similar objects stored locally. In some applications of similarity caches, queries and objects are naturally represented as points in a continuous space. Examples include 360° videos where user's head orientation-expressed in spherical coordinates determines what part of the video needs to be retrieved, and recommendation systems where the objects are embedded in a finite-dimensional space with a distance metric to capture content dissimilarity. Existing similarity caching policies are simple modifications of classic policies like LRU, LFU, and qLRU and ignore the continuous nature of the space where objects are embedded. In this paper, we propose GRADES, a new similarity caching policy that uses gradient descent to navigate the continuous space and find the optimal objects to store in the cache. We provide theoretical convergence guarantees and show GRADES increases the similarity of the objects served by the cache in both applications mentioned above

GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER⁺) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER⁺breast cancer cells</p> <p>Methods</p> <p>We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.</p> <p>Results</p> <p>GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.</p> <p>Conclusion</p> <p>Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER⁺breast cancer.</p

Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy

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The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival