Chitosan/Ellagic Acid Composite Materials for Local Cancer Therapy

Current advances in the drug delivery have improved the therapeutic efficacy of the drug and minimized risks of side effects associated with toxicity of the drug. Implantable polymeric delivery system has gained increasing attentions for controlled drug release and localized treatments. In comparison to conventional chemotherapy, polymeric delivery systems are implantable at a local targeted site and biodegradable after a sufficient therapeutic span. The objectives of this project were to fabricate and characterize an implantable polymeric vehicle for a local chemotherapy and investigate its biological properties against cancer cells including human WM115 melanoma, human U87 glioblastoma, and rat C6 glioma cells in vitro andin vivo. In this study, a natural chitosan polymer was employed as a drug vehicle and ellagic acid (EA), a naturally occurring phenolic compound, was incorporated as a therapeutic agent. The chitosan/ellagic acid composite films were developed by combining 1% (w/v) chitosan solution with different concentrations (0.05, 0.1, 0.5, 1, or 20% (w/v)) of ellagic acid for a local chemotherapy. Characterization of composite films was performed on chemical structure, crystallinity, surface morphology, degradation behavior, and release profile. Cancer cell activity on the composite films was evaluated through direct and indirect cell culture using MTS assay. Anti-cancer mechanism of the composite films against cancer cells was investigated using apoptosis assay, caspase-3 activation, western blot for p53, and anti-angiogenesis assays. In the in vivo study, an animal subcutaneous model was used to assess the anti-tumor effect of the composite film on rat C6 glioma. Treatments were initiated by implanting the composite films onto the tumor. The tumor growth was monitored by measuring tumor volume using a caliper, an ultrasound machine, and an optical imaging system. The chitosan/ellagic acid composite films exhibited increase in amide and ester linkages, diffraction peaks of the crystallized ellagic acid, enhanced surface roughness, and hydrophilicity with increasing concentration of ellagic acid. The composite films degraded enzymatically, indicated by at least a 5 times higher concentration of free amino groups in the incubation medium at 3 weeks compared with 1 day. They also displayed a sustained slow release of ellagic acid in vitro for 3 weeks incubation. Anti-cancer activity of the composite films was ellagic acid concentration dependent by inducing apoptosis of cancer cells and suppressing angiogenesis. Significant inhibitory effect (p\u3c0.05) was found in the composite films containing 0.5% (w/v) of ellagic acid or higher compared with other groups. Study of a rat C6 glioma model demonstrated that the composite film (Ch/EA20) significantly inhibited tumor growth compared with control groups in vivo. Tumor volume increase in Ch/EA20 group was 9 times lower than that in control groups at 3 weeks observation by measuring a caliper. No severe weight loss (\u3e10% wt.) was observed from all groups. Histology observation indicated no evidence of severe toxicity surrounding the composite films. The high efficacy and low toxicity of the composite film was attributed to the slow release and localized effect of ellagic acid. In order to further improve the delivery method and efficacy, chitosan based injectable hydrogel was developed for a local administration of ellagic acid to avoid surgical complications. Studies of the chitosan gel were performed with regard to chemical structure, surface morphology, viscoelasticity, release profile, and degradation behavior. Biocompatibility and anti-cancer activity on chitosan gel delivery system were examined. The results showed that the injectable chitosan liquid formulation underwent thermal gelation at body temperature via hydrophobic interactions using β-glycerophosphate salt (β-GP). Sol-gel transition was dependent on final pH values of the chitosan/β-GP solution and temperature. Dialysis of chitosan solution reduced the β-GP needed to reach pH 7.2, resulting in 4 times higher cell viability than undialyzed chitosan gel at 3 days culture. This result indicates improved biocompatibility of the delivery system. The chitosan/β-GP gels were enzymatically degradable for 3 weeks incubation and inhibited cancer cell growth in vitro in an ellagic acid concentration dependent manner. The significant inhibitory effect (p\u3c0.05) was found in the gel containing 1% (w/v) of ellagic acid compared with other groups. Viability of U87 cells and C6 cells cultured on chitosan gels containing 1% (w/v) of ellagic acid were lower than the same cells on chitosan gels at 3 days incubation by 3.8 times and 6.5 times, respectively. This research has demonstrated that the chitosan/ellagic acid delivery system is a promising biomaterial for a local cancer treatment. This study has also suggested a potential strategy with higher efficacy and lower toxicity to treat tumors by the combination of naturally based biopolymers such as chitosan and phenolic compounds such as ellagic acid. This study provides some rationale for further investigation of implantable polymeric delivery system

A novel regulator of the p53-mediated mitochondrial apoptotic pathway

The p53 tumor suppressor protein induces apoptosis in response to genotoxic and environmental stress. Recent studies have revealed the existence of a transcription-independent mitochondrial p53 apoptosis pathway, however the mechanism regulating p53 translocation to mitochondria and subsequent initiation of apoptosis was not known. Here, we show that Tid1, also known as mtHsp40 or Dnaja3, interacts with p53 and directs its translocation to mitochondria in cells exposed to hypoxia. Overexpression of Tid1 in tumor cells promoted mitochondrial localization of both wildtype and mutant forms of p53 and was able to restore the pro-apoptotic activity of mutant p53 proteins that were otherwise unable to induce apoptosis. Tid1's mitochondrial signal sequence and DnaJ domain were both required for the movement of the p53-Tid1 complex from the cytosol to the mitochondria. Our findings establish Tid1 as a novel regulator of p53 localization and apoptotic function

Survivorship in International Chain Restaurant in Korea

Several western chains have done well in Korea, while others have withdrawn from the market. The authors summarize the current operational results of western chain restaurants in Korea, report positive impacts of western foodservice firms, and analyze the key elements leading to their survival and non-survival. Some lessons could be used as tools to establish entrance strategies of western chain restaurants in Korea as well as in other Asian market

Application of Depth-Averaged 2D Numerical Model for Evaluation of the Vegetal Resistance in a Natural River

Source: ICHE Conference Archive - https://mdi-de.baw.de/icheArchiv

A house price valuation based on the random forest approach: the mass appraisal of residential property in South Korea

Mass appraisal is the standardized procedure of valuing a large number of properties at the same time and is commonly used to compute real estate tax. While a hedonic pricing model based on the ordinary least squares (OLS) linear regression has been employed as the traditional method in this process, the stability and accuracy of the model remain questionable. This paper investigates the features of a house price predictor based on the Random Forest (RF) method by comparing it with that of a conventional hedonic pricing model. We used apartment transaction data from the period of 2006 to 2017 in the district of Gangnam, one of the most developed areas in South Korea. Using a data set covering 40% of all transactions in the sample area, we demonstrate that the accuracy of a machine learning-based predictor can be surprisingly high. The average of percentage deviations between the predicted and the actual market price was found to be only around 5.5% in the RF predictor, whereas it was almost 20% in the OLS-based predictor. With the RF predictor, the probability of the predicted price being within 5% of its actual market price was 72%, while only about 17.5% of the regression-based predictions fell within the same range. These results show that, in the practice of mass appraisal, the RF method may be a useful complement to the hedonic models, as it more adequately captures the complexity or non-linearity of actual housing markets. First published online 03 February 202

Measuring national capability over big science's multidisciplinarity: A case study of nuclear fusion research

In the era of big science, countries allocate big research and development budgets to large scientific facilities that boost collaboration and research capability. A nuclear fusion device called the "tokamak" is a source of great interest for many countries because it ideally generates sustainable energy expected to solve the energy crisis in the future. Here, to explore the scientific effects of tokamaks, we map a country's research capability in nuclear fusion research with normalized revealed comparative advantage on five topical clusters-material, plasma, device, diagnostics, and simulation-detected through a dynamic topic model. Our approach captures not only the growth of China, India, and the Republic of Korea but also the decline of Canada, Japan, Sweden, and the Netherlands. Time points of their rise and fall are related to tokamak operation, highlighting the importance of large facilities in big science. The gravity model points out that two countries collaborate less in device, diagnostics, and plasma research if they have comparative advantages in different topics. This relation is a unique feature of nuclear fusion compared to other science fields. Our results can be used and extended when building national policies for big science.11Yscopu