Search

During the COVID-19 pandemic, unexpected activity patterns emerged among Yucatan mini-swine models for heart failure and atrial fibrillation. As part of our laboratory research, we tracked activity data by FitBark™ collars that the Yucatan mini-swine wore. Previously, staff engaged with the swine daily, such as applying lotion and conducting 6-min treadmill runs. However, pandemic restrictions reduced interaction to 1 or 2 times a week, often for less than 10 min each session. Contrary to expectations, there was a significant increase in the swine's activity levels during these minimal interaction periods. After cleaning, moisturizing, weighing, and FitBark data collection, staff engaged with the swine through feeding and play. Three time frames were analyzed: prepandemic, pandemic, and reentry. Prepandemic and reentry periods involved daily 15-min interactions with 2 staff members per swine to maintain cleanliness and health. During the pandemic, interaction was reduced to 1 or 2 times weekly. The hours between 1000 and 1400 were designated as 'passive activity', representing the swines' isolated behavior, unaffected by staff interaction. The chronic heart failure swine (n = 3) had an average passive activity area under the curve prepandemic value of 47.23 ± 2.52 compared with pandemic 57.09 ± 2.90, pandemic 57.09 ± 2.90 compared with reentry 50.44 ± 1.61, and prepandemic compared with reentry. The atrial fibrillation swine (n = 3) had an average passive activity area under the curve minimal interaction (mimicking pandemic) value of 59.27 ± 6.67 compared with interaction (mimicking prepandemic or reentry) 37.63 ± 1.74. The heightened activity levels during minimal interaction suggest physiologic and psychologic changes in the animals due to reduced socialization. This highlights the importance of enrichment and interaction in research animals and underscores the broader impact of the COVID-19 pandemic on research outcomes. These findings could also shed light on the effects of the pandemic on human behavior.

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45 pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF., (© 2023. The Author(s).)

In swine models, there are well-established protocols for creating a closed-chest myocardial infarction (MI) as well as protocols for characterization of cardiac function with cardiac magnetic resonance (CMR). This methods manuscript outlines a novel technique in CMR data acquisition utilizing smart-signal gradient recalled echo (GRE)-based array sequences in a free-breathing swine heart failure model allowing for both high spatial and temporal resolution imaging. Nine male Yucatan mini swine weighing 48.7 ± 1.6 kg at 58.2 ± 3.1 weeks old underwent the outlined imaging protocol before and 1-month after undergoing closed chest left anterior descending coronary artery (LAD) occlusion/reperfusion. The left ventricular ejection fraction (LVEF) at baseline was 59.3 ± 2.4% and decreased to 48.1 ± 3.7% 1-month post MI (P = 0.029). The average end-diastolic volume (EDV) at baseline was 55.2 ± 1.7 ml and increased to 74.2 ± 4.2 ml at 1-month post MI (P = 0.001). The resulting images from this novel technique and post-imaging analysis are presented and discussed. In a Yucatan swine model of heart failure via closed chest left anterior descending coronary artery (LAD) occlusion/reperfusion, we found that CMR with GRE-based array sequences produced clinical-grade images with high spatial and temporal resolution in the free-breathing setting., (© 2022. The Author(s).)

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are under preclinical investigation as a cell-based therapy for heart failure post-myocardial infarction. In a previous study, tissue-engineered cardiac grafts were found to improve hosts' cardiac electrical and mechanical functions. However, the durability of effect, immune response, and in vitro properties of the tissue graft remained uncharacterized. This present study is aimed at confirming the graft therapeutic efficacy in an immune-competent chronic heart failure (CHF) model and providing evaluation of the in vitro properties of the tissue graft., Methods: hiPSC-CMs and human dermal fibroblasts were cultured into a synthetic bioabsorbable scaffold. The engineered grafts underwent epicardial implantation in infarcted immune-competent male Sprague-Dawley rats. Plasma samples were collected throughout the study to quantify antibody titers. At the study endpoint, all cohorts underwent echocardiographic, hemodynamic, electrophysiologic, and histopathologic assessments., Results: The epicardially placed tissue graft therapy improved ( p < 0.05) in vivo and ex vivo cardiac function compared to the untreated CHF cohort. Total IgM and IgG increased for both the untreated and graft-treated CHF cohorts. An immune response to the grafts was detected after seven days in graft-treated CHF rats only. In vitro , engineered grafts exhibited responsiveness to beta-adrenergic receptor agonism/antagonism and SERCA inhibition and elicited complex molecular profiles., Conclusions: This hiPSC-CM-derived cardiac graft improved systolic and diastolic cardiac function in immune-competent CHF rats. The improvements were detectable at seven weeks post-graft implantation despite an antibody response beginning at week one and peaking at week three. This suggests that non-integrating cell-based therapy delivered by a bioengineered tissue graft for ischemic cardiomyopathy is a viable treatment option., Competing Interests: The work outlined in this report was the basis for forming the commercial entity Avery Therapeutics, Inc. Drs. Goldman, Koevary, Lancaster, and Ms. Sherry Daugherty have disclosed a financial interest in Avery Therapeutics to the University of Arizona. In addition, the University of Arizona has a financial interest in Avery Therapeutics. These interests have been reviewed and are being managed by the University of Arizona in accordance with its policies on outside interests. All other authors have no relevant conflicts to disclose., (Copyright © 2021 Ikeotunye Royal Chinyere et al.)

Ovarian cancer is the deadliest gynecologic cancer due predominantly to late diagnosis. Early detection of ovarian cancer can increase 5-year survival rates from 40% up to 92%, yet no reliable early detection techniques exist. Multiphoton microscopy (MPM) is a relatively new imaging technique sensitive to endogenous fluorophores, which has tremendous potential for clinical diagnosis, though it is limited in its application to the ovaries. Wide-field fluorescence imaging (WFI) has been proposed as a complementary technique to MPM, as it offers high-resolution imagery of the entire organ and can be tailored to target specific biomarkers that are not captured by MPM imaging. We applied texture analysis to MPM images of a mouse model of ovarian cancer. We also conducted WFI targeting the folate receptor and matrix metalloproteinases. We find that texture analysis of MPM images of the ovary can differentiate between genotypes, which is a proxy for disease, with high statistical significance (p  <  0.001). The wide-field fluorescence signal also changes significantly between genotypes (p  <  0.01). We use the features to classify multiple tissue groups to over 80% accuracy. These results suggest that MPM and WFI are promising techniques for the early detection of ovarian cancer.

Transgenic TgMISIIR-TAg (TAg) mice express the oncogenic virus SV40 in Mullerian epithelial cells. Female TAg mice spontaneously develop epithelial ovarian carcinoma, the most common type of ovarian cancer in women. Female TAg mice are infertile, but the reason has not been determined. We therefore investigated whether female TAg mice undergo puberty, demonstrate follicular development, maintain regular cycles, and ovulate. Ovarian cancers in women commonly develop after menopause. The occupational chemical 4-vinylcyclohexene diepoxide (VCD) accelerates follicle degeneration in the ovaries of rats and mice, causing early ovarian failure. We therefore used VCD dosing of mice to develop an animal model for menopause. The purpose of this study was to characterize reproductive parameters in female TAg mice and to investigate whether the onset of ovarian failure due VCD dosing differed between female TAg and WT C57BL/6 mice. As in WT female mice, TAg female mice underwent puberty (vaginal opening) and developed cyclicity in patterns that were similar between the groups. Vehicle-only TAg mice had fewer ovulations (numbers of corpora lutea) than WT animals. VCD exposure delayed the onset of puberty (day of first estrus) in TAg as compared with WT mice. Morphologic evaluation of ovaries revealed many more degenerating follicles in TAg mice than WT mice, and more VCD-dosed TAg mice were in ovarian failure than VCD-dosed WT mice. These results suggest that despite showing similar onset of sexual maturation, TAg mice have increased follicular degeneration and fewer ovulations than WT. These features may contribute to the inability of female TAg mice to reproduce.

Ovarian cancer has the lowest survival rate among all gynecologic cancers predominantly due to late diagnosis. Early detection of ovarian cancer can increase 5-year survival rates from 40% up to 92%, yet no reliable early detection techniques exist. Optical coherence tomography (OCT) is an emerging technique that provides depth-resolved, high-resolution images of biological tissue in real-time and demonstrates great potential for imaging of ovarian tissue. Mouse models are crucial to quantitatively assess the diagnostic potential of OCT for ovarian cancer imaging; however, due to small organ size, the ovaries must first be separated from the image background using the process of segmentation. Manual segmentation is time-intensive, as OCT yields three-dimensional data. Furthermore, speckle noise complicates OCT images, frustrating many processing techniques. While much work has investigated noise-reduction and automated segmentation for retinal OCT imaging, little has considered the application to the ovaries, which exhibit higher variance and inhomogeneity than the retina. To address these challenges, we evaluate a set of algorithms to segment OCT images of mouse ovaries. We examine five preprocessing techniques and seven segmentation algorithms. While all preprocessing methods improve segmentation, Gaussian filtering is most effective, showing an improvement of 32 % ± 1.2 % . Of the segmentation algorithms, active contours performs best, segmenting with an accuracy of 94.8 % ± 1.2 % compared with manual segmentation. Even so, further optimization could lead to maximizing the performance for segmenting OCT images of the ovaries.

With early detection, 5-year survival rates for ovarian cancer exceed 90%, yet no effective early screening method exists. Emerging consensus suggests over 50% of the most lethal form of the disease originates in the fallopian tube. Twenty-eight women undergoing oophorectomy or debulking surgery provided informed consent for the use of surgical discard tissue samples for multispectral fluorescence imaging. Using multiple ultraviolet and visible excitation wavelengths and emissions bands, 12 fluorescence and 6 reflectance images of 47 ovarian and 31 fallopian tube tissue samples were recorded. After imaging, each sample was fixed, sectioned, and stained for pathological evaluation. Univariate logistic regression showed cancerous tissue samples had significantly lower intensity than noncancerous tissue for 17 image types. The predictive power of multiple image types was evaluated using multivariate logistic regression (MLR) and quadratic discriminant analysis (QDA). Two MLR models each using two image types had receiver operating characteristic curves with area under the curve exceeding 0.9. QDA determined 56 image type combinations with perfect resubstituting using as few as five image types. Adaption of the system for future in vivo fallopian tube and ovary endoscopic imaging is possible, which may enable sensitive detection of ovarian cancer with no exogenous contrast agents.