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Next generation thiazolyl ketone inhibitors of cytosolic phospholipase A2 α for targeted cancer therapy
Abstract Eicosanoids are key players in inflammatory diseases and cancer. Targeting their production by inhibiting Group IVA cytosolic phospholipase A 2 (cPLA 2 α) offers a promising approach for cancer therapy. In this study, we synthesize a second generation of thiazolyl ketone inhibitors of cPLA 2 α starting with compound GK470 (AVX235) and test their in vitro and cellular activities. We identify a more potent and selective lead molecule, GK420 (AVX420), which we test in parallel with AVX235 and a structurally unrelated compound, AVX002 for inhibition of cell viability across a panel of cancer cell lines. From this, we show that activity of polycomb group repressive complex 2 is a key molecular determinant of sensitivity to cPLA 2 α inhibition, while resistance depends on antioxidant response pathways. Consistent with these results, we show that elevated intracellular reactive oxygen species and activating transcription factor 4 target gene expression precede cell death in AVX420-sensitive T-cell acute lymphoblastic leukemia cells. Our findings imply cPLA 2 α may support cancer by mitigating oxidative stress and inhibiting tumor suppressor expression and suggest that AVX420 has potential for treating acute leukemias and other cancers that are susceptible to oxidative cell death.
NEJM at ESC — Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy
Increased diagnosis of hepato-biliary-pancreatic cancer after cholecystectomy: a population-based study
Comparing C3, 4, and 5 nerve root block and interscalene with intermediate cervical plexus block in diaphragmatic motion for clavicle surgery
Microstructure and mechanical properties of highly porous Hastelloy-X nickel superalloy produced by a space holder approach
Abstract Highly porous nickel-based superalloys appear as attractive candidates to be applied e.g. as seals in gas turbine engines instead of honeycomb structures. Among various methods of producing open-porous materials, a space holder approach provides number of benefits regarding economic and ecological aspects of production. In this work, the pioneering results of microstructure and mechanical properties analyses of highly porous Hastelloy-X nickel superalloy produced by the space holder approach, are presented. The materials were fabricated by using spherical fine Hastelloy-X powders and carbamide particles as batch materials. A multi-step powder metallurgy and thermomechanical processing was applied to produce open porous samples having a total volumetric porosity of 50, 60 and 70%. The produced materials were subjected to non-destructive (X-ray computed tomography) and metallographic inspections. Mechanical properties of the porous Hastelloy-X samples were examined in static room temperature compression tests, to discuss the effect of obtained porosity on compressive response.