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Platelet extracellular vesicles (PEVs) are an emerging delivery vehi for anticancer drugs due to their ability to target and remain in the tumor microenvironment. However, there is still a lack of understanding regarding yields, safety, drug loading efficiencies, and efficacy of PEVs. In this study, various methods were compared to generate PEVs from clinical-grade platelets, and their properties were examined as vehicles for doxorubicin (DOX). Sonication and extrusion produced the most PEVs, with means of 496 and 493 PEVs per platelet (PLT), respectively, compared to 145 and 33 by freeze/thaw and incubation, respectively. The PEVs were loaded with DOX through incubation and purified by chromatography. The size and concentration of the PEVs and PEV-DOX were analyzed using dynamic light scattering and nanoparticle tracking analysis. The results showed that the population sizes and concentrations of PEVs and PEV-DOX were in the ranges of 120-150 nm and 1.2-6.2 × 1011 particles/mL for all preparations. The loading of DOX determined using fluorospectrometry was found to be 2.1 × 106, 1.7 × 106, and 0.9 × 106 molecules/EV using freeze/thaw, extrusion, and sonication, respectively. The internalization of PEVs was determined to occur through clathrin-mediated endocytosis. PEV-DOX were more efficiently taken up by MDA-MB-231 breast cancer cells compared to MCF7/ADR breast cancer cells and NIH/3T3 cells. DOX-PEVs showed higher anticancer activity against MDA-MB-231 cells than against MCF7/ADR or NIH/3T3 cells and better than acommercial liposomal DOX formulation. In conclusion, this study demonstrates that PEVs generated by PLTs using extrusion, freeze/thaw, or sonication can efficiently load DOX and kill breast cancer cells, providing a promising strategy for further evaluation in preclinical animal models. The study findings suggest that sonication and extrusion are the most efficient methods to generate PEVs and that PEVs loaded with DOX exhibit significant anticancer activity against MDA-MB-231 breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: Esophageal stricture (ES) and gastric outlet obstruction (GOO) can occurred in patients injured by the ingestion of corrosive agents. These complications may occur concurrently but has not been reported in the literature. The aims of this study are to assess the effects and complications of endoscopic-guided balloon dilations (EBD) in patients with corrosive-induced upper gastrointestinal strictures, either ES or GOO alone and simultaneous occurrences of both (ES + GOO). Methods: From July 2002 to December 2009, 36 patients with corrosive-induced upper gastrointestinal strictures in a tertiary hospital were recruited into this study. The patients were divided into three groups, ES group (n = 18), GOO (n = 7), and ES + GOO group (n = 11). All strictures were dilated under direct visualization by using throughthe- scope balloon catheters to the end point of 15 mm. The end-point of treatment was successful ingestion of a solid or semisolid diet without additional dilation for more than 12 months. Results: These 36 patients included 15 males and 21 females with average age of 47 years ranging from 25 to 79 years. The success rates for ES group is significantly better than GOO and ES + GOO group (83.3% vs. 57.1% vs. 36.4% p = 0.035). Less complications were observed in ES group than in GOO and ES + GOO group (16.7% vs. 42.9% vs. 36.4%, p = 0.041). GOO group needed more sessions of dilations in order to achieve success dilations than ES and GOO groups (13.7 ± 4.9 vs. 6.1 ± 4.7 vs. 5.5 ± 2.1, p = 0.011). Conclusions: Corrosive injuries complicated with ES can be effectively and safely treated by EBD. However, the success rates declined significantly in patients with GOO with or without ES and amore complications occurred. [ABSTRACT FROM AUTHOR]

Two Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 7 (SENP7) variants are naturally expressed in breast epithelia. Breast cancer (BCa) onset down-regulates the short SENP7 splice variant (SENP7S) and enhances the long transcript (SENP7L). Here, we show that SENP7L induction promotes gene expression profiles that favor aberrant proliferation and initiate epithelial-mesenchymal transition (EMT). SENP7L exhibits an interaction domain for the epigenetic remodeler heterochromatin protein 1 α (HP1α) and isopeptidase activity against SUMO-modified HP1α. Loss of this interaction domain, as observed with SENP7S, favors HP1α SUMOylation. SUMOy-lated HP1α is enriched at E2F-responsive and mesenchymal gene promoters, silences transcription of these genes, and promotes cellular senescence. Elevated SENP7L renders HP1α hypo-SUMOylated, which relieves transcriptional repression of the same genes and concurrently decreases transcription of epithelial-promoting genes via an HP1α-independent mechanism. Consequently, SENP7L levels correlate with EMT, motility, and invasiveness of BCa cells. Stable knockdown of elevated SENP7L levels lessens the dissemination of highly metastatic BCa cells to the lungs from primary implantation sites in in vivo studies. Thus, differential splicing of the SENP7 regulates either tumor suppression or progression. [ABSTRACT FROM AUTHOR]

Although insulin resistance is recognized as a potent and prevalent risk factor for coronary heart disease, less is known as to whether insulin resistance causes an altered cardiac phenotype independent of coronary atherosclerosis. In this study, we investigated the relationship between insulin resistance and cardiac contractile dysfunctions by generating a new insulin resistance animal model with rats on high cholesterol-fructose diet. Male Sprague-Dawley rats were given high cholesterol-fructose (HCF) diet for 15 wk; the rats developed insulin resistance syndrome characterized by elevated blood pressure, hyperlipidemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. The results show that HCF induced insulin resistance not only in metabolic-response tissues (i.e., liver and muscle) but also in the heart as well. Insulin-stimulated cardiac glucose uptake was significantly reduced after 15 wk of HCF feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling along with glucose transporter GLUT4 translocation. Basal fatty acid transporter FATP1 levels were increased in HCF rat hearts. The cardiac performance of the HCF rats exhibited a marked reduction in cardiac output, ejection fraction, stroke volume, and end-diastolic volume. It also showed decreases in left ventricular end-systolic elasticity, whereas the effective arterial elasticity was increased. In addition, the relaxation time constant of left ventricular pressure was prolonged in the HCF group. Overall, these results indicate that insulin resistance reduction of cardiac glucose uptake is associated with defects in insulin signaling. The cardiac metabolic alterations that impair contractile functions may lead to the development of cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: This study addressed the effects of apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, on hepatic oxidative burden and liver injury during diet-induced hypercholesterolaemia. Methods and Results: Male Wistar rats were fed a 4% cholesterol-enriched diet for 3 weeks. Apocynin was administered in drinking water concurrently. The high-cholesterol diet (HC) significantly increased the serum level of cholesterol and hepatic cholesterol ester deposition, and these parameters were similar between the HC and high-cholesterol diet plus apocynin (HCA) groups. The HC group showed abnormal liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (Alk-P)] as well as increased Evans blue extravasation and macrophages infiltration. Apocynin treatment could suppress these inflammation-related parameters. In vivo measurement of NADPH-derived cellular autofluorescence suggested that HC increased oxidative stress in hepatocytes. Biochemical analysis of redox status including thiobarbituric acid reactive substances, reduced glutathione, and oxidized glutathione also confirmed the phenomenon. Apocynin treatment was able to alleviate these indices of oxidative burden owing to HC. Furthermore, apocynin-abrogated HC induced gp91phox expression, suggesting the involvement of NADPH oxidase in the pathogenesis. Conclusions: We concluded that apocynin suppressed NADPH oxidase activation and subsequent liver injuries owing to high-cholesterol intake in rats. The impacts of cholesterol metabolism disorders on pathogenesis and progression of steatohepatitis warrant further clinical investigation. [ABSTRACT FROM AUTHOR]

Demonstrates the effectiveness of imaging in a tissue phantom with isotropic scattering using polarization discrimination combined with the time gating method. Effectiveness of the simple polarization discrimination technique when it was applied to filamentous tissues; Use of the time-gated degree of polarization imaging technique; Application of the technique to the characterization of myocardial tissues and in showing the difference between normal and abnormal tissues; Demonstration of a novel method for target depth determination in a turbid medium based on co-polarized light measurements.

Herein, we propose a continuous-wave laser-induced forward transfer (CW-LIFT) system that possesses high printing quality with a high printing success rate. CW-LIFT can automatically deposit droplets equally and uniformly as a customized pattern. In this study, we selected an 830 nm near-infrared CW laser and applied a 20× microscope objective lens to highly focus the laser beam. In addition, a 16 nm gold thin film was used as the energy-absorbing layer for CW-LIFT. We demonstrated that the CW-LIFT can print liquid bioink and deposit cells in a controlled and precise way. [ABSTRACT FROM AUTHOR]

We measure in vitro tissue birefringence in the liver of hypercholesterolemic rats with polarization-sensitive optical coherence tomography. Tissue birefringence is determined by measuring the phase retardation as a function of tissue depth. The birefringence of such a sample is usually due to the narrow fibrous structures that cannot be resolved by a standard optical coherence tomography system. Anisotropic structures are formed in the hypercholesterolemic rat liver, which is quite different from the isotropic nature of healthy liver. Birefringence is evaluated to give an order of magnitude of 4.48×10−4 at 790 nm in hypercholesterolemic rat liver. The infiltration of macrophages and increased collagen deposition should be major causes for tissue birefringence in hypercholesterolemic liver. [ABSTRACT FROM AUTHOR]