Functional analysis of arteriovenous fistulae in non-contrast magnetic resonance images.

BACKGROUND AND OBJECTIVE: Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis vascular access and their successful maturation is critical to reduce patient morbidity, mortality, cost, and improve quality of life. Peri-anastomotic venous segment stenosis is the primary cause of AVF maturation failure. The objective is to develop a software protocol for the functional analysis of arteriovenous fistula. METHOD: We have developed a standard protocol for the anatomical analysis of the AVF to better understand the mechanisms involved in AVF stenosis and to identify future imaging biomarkers for AVF success or failure using non-contrast magnetic resonance imaging (MRI). The 3D model of the AVF is created using a polar dynamic programming technique. Analysis has been performed on six Yorkshire cross domestic swine, but techniques can be applied into clinical settings. RESULTS: Differences in AVF angles and vein curvature are associated with significant variability of venous cross-sectional area. This suggests that the pattern of stenosis is likely to be dependent upon hemodynamic profiles which are largely determined by AVF anatomical features and could play an important role in AVF maturation. CONCLUSIONS: This protocol enables us to visualize and study the hemodynamic profiles indirectly allowing early stratification of patients into high and low risk groups for AVF maturation failure. High risk patients could then be targeted with an enhanced process of care or future maturation enhancing therapies resulting in a much-needed precision-medicine approach to dialysis vascular access.

Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

Automated High-Throughput Damage Scoring of Zebrafish Lateral Line Hair Cells After Ototoxin Exposure.

Zebrafish have emerged as a powerful biological system for drug development against hearing loss. Zebrafish hair cells, contained within neuromasts along the lateral line, can be damaged with exposure to ototoxins, and therefore, pre-exposure to potentially otoprotective compounds can be a means of identifying promising new drug candidates. Unfortunately, anatomical assays of hair cell damage are typically low-throughput and labor intensive, requiring trained experts to manually score hair cell damage in fluorescence or confocal images. To enhance throughput and consistency, our group has developed an automated damage-scoring algorithm based on machine-learning techniques that produce accurate damage scores, eliminate potential operator bias, provide more fidelity in determining damage scores that are between two levels, and deliver consistent results in a fraction of the time required for manual analysis. The system has been validated against trained experts using linear regression, hypothesis testing, and the Pearson's correlation coefficient. Furthermore, performance has been quantified by measuring mean absolute error for each image and the time taken to automatically compute damage scores. Coupling automated analysis of zebrafish hair cell damage to behavioral assays for ototoxicity produces a novel drug discovery platform for rapid translation of candidate drugs into preclinical mammalian models of hearing loss.

A Fully Automated High-Throughput Zebrafish Behavioral Ototoxicity Assay.

Zebrafish animal models lend themselves to behavioral assays that can facilitate rapid screening of ototoxic, otoprotective, and otoregenerative drugs. Structurally similar to human inner ear hair cells, the mechanosensory hair cells on their lateral line allow the zebrafish to sense water flow and orient head-to-current in a behavior called rheotaxis. This rheotaxis behavior deteriorates in a dose-dependent manner with increased exposure to the ototoxin cisplatin, thereby establishing itself as an excellent biomarker for anatomic damage to lateral line hair cells. Building on work by our group and others, we have built a new, fully automated high-throughput behavioral assay system that uses automated image analysis techniques to quantify rheotaxis behavior. This novel system consists of a custom-designed swimming apparatus and imaging system consisting of network-controlled Raspberry Pi microcomputers capturing infrared video. Automated analysis techniques detect individual zebrafish, compute their orientation, and quantify the rheotaxis behavior of a zebrafish test population, producing a powerful, high-throughput behavioral assay. Using our fully automated biological assay to test a standardized ototoxic dose of cisplatin against varying doses of compounds that protect or regenerate hair cells may facilitate rapid translation of candidate drugs into preclinical mammalian models of hearing loss.