Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.

Highlights d Parthenolide covalently reacts with C427 of FAK1 to inhibit FAK1 activity d Parthenolide impairs FAK1 signaling in breast cancer cells d Other sesquiterpene lactone natural products also target FAK1

Parthenolide, a natural product from the feverfew plant and member of the large family of sesquiterpene lactones, exerts multiple biological and therapeutic activities including anti-inflammatory and anti-cancer effects. Herein, we further study parthenolide mechanism of action using activity-based protein profiling (ABPP)-based chemoproteomic platforms to map additional covalent targets engaged by parthenolide in human breast cancer cells. We find that parthenolide, as well as other related exocyclic methylene lactonecontaining sesquiterpenes, covalently modify cysteine 427 (C427) of focal adhesion kinase 1 (FAK1) leading to impairment of FAK1-dependent signaling pathways and breast cancer cell proliferation, survival, and motility.These studies reveal a novel functional target exploited by members of a large family of anticancer natural products.

Introduction: Emboli events are associated with the aortic cannula insertion and final position in the ascending aorta. However, the impact of subtle changes in aortic cannula movement and flow influencing embolic transport throughout the aortic arch is not well understood. The present study evaluated the aortic cannula’s outflow and orientation effect on emboli entering the aortic branch arteries. Methods: A simplified aortic computational model was anteriorly cannulated in the distal ascending aorta with a 21-French straight aortic cannula, and two orientations were analysed by injecting gaseous and solid emboli at pump flows 2, 3 and 5 L/minute. The first aortic cannula orientation (forward flow cannula) was directed towards the lesser curvature. The second aortic cannula orientation (rear flow cannula) was tilted slightly backwards by 15°, providing flow in the retrograde direction. Results: Forward flow cannula produced a primary arch flow, whereas rear flow cannula produced a secondary arch flow resulting in four times longer emboli arch resident times than forward flow cannula. The rear flow cannula had the highest percentage of gaseous emboli entering the brachiocephalic artery of 8%, 12% and 36% (at 2, 3 and 5 L/minute, respectively). Rear flow cannula provided a positive aortic branch arterial flow at all pump flows, whereas at forward flow cannula, the brachiocephalic artery experienced retrograde flows of −1.0% (3 L/minute) and −4.0% (5 L/minute), with the left common carotid −0.23% (5 L/minute). No significant number of solid emboli entered the aortic branch arteries. Conclusion: This numerical study illustrated distinct trajectory behaviours between gaseous and solid emboli where slight changes in aortic cannula orientation influenced idealised emboli direction with higher pump flows magnifying the effects.