Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.

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Magnetic resonance imaging (MRI) provides images for estimating fetal volume and weight, but manual delineations are time consuming. The aims were to (1) validate an algorithm to automatically quantify fetal volume by MRI; (2) compare fetal weight by Hadlock’s formulas to that of MRI; and (3) quantify fetal blood flow and index flow to fetal weight by MRI. Forty-two fetuses at 36 (29–39) weeks gestation underwent MRI. A neural network was trained to segment the fetus, with 20 datasets for training and validation, and 22 for testing. Hadlock’s formulas 1–4 with biometric parameters from MRI were compared with weight by MRI. Blood flow was measured using phase-contrast MRI and indexed to fetal weight. Bland–Altman analysis assessed the agreement between automatic and manual fetal segmentation and the agreement between Hadlock’s formulas and fetal segmentation for fetal weight. Bias and 95% limits of agreement were for automatic versus manual measurements 4.5 ± 351 ml (0.01% ± 11%), and for Hadlock 1–4 vs MRI 108 ± 435 g (3% ± 14%), 211 ± 468 g (7% ± 15%), 106 ± 425 g (4% ± 14%), and 179 ± 472 g (6% ± 15%), respectively. Umbilical venous flow was 406 (range 151–650) ml/min (indexed 162 (range 52–220) ml/min/kg), and descending aortic flow was 763 (range 481–1160) ml/min (indexed 276 (range 189–386) ml/min/kg). The automatic method showed good agreement with manual measurements and saves considerable analysis time. Hadlock 1–4 generally agree with MRI. This study also illustrates the confounding effects of fetal weight on absolute blood flow, and emphasizes the benefit of indexed measurements for physiological assessment.