Power, Nicholas Edgar

ABSTRACT Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster, an emerging model for kidney stone disease research, was adapted as a high-throughput functional drug screening platform independent of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high-performance liquid chromatography and atomic force microscopy, arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. When used to treat patient urine samples, arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions, owing to its oxalate-centric mode of action. The discovery of this novel antilithogenic compound via D. melanogaster, independent of a mammalian model, brings greater recognition to this platform, for which metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high-throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen. This article has an associated First Person interview with the first authors of the paper.

During contrast-enhanced ultrasound (CEUS) imaging of tumor microvascular perfusion, nearby arteriole enhancement can be a dominant feature of the wash-in kinetics that obscures the perfusion characteristics of the capillary bed. This presentation demonstrates that statistical wash-in curves generated using our compound CEUS speckle model1 exhibit two distinct phases corresponding to “fast-flow” and “slow-flow” enhancement that can be detected by fitting a linear combination of two monoexponential functions with different time constants. CEUS cine loops were acquired from a patient-derived xenograft model of renal cell carcinoma, where fresh tumor fragments were engrafted into the chicken embryo chorioallantoic membrane. Subharmonic CEUS images were acquired at 18 MHz using a destruction-replenishment protocol. Enhancement of manually segmented tumor cross-sections was analyzed offline in MATLAB. The CEUS cine loops from this xenograft model frequently exhibited in-plane arteriole enhancement. The two-phase fit discriminated a slow-flow component in 26.6% of time-intensity wash-in curves and 62.9% of the statistical wash-in curves, leading to a decrease in estimated tumor blood volume by 22.1% and 24.7%, respectively, compared to a simple monoexponential fit. These results suggest that conventional CEUS processing may frequently overestimate capillary blood volume. 1M.R. Lowerison et al., Med. Phys. 44, 99-111 (2017).