Spheroid-Induced Epithelial-Mesenchymal Transition Provokes Global Alterations of Breast Cancer Lipidome: A Multi-Layered Omics Analysis

Metabolic rewiring has been recognized as an important feature to the progression of cancer. However, the essential components and functions of lipid metabolic networks in breast cancer progression are not fully understood. In this study, we investigated the roles of altered lipid metabolism in the malignant phenotype of breast cancer. Using a spheroid-induced epithelial-mesenchymal transition (EMT) model, we conducted multi-layered lipidomic and transcriptomic analysis to comprehensively describe the rewiring of the breast cancer lipidome during the malignant transformation. A tremendous homeostatic disturbance of various complex lipid species including ceramide, sphingomyelin, ether-linked phosphatidylcholines, and ether-linked phosphatidylethanolamine was found in the mesenchymal state of cancer cells. Noticeably, polyunsaturated fatty acids composition in spheroid cells was significantly decreased, accordingly with the gene expression patterns observed in the transcriptomic analysis of associated regulators. For instance, the up-regulation of SCD, ACOX3, and FADS1 and the down-regulation of PTPLB, PECR, and ELOVL2 were found among other lipid metabolic regulators. Significantly, the ratio of C22:6n3 (docosahexaenoic acid, DHA) to C22:5n3 was dramatically reduced in spheroid cells analogously to the down-regulation of ELOVL2. Following mechanistic study confirmed the up-regulation of SCD and down-regulation of PTPLB, PECR, ELOVL2, and ELOVL3 in the spheroid cells. Furthermore, the depletion of ELOVL2 induced metastatic characteristics in breast cancer cells via the SREBPs axis. A subsequent large-scale analysis using 51 breast cancer cell lines demonstrated the reduced expression of ELOVL2 in basal-like phenotypes. Breast cancer patients with low ELOVL2 expression exhibited poor prognoses (HR = 0.76, CI = 0.67–0.86). Collectively, ELOVL2 expression is associated with the malignant phenotypes and appear to be a novel prognostic biomarker in breast cancer. In conclusion, the present study demonstrates that there is a global alteration of the lipid composition during EMT and suggests the down-regulation of ELOVL2 induces lipid metabolism reprogramming in breast cancer and contributes to their malignant phenotypes

QT Prolongation and Life Threatening Ventricular Tachycardia in a Patient Injected With Intravenous Meperidine (Demerol®)

QT prolongation is a serious adverse drug effect, which is associated with an increased risk of Torsade de pointes and sudden death. Many drugs, including both cardiac and non-cardiac drugs, have been reported to cause prolongation of QT interval. Although meperidine has not been considered proarrhythmic, we present a unique case of a 16-year-old boy without an underlying cardiac disease, who developed polymorphic ventricular tachycardia, ventricular fibrillation and QT prolongation after an intravenous meperidine injection. He had no mutation in long QT syndrome genes (KCNQ1, KCNH2, and SCN5A), but single nucleotide polymorphisms were reported, including H558R in SCNA5A and K897T in KCNH2

Prediction of Recurrence by Preoperative Intratumoral FDG Uptake Heterogeneity in Endometrioid Endometrial Cancer

PURPOSE: To investigate the prognostic value of preoperative intratumoral 18F-FDG uptake heterogeneity (IFH) derived from positron emission tomography (PET)/computed tomography (CT) in patients with endometrioid endometrial cancer. METHODS: We retrospectively evaluated clinicopathological data from patients with pathologically proven endometrioid endometrial cancer who had undergone 18F-FDG PET/CT scans before surgery. Patients were divided into two groups according to their IFH. The main outcome measure was disease-free survival (DFS). RESULTS: Between January 2010 and January 2015, data from 72 patients were available for analysis. The median duration of DFS was 23 months (range, 6 to 57 months), and 4 (5.6%) patients experienced recurrence. There were significant differences in tumor size, IFH, and DFS between patients with and without recurrence. In regression analysis, high IFH value [P = .007, hazard ratio (HR) 2.545, 95% confidence interval (CI) 1.468-8.674] was the only independent risk factor for recurrence. The Kaplan-Meier survival graphs showed that DFS significantly differed in groups categorized based on IFH (P < .001, log-rank test). CONCLUSIONS: Preoperative IFH measured by 18F-FDG PET/CT was associated with recurrence of endometrioid endometrial cancer. The finding supports evidence that FDG-based heterogeneity can be a novel and useful predictor of endometrioid endometrial cancer recurrence

Development of Automatic Crack Growth Simulation Program Based on Finite Element Analysis

A crack growth simulation program based on the advanced iterative-finite element method (AI-FEM) was developed to predict realistic crack growth of structures. The developed program was suggested to calculate the exact stress intensity factor for arbitrary structures by regenerating the crack tip mesh as the crack grows. The main advantages of the developed program are to estimate each different crack growths along the crack tip line and to simulate the cracking transition from a surface crack to a through-wall crack under a complex stress field. For these purposes, the sensitivity analyses were performed for various influence variables on stress intensity factors, such as element types and crack dimensions. Based on the results of sensitivity analyses, the appropriate criteria for crack tip modeling to be used in AI-FEM were suggested to calculate sufficient converged SIF. The program developed in this research was validated through stress corrosion crack growth and natural crack growth examples including cracking transition, and it was confirmed that the program simulates crack growth well and has reasonable methods for cracking transition

Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts

Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G&gt;A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload

Reactivity and Curing Efficiency of Isocyanate Cross-Linkers with Imidazole-Based Blocking Agents for Low-Temperature Curing of Automotive Clearcoats

For the application of low-temperature curing on automotive clearcoats, isocyanate cross-linkers blocked with imidazole derivatives were newly synthesized. The effect of the alkyl groups in the imidazole derivatives on the deblocking behavior and curing kinetics was investigated. The free isocyanate groups exposed by the deblocking of imidazole-based blocking agents were monitored by real-time Fourier-transform infrared spectroscopy. The bond dissociation energy, activation energy of deblocking, and H-N distance were interpreted through density functional theory simulation of various imidazole-based blocked isocyanates. To evaluate their applicability to automotive clearcoats, the synthesized imidazole-based blocked isocyanates were mixed with a polyol binder containing hydroxyl groups, and the clearcoat samples were cured at relatively low curing temperatures (100, 110, and 120 degrees C). The real-time storage modulus was measured using a rotational rheometer to elucidate the thermal curing dynamics by the blocking agents. In addition, the surface hardness of the cured clearcoat layers, which is affected by the chemical structure of the imidazole derivatives, was evaluated by nanoindentation test. In-depth analyses of the deblocking behaviors and thermal curing properties of clearcoats using imidazole-based blocked isocyanates demonstrated that the newly developed coating system could be suitably applied for the development of low-temperature curing technology

Pre-Oxidation Effect of a Zirconium-silicide Sputtered Surface on Boiling Performance and Oxidation Resistance

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Modeling and Analysis of a Low-Voltage DC Distribution System

It is well known that the Low-Voltage DC (LVDC) distribution system is a promising topology as a future smart distribution system due to its high efficiency and reliability. However, there are still some challenges in the construction and implementation of an LVDC system. For practical application of the LVDC system, therefore, it is necessary to perform any simulation in advance by considering various conditions that can occur in an LVDC system. In order to provide a foundation for analyzing a DC system, this paper presents an LVDC distribution system model including essential components such as power electronic devices, Distributed Energy Resource (DER), and Energy Storage System (ESS), which can be considered for implementation in an LVDC system using Electro-Magnetic Transient Program (EMTP) software. Moreover, an analysis of the characteristic in both the steady state and the transient state is conducted in an LVDC distribution system