Existing models of aortic stenosis (AS) are limited to inducing left ventricular pressure overload. As they have reduced control over the severity of aortic constriction, the clinical relevance of these models is largely hindered by their inability to mimic AS hemodynamics and recapitulate ow patterns associated with congenital valve defects, responsible for the accelerated onset and progression of AS. Here we report the development of a highly tunable bio-inspired soft robotic tool that enables the recapitulation of AS in a porcine model, in which customization of actuation patterns allows hemodynamic mimicry of AS and congenital aortic valve defects. In vitro and computational tools including lumped-parameter, nite element, and computational uid dynamics platforms were developed to predict the hemodynamics induced by the bio-inspired soft robotic sleeve. The controllability of our in vivo model and its ability to replicate ow patterns of AS and congenital defects were demonstrated in swine through echocardiography, left ventricular catheterization, and magnetic resonance imaging. This work supports the use of soft robotics to simulate human physiology and disease, while paving the way towards the development of patient-speci c models of AS and congenital defects that can guide clinical decisions to improve the management and treatment of these patients.
Background Late gadolinium enhancement cardiac magnetic resonance imaging is an effective and reproducible method for characterizing myocardial infarction. However, gadolinium‐based contrast agents are contraindicated in patients with acute and chronic renal insufficiency. In addition, several recent studies have noted tissue deposition of free gadolinium in patients who have undergone serial contrast‐enhanced magnetic resonance imaging. There is a clinical need for alternative forms of magnetic resonance imaging contrast agents that are acceptable in the setting of renal insufficiency. Methods and Results Three days after 80 minutes of ischemia/reperfusion of the left anterior descending coronary artery, cardiac magnetic resonance imaging was performed to assess myocardial lesion burden using both contrast agents. Late gadolinium enhancement cardiac magnetic resonance imaging was examined 10 and 15 minutes after contrast injection. Contrast agents were administered in alternating manner with a 2‐ to 3‐hour washout period between contrast agent injections. Lesion evaluation and image processing were performed using Segment Medviso software. Mean infarct size and transmurality, measured using RVP‐001, were not different compared with those measured using late gadolinium enhancement images. Bland‐Altman analysis demonstrated a nominal bias of 0.13 mL (<1% of average total lesion volume) for RVP‐001 in terms of gross infarct size measurement. Conclusions The experimental manganese‐based contrast agent RVP‐001 appears to be an effective agent for assessment of myocardial infarction location, size, and transmurality, and it may be useful as an alternative to gadolinium‐based agents.
Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression.
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