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102. In vivoevaluation of bioprinted cardiac patches composed of cardiac-specific extracellular matrix and progenitor cells in a model of pediatric heart failure

Author

Bejleri, Donald, Robeson, Matthew J., Brown, Milton E., Hunter, Jervaughn, Maxwell, Joshua T., Streeter, Benjamin W., Brazhkina, Olga, Park, Hyun-Ji, Christman, Karen L., and Davis, Michael E.

Abstract

Pediatric patients with congenital heart defects (CHD) often present with heart failure from increased load on the right ventricle (RV) due to both surgical methods to treat CHD and the disease itself. Patients with RV failure often require transplantation, which is limited due to lack of donor availability and rejection. Previous studies investigating the development and in vitroassessment of a bioprinted cardiac patch composed of cardiac extracellular matrix (cECM) and human c-kit + progenitor cells (hCPCs) showed that the construct has promise in treating cardiac dysfunction. The current study investigates in vivocardiac outcomes of patch implantation in a rat model of RV failure. Patch parameters including cECM-inclusion and hCPC-inclusion are investigated. Assessments include hCPC retention, RV function, and tissue remodeling (vascularization, hypertrophy, and fibrosis). Animal model evaluation shows that both cell-free and neonatal hCPC-laden cECM-gelatin methacrylate (GelMA) patches improve RV function and tissue remodeling compared to other patch groups and controls. Inclusion of cECM is the most influential parameter driving therapeutic improvements, with or without cell inclusion. This study paves the way for clinical translation in treating pediatric heart failure using bioprinted GelMA-cECM and hCPC-GelMA-cECM patches.

Published
2022
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104. Controlled JAGGED1 delivery induces human embryonic palate mesenchymal cells to form osteoblasts

Author

De La Croix Ndong, Jean, Stephenson, Yvonne, Davis, Michael E., García, Andrés J., and Goudy, Steven

Subjects
Osteoblasts, Receptors, Notch, Cell Survival, Palate, technology, industry, and agriculture, Gene Transfer Techniques, Apoptosis, Cell Count, Cell Differentiation, macromolecular substances, CHO Cells, Article, Polyethylene Glycols, Maleimides, Mesoderm, Kinetics, Cricetulus, Cricetinae, Animals, Humans, Jagged-1 Protein, Cell Proliferation
Abstract

Osteoblast commitment and differentiation are controlled by multiple growth factors including members of the Notch signaling pathway. JAGGED1 is a cell surface ligand of the Notch pathway that is necessary for murine bone formation. The delivery of JAGGED1 to induce bone formation is complicated by its need to be presented in a bound form to allow for proper Notch receptor signaling. In this study, we investigate whether the sustained release of JAGGED1 stimulates human mesenchymal cells to commit to osteoblast cell fate using polyethylene glycol malemeide (PEG-MAL) hydrogel delivery system. Our data demonstrated that PEG-MAL hydrogel constructs are stable in culture for at least three weeks and maintain human mesenchymal cell viability with little cytotoxicity in vitro. JAGGED1 loaded on PEG-MAL hydrogel (JAGGED1-PEG-MAL) showed continuous release from the gel for up to three weeks, with induction of Notch signaling using a CHO cell line with a Notch1 reporter construct, and qPCR gene expression analysis in vitro. Importantly, JAGGED1-PEG-MAL hydrogel induced mesenchymal cells towards osteogenic differentiation based on increased Alkaline phosphatase activity and osteoblast genes expression including RUNX2, ALP, COL1, and BSP. These results thus indicated that JAGGED1 delivery in vitro using PEG-MAL hydrogel induced osteoblast commitment, suggesting that this may be a viable in vivo approach to bone regeneration. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 552-560, 2018.

Published
2017

105. Lower your costs by making your operations more efficient

Author

Davis, Michael E.

Subjects
Wage payment systems, Cost control -- Equipment and supplies, Business, Human resources and labor relations, Insurance
Abstract

Business is analogous to a boat traveling upstream. A benefits administrator, to move upstream, must aid himself with an electronic system. He can obtain a definite advantage by enhancing his electronic systems to lower expenses of providing services. Thus, a benefits administrator can identify the areas where improvements can be made that will provide benefit to the operation and, then, implement them gradually.

Published
1992

108. Assessment of milk yield and nursing calf feed intake equations in predicting calf feed intake and weaning weight among breeds.

Author

Lancaster, Phillip A., Tedeschi, Luis O., Buessing, Zach, and Davis, Michael E.

Abstract

Nutrition models are important tools in management decisions, but improvements are needed for cow–calf producers to accurately predict nursing calf performance. Therefore, the objective of this study was to assess the ability of published milk yield (MY) and forage intake equations to predict calf feed intake and weaning weight (WW) using an independent, multi-breed dataset. A dataset with 406 nursing calves was used to evaluate two MY equations: 1) National Academies of Sciences, Engineering, and Medicine (2016) (NASEM) and 2) Wood (1967) (WOOD) and five feed intake equations: 1) equations from Table 9.1 in Tedeschi et al. (2006) (TED06), 2) equations 2 to 7 in Baker et al. (1976) (BAK76), 3) equation 25 in Tedeschi and Fox (2009) (TED09A), 4) equations 17, 19, and 24 in Tedeschi and Fox (2009) (TED09B), and 5) equation from Holloway et al. (1982) (HOL82). MY was measured at 14-d interval by hand milking, and individual feed intake of nursing calves was determined during a 240-d nursing period. Calf birth and WW were measured on days 0 and 240, respectively. Each combination of MY and feed intake equation was used to predict calf feed intake and WW from observed MY, calf birth weight, and calf slaughter weight. Predicted and observed values were compared using concordance correlation coefficient (CCC) and mean bias (MB). Factors affecting the deviation between observed and predicted values were analyzed using regression, and a revised equation was developed. Feed intake equations poorly predicted observed feed intake with CCC < 0.4 and MB ranged from −108% to 69%. However, statistics were slightly improved when using WOOD rather than the NASEM MY equation. BAK76 and TED09B feed intake equations were considerably more accurate (MB = −14.4% to 13.0%) in predicting feed intake but still not precise (CCC < 0.30). Predictions of WW had CCC ranging from 0.19 to 0.71 and MB ranging from −25.9% to 41.8% and were not significantly affected by the MY equation. TED06 and BAK76 feed intake equations were the most precise (CCC > 0.60) and accurate (MB = 1.7% to 8.5%) in predicting WW. Sire breed accounted for significant variation in the deviation between observed and predicted values of feed intake and in a revised equation to predict total feed energy intake from total milk energy intake. In conclusion, refinements of feed intake equations for nursing calves need to account for breed to improve current nutrition models. [ABSTRACT FROM AUTHOR]

Published
2021
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122. Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure

Author

Agarwal, Udit, primary, Smith, Amanda W., additional, French, Kristin M., additional, Boopathy, Archana V., additional, George, Alex, additional, Trac, David, additional, Brown, Milton E., additional, Shen, Ming, additional, Jiang, Rong, additional, Fernandez, Janet D., additional, Kogon, Brian E., additional, Kanter, Kirk R., additional, Alsoufi, Baahaldin, additional, Wagner, Mary B., additional, Platt, Manu O., additional, and Davis, Michael E., additional

Published
2016
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124. Electrical Stimulation of pediatric cardiac‐derived c‐kit+progenitor cells improves retention and cardiac function in right ventricular heart failure

Author

Maxwell, Joshua T., Trac, David, Shen, Ming, Brown, Milton E., Davis, Michael E., Chao, Myra S., Supapannachart, Krittin J., Zaladonis, Carly A., Baker, Emily, Li, Martin L., Zhao, Jennifer, and Jacobs, Daniel I.

Abstract

Nearly 1 in every 120 children born has a congenital heart defect. Although surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. Although primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Here, we investigate the ability of electrical stimulation (ES) to enhance the retention and therapeutic function of pediatric cardiac‐derived c‐kit+progenitor cells (CPCs) in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES‐CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes and increased in vitro survival and adhesion of cells. Specifically, upregulation of β1 and β5 integrins contributed to the increased retention of ES‐CPCs. Lastly, we show that ES induces CPCs to release higher levels of pro‐reparative factors in vitro. These findings suggest that ES can be used to increase the retention, survival, and therapeutic effect of human c‐kit+progenitor cells and can have implications on a variety of cell‐based therapies. Stem Cells2019;37:1528–1541 Top, Conceptual diagram of ex vivomodification of cells. Cells are isolated, modified, and administered to patients as autologous or allogeneic therapies. Bottom, ex vivo modification of pediatric cardiac‐derived progenitor cells with electrical stimulation promotes retention of cells and improves cardiac function in a rat model of heart failure.

Published
2019
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125. Evaluation of Hydrogels Presenting Extracellular Matrix-Derived Adhesion Peptides and Encapsulating Cardiac Progenitor Cells for Cardiac Repair

Author

Bhutani, Srishti, Nachlas, Aline L.Y., Brown, Milton E., Pete, Tionne, Johnson, Christopher T., García, Andrés J., and Davis, Michael E.

Abstract

Cell therapy is an emerging paradigm for the treatment of heart disease. In spite of the exciting and promising preclinical results, the benefits of cell therapy for cardiac repair in patients have been modest at best. Biomaterials-based approaches may overcome the barriers of poor differentiation and retention of transplanted cells. In this study, we prepared and tested hydrogels presenting extracellular matrix (ECM)-derived adhesion peptides as delivery vehicles for c-kit+cardiac progenitor cells (CPCs). We assessed their effects on cell behavior in vitro as well as cardiac repair in rats undergoing ischemia reperfusion. Hydrogels presenting the collagen-derived GFOGER peptide induced cardiomyocyte differentiation of CPCs as demonstrated by increased expression of cardiomyocyte structural proteins. However, conditioned media obtained from GFOGER hydrogels showed lower levels of secreted reparative factors. Interestingly, following injection in rats undergoing ischemia-reperfusion, treatment with CPCs encapsulated in nonadhesive RDG-presenting hydrogels resulted in the preservation of cardiac contractility and attenuation of postinfarct remodeling whereas the adhesion peptide-presenting hydrogels did not induce any functional improvement. Retention of cells was significantly higher when delivered with nonadhesive hydrogels compared to ECM-derived peptide gels. These data suggest that factors including cell differentiation state, paracrine factors and interaction with biomaterials influence the effectiveness of biomaterials-based cell therapy. A holistic consideration of these multiple variables should be included in cell-biomaterial combination therapy designs.

Published
2024
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132. Controlled JAGGED1 delivery induces human embryonic palate mesenchymal cells to form osteoblasts.

Author

Ndong, Jean De La Croix, Stephenson, Yvonne, Davis, Michael E., García, Andrés J., and Goudy, Steven

Abstract

Osteoblast commitment and differentiation are controlled by multiple growth factors including members of the Notch signaling pathway. JAGGED1 is a cell surface ligand of the Notch pathway that is necessary for murine bone formation. The delivery of JAGGED1 to induce bone formation is complicated by its need to be presented in a bound form to allow for proper Notch receptor signaling. In this study, we investigate whether the sustained release of JAGGED1 stimulates human mesenchymal cells to commit to osteoblast cell fate using polyethylene glycol malemeide (PEG-MAL) hydrogel delivery system. Our data demonstrated that PEG-MAL hydrogel constructs are stable in culture for at least three weeks and maintain human mesenchymal cell viability with little cytotoxicity in vitro. JAGGED1 loaded on PEG-MAL hydrogel (JAGGED1-PEG-MAL) showed continuous release from the gel for up to three weeks, with induction of Notch signaling using a CHO cell line with a Notch1 reporter construct, and qPCR gene expression analysis in vitro. Importantly, JAGGED1-PEG-MAL hydrogel induced mesenchymal cells towards osteogenic differentiation based on increased Alkaline phosphatase activity and osteoblast genes expression including RUNX2, ALP, COL1, and BSP. These results thus indicated that JAGGED1 delivery in vitro using PEG-MAL hydrogel induced osteoblast commitment, suggesting that this may be a viable in vivo approach to bone regeneration. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 552-560, 2018. [ABSTRACT FROM AUTHOR]

Published
2018
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133. High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction.

Author

Junyu Yang, Brown, Milton E., Hanshuo Zhang, Martinez, Mario, Zhihua Zhao, Srishti Bhutani, Shenyi Yin, Trac, David, Jianzhong Jeff Xi, and Davis, Michael E.

Subjects
MICRORNA, MYOCARDIAL infarction, NADPH oxidase
Abstract

Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases. [ABSTRACT FROM AUTHOR]

Published
2017
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139. Letter to All Guerrilleros: Unifying the Mindanao Resistance Movement and Unconventional Warfare

Author

ARMY COMMAND AND GENERAL STAFF COLL FORT LEAVENWORTH KS SCHOOL OF ADVANCED MILITARY STUDIES, Davis, Michael E., ARMY COMMAND AND GENERAL STAFF COLL FORT LEAVENWORTH KS SCHOOL OF ADVANCED MILITARY STUDIES, and Davis, Michael E.

Abstract

United States Special Forces have established a well-deserved reputation as experts in direct action operations to kill or capture high-value targets over the course of the Global War on Terror. In doing so, they have neglected their core mission of unconventional warfare. This monograph uses history, theory, and doctrine to study the successful guerrilla operations conducted in the Philippines against occupying Japanese forces and provides lessons in motivating individuals or groups to join or support guerrilla movements that can be applied to current or future unconventional warfare scenarios to support United States' operational objectives. This monograph begins with an overview of theories of cooperation and resistance that describe common factors that motivate and deter people from joining or supporting guerrilla groups. These factors are then compared with successful and unsuccessful attempts to build a resistance movement using case studies taken from the Philippine Islands during World War II. Finally, the historical record is compared to current United States policy and doctrine for unconventional warfare to explain the importance of gaining support for resistance movements and ways in which unconventional warfare can compliment conventional campaigns., The original document contains color images.

Published
2011

140. Letter to all guerrilleros : unifying the Mindanao resistance movement and unconventional warfare, a monograph

Author

Davis, Michael E. and Davis, Michael E.

Abstract

"United States Special Forces have established a well-deserved reputation as experts in direct action operations to kill or capture high-value targets over the course of the Global War on Terror. In doing so, they have neglected their core mission of unconventional warfare. This monograph uses history, theory, and doctrine to study the successful guerrilla operations conducted in the Philippines against occupying Japanese forces and provides lessons in motivating individuals or groups to join or support guerrilla movements that can be applied to current or future unconventional warfare scenarios to support United States' operational objectives. This monograph begins with an overview of theories of cooperation and resistance that describe common factors that motivate and deter people from joining or supporting guerrilla groups. These factors are then compared with successful and unsuccessful attempts to build a resistance movement using case studies taken from the Philippine Islands during World War II. Finally, the historical record is compared to current United States policy and doctrine for unconventional warfare to explain the importance of gaining support for resistance movements and ways in which unconventional warfare can compliment conventional campaigns."--Page iii.

Published
2011

142. Cellular Encapsulation Enhances Cardiac Repair

Author

Levit, Rebecca D., primary, Landázuri, Natalia, additional, Phelps, Edward A., additional, Brown, Milton E., additional, García, Andrés J., additional, Davis, Michael E., additional, Joseph, Giji, additional, Long, Robert, additional, Safley, Susan A., additional, Suever, Jonathan D., additional, Lyle, Alicia N., additional, Weber, Collin J., additional, and Taylor, W. Robert, additional

Published
2013
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