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Hyperactivated m-calpain affects acquisition of doxorubicin resistance in breast cancer cells
No full textBackground: Doxorubicin is commonly using chemotherapeutic agents for breast cancer. However, doxorubicin has limitations in clinical use because of dose-dependent cardiotoxicity and drug resistance. Despite of previously reported studies about mechanisms of doxorubicin resistance including overexpression of P-gp and abnormal expression and mutation of topoisomerase IIα, resistance to this agent still abundantly occur and is regarded as a major obstacle to successful treatment. Methods: We have established doxorubicin resistant T47D cells. Intracellular calcium and ROS levels and calpain activity were measured using fluorometric experiments. Cell viability assay, cell cycle analysis, immunofluorescence and western blot analysis were performed to evaluate m-calpain specific truncation of topoisomerase IIα and molecular mechanism in doxorubicin resistant cells. Results: We observed that doxorubicin treatment increased intracellular calcium and ROS (Reactive Oxygen Species) in parental and doxorubicin resistant T47D cells. The increases in intracellular calcium and ROS were much greater in doxorubicin resistant T47D cells, which led to higher activity of calpains. Hyperactivated m-calpain, but not μ-calpain, specifically induced cleavage of topoisomerase IIα and accumulation of truncated topoisomerase IIα in the cytoplasm. The increase in cytoplasmic truncated topoisomerase IIα reduced the efficacy of doxorubicin. Doxorubicin resistant T47D cells, with hyperactivated m-calpain and truncated cytosolic topoisomerase IIα, obtained cross-resistance to other topoisomerase II-targeting drugs. Conclusion: Hyperactivated m-calpain induced cytoplasmic accumulation of truncated topoisomerase IIα in doxorubicin resistant T47D cells. General significance: These data provide a new mechanism of doxorubicin resistance and suggest a novel strategy for overcoming drug resistance in topoisomerase IIα-targeting therapy. © 2018 Elsevier B.V.Ministry of Education, Science and Technolog
Optimal design of hydraulic fracturing in porous media using the phase field fracture model coupled with genetic algorithm
No full textWe present a framework for the coupling of fluid-filled fracture propagation and a genetic inverse algorithm for optimizing hydraulic fracturing scenarios in porous media. Fracture propagations are described by employing a phase field approach, which treats fracture surfaces as diffusive zones rather than of interfaces. Performance of the coupled approach is provided with applications to numerical experiments related to maximizing production or reservoir history matching for emphasizing the capability of the framework. © 2018, Springer International Publishing AG, part of Springer Nature.U.S. Department of Energ
Chest wall recurrence in pT1-2N0-1 breast cancer patients after mastectomy without radiotherapy
No full textPurpose: In correlation with the nodal status in the era of modern radiotherapy, the chest wall recurrence (CWR) rate was investigated in pT1-2N0-1 breast cancer patients after a mastectomy without post-mastectomy radiotherapy (PMRT). Methods: The data from the patients participating in two South Korean multi-institutional studies (KROG 14–22; N = 1842 and KROG 14–23; N = 1382) were analyzed. In total, 3224 pT1-2N0-1 breast cancer patients who underwent mastectomy without PMRT were analyzed. Results: The median follow-up time was 72.2 months (range 0.8–125.2 months). The overall CWRs during the follow-up period were 1.68% in N0 patients and 2.82% in N1 patients. There was no statistically significant difference in 5-year and 10-year CWR-free survival (CWRFS) between the N0 and N1 patients. Of the 70 patients with CWR, 33 (1% of all the patients) had isolated CWR, and the 10-year overall survival rate in this group was 96.9%. After the propensity score matching of the N0 and N1 groups, there was still no difference in CWRFS by nodal status. Conclusions: The incidence of CWR in pT1-2N0-1 breast cancer patients is very low, especially with isolated recurrence. Also, the obtained data showed that the nodal status had no impact on CWRFS. © 2018, Springer Science+Business Media, LLC, part of Springer Nature
Aerosol as a potential factor to control the increasing torrential rain events in urban areas over the last decades
No full textThis study examines the role played by aerosol in torrential rain that occurred in the Seoul area, which is a conurbation area where urbanization has been rapid in the last few decades, using cloud-system-resolving model (CSRM) simulations. The model results show that the spatial variability in aerosol concentrations causes the inhomogeneity of the spatial distribution of evaporative cooling and the intensity of associated outflow around the surface. This inhomogeneity generates a strong convergence field in which torrential rain forms. With the increases in the variability in aerosol concentrations, the occurrence of torrential rain increases. This study finds that the effects of the increases in the variability play a much more important role in the increases in torrential rain than the much-studied effects of the increases in aerosol loading. Results in this study demonstrate that for a better understanding of extreme weather events such as torrential rain in urban areas, not only changing aerosol loading but also changing aerosol spatial distribution since industrialization should be considered in aerosol-precipitation interactions
Lorentzian Lattices and E-Polytopes
No full textWe consider certain En-type root lattices embedded within the standard Lorentzian lattice Z(n+1) (3 <= n <= 8) and study their discrete geometry from the point of view of del Pezzo surface geometry. The lattice Z(n+1) decomposes as a disjoint union of affine hyperplanes which satisfy a certain periodicity. We introduce the notions of line vectors, rational conic vectors, and rational cubics vectors and their relations to E-polytopes. We also discuss the relation between these special vectors and the combinatorics of the Gosset polytopes of type (n-4)(21)
Smoking aggravates ventricular arrhythmic events in non-ischemic dilated cardiomyopathy associated with a late gadolinium enhancement in cardiac MRI
No full textSmoking is known to increase cardiovascular events, but the association and mechanisms between smoking and ventricular arrhythmic events in dilated cardiomyopathy ( DCMP) are unknown. The purpose of this study is to investigate the hypothesis that smoking is associated with sudden cardiac death (SCD) and ventricular arrhythmia in DCMP patients. We enrolled 378 patients who underwent cardiovascular magnetic resonance imaging (cMRI) and were diagnosed with DCMP at two general hospitals in Korea. The clinical data and left ventricular late-gadolinium enhancement (LV-LGE) of all patients were analyzed according to being never-smokers or smokers. Smokers were more likely to be male than never-smokers, but there was no other clinical difference between them. Smokers had a greater LV-LGE ratio, and multi-segment involvement of LV-LGEs. Smoking and a low left ventricular (LV) ejection fraction were significant predictors of the presence of LV-LGEs even after adjusting for optimal medical therapy. In addition, smokers had a higher fatal ventricular arrhythmic (FVA; sustained ventricular tachycardia, and ventricular fibrillation) and FVA + SCD, and ex-smokers had a similar FVA to never-smokers during 44.3 +/- 36.4 months of follow-up. Finally, smoking independently increased the FVA + SCD even after adjusting for the clinical variables and LV-LGE. Smoking is associated with a multi-segmental involvement of LV-LGE and increased FVA + SCD in DCMP patients when compared to never-smokers
Bioformation of Volatile and Nonvolatile Metabolites by Saccharomycopsis fibuligera KJJ81 Cultivated under Different Conditions-Carbon Sources and Cultivation Times
No full textSaccharomycopsis fibuligera KJJ81 isolated from nuruk is an amylolytic yeast that is widely used as a microbial starter in various fermented foods. Volatile and nonvolatile metabolites of S. fibuligera KJJ81 were investigated according to different carbon sources and cultivation times using a nontargeted metabolomic approach. Partial-least-squares discriminant analysis was applied to determine the major metabolites, which were found to be closely related to the clustering and discrimination of S. fibuligera KJJ81 samples. Some volatile metabolites derived from phenylalanine, such as 2-phenylethanol, 2-phenylethyl acetate, and ethyl phenylacetate, were predominantly found in cultivation medium containing glucose (YPD medium). In addition, the level of 2-phenylethanol increased continuously with the cultivation time. In terms of nonvolatile metabolites, carbohydrates (mannose, arabitol, and mannitol), fatty acids (palmitic acid and stearic acid), organic acids (oxalic acid and succinic acid), and amino acids (isoleucine, serine, alanine, glutamic acid, glycine, proline, phenylalanine, and threonine) were the main contributors to S. fibuligera KJJ81 samples cultivated in YPD medium according to cultivation time. These results show that the formation of volatile and nonvolatile metabolites of S. fibuligera KJJ81 can be significantly affected by both the carbon sources and the cultivation time
Discovery of Ezrin Expression as a Potential Biomarker for Chemically Induced Ocular Irritation Using Human Corneal Epithelium Cell Line and a Reconstructed Human Cornea-like Epithelium Model
No full textNumerous studies have attempted to develop a new in vitro eye irritation test (EIT). To obtain more reliable results from EIT, potential new biomarkers that reflect eye irritation by chemicals must be identified. We investigated candidate biomarkers for eye irritation, using a proteomics approach. Sodium lauryl sulfate (SLS) or benzalkonium chloride (BAC) was applied on a reconstructed human cornea-like epithelium model, MCTT HCE, and corneal protein expression was examined by two-dimensional gel electrophoresis. We found that ezrin (EZR) was significantly upregulated by SLS or BAC. In addition, upregulation of EZR in immortalized human corneal cells treated with SLS or BAC was confirmed by quantitative reverse transcription-PCR and western blot analysis. Furthermore, other well-known eye irritants such as cetylpyridinium bromide, Triton X-100, cyclohexanol, ethanol, 2-methyl-1-pentanol, and sodium hydroxide significantly increased EZR expression in immortalized human corneal cells. Induction of EZR promoter activity in irritant-treated human corneal cells was confirmed by a luciferase gene reporter assay. In conclusion, EZR expression may be a potential biomarker for detecting eye irritation, which may substantially improve the performance of in vitro EIT
Does hunger for bonuses drive the dependence between claim frequency and severity ?
No full textAuto ratemaking models have traditionally assumed independence between claim frequency and severity. With the development of insurance claim models that can accommodate dependence between claim frequency and severity, a series of recent studies has revealed that the aforementioned dependence between frequency and severity exists for auto insurance claims, demonstrating the validity of such models. However, the underlying process that creates this dependence has received little attention in the literature. Thus, we show that a rational decision-making process of drivers known as bonus hunger can systemically induce dependence between the claim frequency and severity even when the ground-up loss frequency and severity are, in fact, independent. Our model, based on the random effect model coupled with the standard bonus-malus system, successfully explains the seemingly contradictory results from the existing literature of weak positive dependence, between the claim frequency and severity for liability claims, and moderately negative dependence for collision claims. Our findings show that the seemingly contradicting dependence structures reported in the literature may be neither accidental nor sample specific. Furthermore, the bonus-hunger process also implies that the level of the claim frequency-severity dependence varies across bonus-malus classes, suggesting that a uniform dependency structure may not be appropriate for auto ratemaking modeling. (C) 2018 Elsevier B.V. All rights reserved
Development of 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and their salts as potent cytotoxic agents and topoisomerase I/II alpha inhibitors
No full textA novel series of 35 angularly fused pentacyclic 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridin-5-ium chlorides were designed and synthesized. Their cytotoxic activities were investigated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Among all screened compounds; 28, 30, 34, 35, 46, 48, 52, and 53 compounds exhibited potent cytotoxic activities against all tested human cancer cell lines. Further, these potent lead cytotoxic agents were evaluated against human Topoisomerase I and II alpha inhibition. Among them, the compound 48 exhibited dual Topoisomerase I and II alpha inhibition especially at 20 mu M concentrations the compound 48 exhibited 1.25 times more potent Topoisomerase II alpha inhibitory activity (38.3%) than the reference drug etoposide (30.6%). The compound 52 also exhibited excellent (88.4%) topoisomerase I inhibition than the reference drug camptothecin (66.7%) at 100 mu M concentrations. Molecular docking studies of the compounds 48 and 52 with topo I discovered that they both intercalated into the DNA single-strand cleavage site where the compound 48 have van der Waals interactions with residues Arg364, Pro431, and Asn722 whilst the compound 52 have with Arg364, Thr718, and Asn722 residues. Both the compounds 48 and 52 have pi-pi stacking interactions with the stacked DNA bases. The docking studies of the compound 48 with topo IIa explored that it was bound to the topo II alpha DNA cleavage site where etoposide was situated. The benzo[f]chromeno[4,3-b][1,7]naphthyridine ring of the compound 48 was stacked between the DNA bases of the cleavage site with pi-pi stacking interactions and there were no hydrogen bond interactions with topo II alpha