Tomasson, M. H. | Search bioRxiv

bioRxiv2026

Post-daunorubicin treatment effects on cardiovascular function in the Ts65Dn mouse model of Down syndrome

Adults with Down syndrome (DS) are two times more likely to be diagnosed with chronic heart failure post-anthracycline chemotherapy compared to age and sex-matched adults without DS. They have an elevated lifetime risk of cardiovascular diseases, increasing their likelihood of anthracycline-induced chronic cardiovascular toxicity. We investigated the chronic effects of daunorubicin on the cardiovascular system of the adult Ts65Dn mouse model of DS compared to wild type euploid mice (WT). WT and Ts65Dn mice received two doses of 2mg/kg or 4mg/kg of daunorubicin or saline and were monitored for up to 117 days. Cardiac and vascular function were evaluated using left ventricular catheterization, histology, pulse wave velocity, and cardiac troponin tests. Survival significantly decreased in the Ts65Dn 4mg/kg group compared to saline controls (p<0.001). Further experiments were carried out with the saline and 2mg/kg groups, which exhibited lower mortality, more consistent with chronic toxicity. Body weight (p=0.001), end-diastolic pressure (p=0.016), and left ventricular mass (p=0.021) decreased in treated mice. The effect of treatment differed significantly between strains for ejection fraction (p=0.029). Pulse wave velocity increased over time (p<0.001). A significant interaction between treatment and strain was observed for collagen in both the left ventricles and thoracic aorta (p=0.002 and p<0.001, respectively). There was a strain difference for cardiac troponin I, indicating an increase in Ts65Dn mice (p=0.020). Daunorubicin treatment results in a distinct cardiovascular remodeling phenotype in Ts65Dn mice. More mechanistic studies are warranted to outline the pathophysiology of anthracycline cardiovascular toxicity in DS.

cancer biology↗

bioRxiv2017

A computational model of MGUS progression to Multiple Myeloma identifies optimum screening strategies and their effects on mortality

Recent advances uncovered therapeutic interventions that might reduce the risk of progression of premalignant diagnoses, such as from Monoclonal Gammopathy of Undetermined Significance (MGUS) to multiple myeloma (MM). It remains unclear how to best screen populations at risk and how to evaluate the ability of these interventions to reduce disease prevalence and mortality at the population level. To address these questions, we developed a computational modeling framework. We used individual-based computational modeling of MGUS incidence and progression across a population of diverse individuals, to determine best screening strategies in terms of screening start, intervals, and risk-group specificity. Inputs were life tables, MGUS incidence and baseline MM survival. We measured MM-specific mortality and MM prevalence following MGUS detection from simulations and mathematical precition modeling. We showed that our framework is applicable to a wide spectrum of screening and intervention scenarios, including variation of the baseline MGUS to MM progression rate and evolving MGUS, in which progression increases over time. Given the currently available progression risk-point estimate of 61% risk, starting screening at age 55 and follow-up screening every 6yrs reduced total MM prevalence by 19%. The same reduction could be achieved with starting age 65 and follow-up every 2yrs. A 40% progression risk reduction per MGUS patient per year would reduce MM-specific mortality by 40%. Generally, age of screening onset and frequency impact disease prevalence, progression risk reduction impacts both prevalence and disease-specific mortality, and screeenign would generally be favorable in high-risk individuals. Screening efforts should focus on specifically identified groups of high lifetime risk of MGUS, for which screening benefits can be significant. Screening low-risk MGUS individuals would require improved preventions.

epidemiology↗