Chemical reprogramming presents an innovative approach for generating induced pluripotent stem cells (iPSCs), bypassing the genetic instability and safe concern associated with viral vector approach. We describe a novel, efficient chemical method for reprogramming human umbilical cord tissue-derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs). Compared to previous sources like adipose tissue and skin, frozen umbilical cord tissue offers an abundant, non-invasive, long-term storable, and ethically sound cell source. Our findings not only showcase the feasibility and safety of utilizing chemical reprogramming on cells from frozen umbilical cords but also underscore its potential in regenerative medicine, especially for developing safer and more effective therapies for cardiovascular diseases.### Competing Interest StatementThe authors have declared no competing interest.

Abstract Introduction. Breast cancer (BC) is the most frequently diagnosed cancer with over 4 million survivors living in the United States. Recent treatment (Tx) advances such as in targeted (e.g. anti-HER2), systemic (e.g. anthracyclines), or combined therapies have supported the increased survival rates but continue to present adverse effects. Cardiotoxicity, which may be induced during or after Tx, is the second highest cause of mortality in BC survivors and also negatively impacts quality of life (QoL). Black/African American (B/AA) patients have higher rates of this effect along with a higher incidence of aggressive BC types. Limited research has targeted vascular function as an area of focus in the cardio-oncology field. Methods. The Discovery and Elimination of Cardio-Oncology Disparities Toward Equity in the Heartland Center is examining how anti-cancer treatments impact vascular function, the potential mitigating effects of exercise and how socioenvironmental factors moderate these effects. The Take Charge during Treatment randomized trial within this Center is testing the feasibility and acceptability of an exercise during treatment program for B/AA and non-Hispanic White (NHW) women newly diagnosed with BC. The study also examines and compares the effects of exercise on VO2 peak and QoL in participants. The 16-week intervention promotes adherence to the American College of Sports Medicine exercise guidelines for cancer survivors and is guided by a certified exercise trainer. To evaluate the intervention, patient's complete surveys including the FACT-B for QoL, a VO2 peak assessment, physical assessments, and anthropometry measurements at baseline (before BC Tx), after the 16-week program, and at a 12-month timepoint. Socioenvironmental factors are examined using participant addresses. Results. To date, 1330 patients were assessed for eligibility, 60 consented, and 49 enrolled and randomized. Herein, we present data on 45 of the 49 (35 NHW, 10 B/AA). The mean age of participants is 52 years (SD=12), most were diagnosed with Stage I or II BC, and they have varied education and income levels. Baseline (pre-treatment) differences are noted by racial group for QoL (Total score – 88 (SD=9) for NHW vs 74 (SD=29) for B/AA; Physical function – 25 (SD=3) for NHW vs 22 (SD=5) for B/AA; Functional – 21 (SD=4) for NHW vs 18 (SD=8) for B/AA), VO2 peak (22 (SD=5) for NHW vs 17 (SD=6) for B/AA), and obesity (NHW – 30%, B/AA – 70%). Cognitive function, pain interference, social isolation and perceived stress were similar across groups. B/AA women were more likely to report living in a highly redlined area (50%) compared to NHW women (3%), with lower percent tree canopy (13% vs 24%) and lower perceived social cohesion (15 vs 19). Reports of discrimination and resilience were similar across groups. Conclusions. Preliminary baseline results suggest that B/AA women enter BC Tx more vulnerable to developing QoL challenges and cardiotoxicity. Neighborhood environmental factors will be further examined to understand the association with adverse outcomes. Citation Format: Estefania Alonso, Melinda Stolley, Kirsten Beyer, Alison Kriegel, Shane Phillips, Matt Durand, Michael E. Widlansky, Amanda L. Kong, Kent Hoskins, Andreas Beyer. Take Charge during Treatment: A randomized exercise trial for breast cancer patients [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C032.

Abstract Nearly 4 million breast cancer survivors live in the United States (U.S.). Continued improvements of cancer therapies (CTx), including targeted treatment options such as anti-HER2 therapy combined with traditional systemic CTx like anthracyclines (ANTs) have made adverse cardiovascular events the leading cause of non-cancer related mortality among BC survivors. Toxicities can be acute and/or reversible (e.g., anti-her2) or may persist for years (ANTs)). Most efforts focus on managing and defining the mechanism of cardiac damage in response to CTx. Yet, systemic vascular function, including microvascular endothelial function, is not only a predictor but also a contributor to a significant number of cardiovascular complications that is mostly overlooked in response to CTx. Little to no mechanistic evidence exists how CTx impacts the human circulation and endothelial function. Systemic inflammation (e.g., Interleukin levels or TLR signaling) is elevated in cancer and CV disease alike, yet the connection of CTx induced endothelial dysfunction has not been explored in breast cancer patients. Black/African American women are at higher risk for cardio-toxicity. Existing literature suggest significant racial differences in immune signaling and microvascular function perhaps explaining varying risk for CV toxicity post-CTx. However, contributing biological, social and environmental factors remain ill defined. The Discovery and Elimination of Cardio-Oncology Disparities for Equity (DECODE) in the Heartland center addresses critical gaps in the literature by testing if an exercise intervention can lower systemic inflammatory load to improve endothelial function and CV risk itself. We propose to: 1) quantify physiological and molecular differences in inflammation and endothelial function before and following CTx among 120 Black/African American and non-Hispanic White women with invasive, non-metastatic BC; 2) test the feasibility and efficacy of an exercise intervention during CTx designed to mitigate the adverse effects of treatment on exercise capacity and QoL; and 3) examine the influence of multi-level socio-ecological factors (individual, interpersonal, institutional, environmental) on inflammation, microvascular endothelial function, QoL and response to the exercise intervention among participants. This presentation presents DECODE’s novel translational study design and methodologies. Citation Format: Melinda Stolley, Andreas Beyer, Kirsten Beyer, Alison Kriegel, David Gutterman, Shane Phillips, Sherry Ann Brown, Kent Hoskins, Rodney Sparapani, Michael Widlansky, Amanda Kong. Understanding and addressing disparities in cancer therapy induced inflammation and associated endothelial dysfunction [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B022.

Background and Aims: Microvascular endothelial dysfunction is a known contributor to and predictor of major adverse cardiovascular events. The loss of nitric oxide (NO)-mediated dilation in the dysfunctional endothelium may be compensated by CYP450 epoxygenase-generated endothelial-derived hyperpolarizing factors (EDHFs) that regulate vascular tone. Our recent data point to a novel family of lactone metabolites of polyunsaturated fatty acids (PUFA-Ls), which are potential EDHFs. Unlike known epoxy-metabolites, their structure is chemically stable and is a poor substrate for the epoxide hydrolase enzyme. Our study aimed to reveal their potential mechanism and physiological function in microvascular dilation. Methods: Human adipose arterioles were extracted from adipose tissues from HTN and normotensive (NT) subjects and detected for their dilation response to EPA-L. Hypertensive rats were administrated with EPA-L and measured for their blood pressure, blood and urine chemistry, and kidney function. Human endothelial cells were used to investigate the EPA-L signaling mechanism by calcium and potassium efflux with antagonists for GPCRs and the PLC-IP3 pathway. Results: Lactone metabolites, derived from arachidonic acid (AA-L) and eicosapentaenoic acid (EPA-L), were shown to mediate endothelial-dependent vasodilation in isolated human microvessels. In hypertensive arterioles, EPA-L-induced dilation was not affected by eNOS inhibitors. In hypertensive rats, EPA-L reduced blood pressure in vivo and restored the microvascular dilation capacity. The mechanism of action revealed to initiate G-protein coupled receptors that activate the PLC-IP3 pathway and mediate calcium flux from the endoplasmic reticulum, resulting in potassium efflux and hyperpolarization of endothelial cells. Conclusions: These results demonstrate that lactone-derived PUFA are potentially EDHFs that may regulate endothelial dysfunction.

Reactive oxygen species (ROS) are important modulators of vascular reactivity. Coronary artery disease (CAD) changes the mechanism of human arteriolar flow-mediated dilation (FMD) from NO to hydrogen peroxide (H2O2), a signaling ROS. Increasing evidence shows that mitochondrial ROS (mtROS) production and the longevity of a cell or organism are inversely related. Telomerase activity (TA), prominent in cellular senescence and tissue aging, shows a reciprocal relationship with mtROS production. Rosiglitazone (Rosi) activates peroxisome proliferator-activated receptor γ (PPARγ) resulting in increased telomerase expression. This could mitigate mtROS production, leading to increased NO bioavailability, improved vascular function, and retardation of atherosclerosis. We hypothesized that PPARγ reduces elevated ROS levels in CAD and converts the mechanism of FMD from H2O2 to NO by increasing telomerase activity. Human adipose arterioles (~200 µm) from discarded pericardial tissue were cannulated for videomicroscopy. Dilation to graded degrees of shear was measured in vessels constricted with endothelin-1. Pharmacological inhibition of TA (BIRBR 1532 10 μM 15-20 h) in vessels from healthy individuals shifted the mechanism of FMD from NO to H2O2 (Panel A+B). In arterioles from patients with CAD, Rosi (10 μM 15-20 h) shifted the mechanism of FMD from H2O2 to NO (Panel C). In vessels from patients with CAD, BIBRB1532 prevented the ability of Rosi to convert the mediator of FMD from NO to H2O2 (D). We conclude that PPARγ signaling increases telomerase activity in the vasculature, which plays a critical and acute role in modulating microvascular function.