Background The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). Objective We tested the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. Methods Gottingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of either allo-MSC + allo-CSC (ACCT: 200 million MSCs/1 million CSCs, n=7), 200 million allo-MSC (n=8), 1 million allo-CSC (n=4), or placebo (Plasma-Lyte A, n=6)]. Swine were assessed by cardiac magnetic resonance imaging (cMR) and pressure volume catheterization. Immune response was tested by histological analyses. Results Both ACCT and allo-MSCs reduced scar size by −11.1±4.8%, (p=0.012) and −9.5±4.8 (p=0.047), respectively. Only ACCT, but not MSC or CSC, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure volume relation (+0.98±0.41 mmHg/mL, p=0.016) The ACCT group had more phospho-histone H3 (pHH3)+ (a marker of mitosis) cardiomyocytes (p=0.04), and non-cardiomyocytes (p=0.0002) compared to the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC swine contained immunotolerant CD3+/CD25+/FoxP3 regulatory T cells (p<0.0001). Histologic analysis showed absent to low grade inflammatory infiltrates without cardiomyocyte necrosis. Conclusion ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunological reaction. Clinical translation to humans is warranted.
The impact of fast-propagating swell on the air–sea momentum exchange and the marine boundary layer is examined based on multiple large-eddy simulations over a range of wind speed and swell parameters in the light-wind–fast-wave regime. A wave-driven supergeostrophic jet forms near the top of the wave boundary layer when the forwarding-pointing (i.e., negative) form drag associated with fast wind-following swell overpowers the positive surface shear stress. The magnitude of the form drag increases with the wavelength and slope and decreases with increasing wind speed, and the jet intensity in general increases with the magnitude of the surface form drag. The resulting negative vertical wind shear above the jet in turn enhances the turbulence aloft. The level of the wind maximum is found to be largely determined by the wavenumber and the ratio of the surface shear stress and form drag: the larger the magnitude of this ratio, the higher the altitude of the wind maximum. Although the simulated wind profile often closely follows the log law in the wave boundary layer, the surface stress derived from the logarithmic wind profile is significantly larger than the actual total surface stress in the presence of swell. Therefore, the Monin–Obukhov similarity theory is generally invalid over swell-dominated ocean. This is attributed to the wave-induced contribution to momentum flux, which decays roughly exponentially in the vertical and is largely independent of local wind shear.
Antihypertensive medications are commonly prescribed and well-studied. Given the widespread use and potential side effects, various theories have been made about the relationship between antihypertensives and malignancy, including melanoma. This review describes the current understanding of the most commonly prescribed antihypertensives and their associations with melanoma. The literature demonstrates that diuretics, specifically hydrochlorothiazide and indapamide, may increase the risk of melanoma. While there is no evidence that antihypertensives have a role in melanoma prevention, non-selective β-blocker therapy has been associated with a decreased risk of disease progression and recurrence and may also improve outcomes in patients undergoing immunotherapy. In addition, experimental studies reveal that angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers have anti-tumor effects, meriting further study.
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