Prognostic implications and interaction of L1 methylation and p53 expression statuses in advanced gastric cancer

Background TP53 is frequently mutated across various tissue types of cancers. In normal cells, long interspersed nuclear element-1 (LINE-1, L1) is mostly repressed by DNA methylation in its 5′ untranslated region but is activated by DNA demethylation process during tumorigenesis. p53 is indispensable for maintaining genomic stability and plays its role in controlling genomic stability by repressing retrotransposon activity. However, it is unclear whether p53 regulates expression or methylation of L1 differently depending on the mutational status of TP53. Four hundred ninety cases of advanced gastric cancer (AGC) were analyzed for their statuses in p53 expression and L1 methylation using immunohistochemistry and pyrosequencing, respectively. Whether L1 methylation and expression statuses were differently affected by types of TP53 mutants was analyzed in gastric cancer cell line. Results By p53 immunohistochemistry, tumors were classified into 4 groups according to the intensity and extent of stained tumor nuclei. L1 methylation level was significantly higher in p53 expression group 1 than in the other groups in which L1 methylation level was similar (P <  0.001). Although L1 methylation and p53 expression statuses were associated with patient survival, multivariate analysis revealed that L1 methylation was an independent prognostic parameter. In in vitro analysis of AGS cells with the introduction of wild type or mutant types of TP53, L1 methylation level and activity were different depending on types of TP53 mutation. Conclusions Findings suggest that L1 methylation level is affected by TP53 mutation status; although, L1 methylation status was an independent prognostic parameter in patients with AGC. Further study is required to elucidate the mechanism of how wild type or mutant p53 affects L1 activity and methylation status of L1 CpG island.This work was supported by a grant from the National Research Foundation (NRF) funded by the Korean Ministry of Science, ICT and Future Planning (2016M3A9B6026921), and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Korean Ministry of Health and Welfare (HI14C1277)

Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification

Study Of A Hybrid Magnet Array For An Electrodynamic Maglev Control

This paper introduces an innovative hybrid array consisting of both permanent and electro magnets. It will enable us to develop an active control mechanism for underdamped electro-dynamic suspension (EDS) Maglev systems. The proposed scheme is based on the Halbach array configuration which takes the major technical advantage from the original Halbach characteristics: a strongly concentrated magnetic field on one side of the array and a cancelled field on the opposite side. In addition, the unique feature of the proposed concept only differs from the Halbach array with permanent magnets. The total magnetic field of the array can be actively controlled through the current of the electro-magnet\u27s coils. As a result, the magnetic force produced by the proposed hybrid array can also be controlled actively. This study focuses on the magnetic characteristics and capability of the proposed array as compared to the basic Halbach concept. The results show that the proposed array is capable of producing not only an equivalent suspension force of the basic Halbach permanent magnet array but also a controlled mode. Consequently, the effectiveness of the proposed array confirms that this study can be used as a technical framework to develop an active control mechanism for an EDS Maglev system. © The Korean Magnetics Society. All rights reserved

A Single-Loop Repetitive Voltage Controller with an Active Damping Control Technique

This paper proposes a single-loop repetitive voltage control strategy which incorporates the active damping control feature for single-phase uninterruptible power supply (UPS) applications. The proposed method reduces the effect of the LC resonant peak, which limits the control bandwidth and deteriorates the stability of the entire control loop by effectively increasing the damping component. Due to the increased stability margin, a repetitive controller working together with a proportional-resonant (PR) controller can be easily adopted. Moreover, the voltage error is minimized even under severe non-linear load conditions. It is confirmed that the proposed single-loop controller achieves excellent and stable voltage regulation performance by evaluating the entire loop-gain of the system and the output impedance. Both the simulation and the experimental results for a 1.5 kW UPS inverter show agree well with the analyses, and the excellence of the proposed method has been verified

Breathing sounds analysis system for early detection of airway problems in patients with a tracheostomy tube

Abstract To prevent immediate mortality in patients with a tracheostomy tube, it is essential to ensure timely suctioning or replacement of the tube. Breathing sounds at the entrance of tracheostomy tubes were recorded with a microphone and analyzed using a spectrogram to detect airway problems. The sounds were classified into three categories based on the waveform of the spectrogram according to the obstacle status: normal breathing sounds (NS), vibrant breathing sounds (VS) caused by movable obstacles, and sharp breathing sounds (SS) caused by fixed obstacles. A total of 3950 breathing sounds from 23 patients were analyzed. Despite neither the patients nor the medical staff recognizing any airway problems, the number and percentage of NS, VS, and SS were 1449 (36.7%), 1313 (33.2%), and 1188 (30.1%), respectively. Artificial intelligence (AI) was utilized to automatically classify breathing sounds. MobileNet and Inception_v3 exhibited the highest sensitivity and specificity scores of 0.9441 and 0.9414, respectively. When classifying into three categories, ResNet_50 showed the highest accuracy of 0.9027, and AlexNet showed the highest accuracy of 0.9660 in abnormal sounds. Classifying breathing sounds into three categories is very useful in deciding whether to suction or change the tracheostomy tubes, and AI can accomplish this with high accuracy

Utilizing inactive storage in a dam reservoir during extreme drought periods

The purpose of this study is to suggest a structural plan for improving the utilization of inactive storage in dam reservoirs, to mitigate extreme drought. Inactive storage in the dam is composed of emergency storage and dead storage. The emergency storage can be used in emergencies such as drought. But, in general, the dead storage for sedimentation is not used, even in an emergency. Therefore, we developed a methodology to determine how the dead storage space can be partially used during extreme drought periods when the sedimentation has not occurred yet. We call this partial space in a dam reservoir “drought storage”. An accurate analysis of sediment levels needs to be performed before calculating drought storage, and so the present sediment level in the dam reservoir was estimated using SED-2D linked with the RMA-2 model of SMS. After considering the additional available storage capacity based on the estimated sediment level, drought storage was finally determined. We also predicted future sediment levels after 100 years and suggest the amount of drought storage available in the future. As a result, we found that the available drought storage will be lower in the future compared to present drought storage, due to the gradual increase in reservoir sedimentation over time in the dam. Further research may be needed to effectively reduce sedimentation in order to increase the drought storage capacity

Convolutional Neural Network Classifies Pathological Voice Change in Laryngeal Cancer with High Accuracy

Voice changes may be the earliest signs in laryngeal cancer. We investigated whether automated voice signal analysis can be used to distinguish patients with laryngeal cancer from healthy subjects. We extracted features using the software package for speech analysis in phonetics (PRAAT) and calculated the Mel-frequency cepstral coefficients (MFCCs) from voice samples of a vowel sound of /a:/. The proposed method was tested with six algorithms: support vector machine (SVM), extreme gradient boosting (XGBoost), light gradient boosted machine (LGBM), artificial neural network (ANN), one-dimensional convolutional neural network (1D-CNN) and two-dimensional convolutional neural network (2D-CNN). Their performances were evaluated in terms of accuracy, sensitivity, and specificity. The result was compared with human performance. A total of four volunteers, two of whom were trained laryngologists, rated the same files. The 1D-CNN showed the highest accuracy of 85% and sensitivity and sensitivity and specificity levels of 78% and 93%. The two laryngologists achieved accuracy of 69.9% but sensitivity levels of 44%. Automated analysis of voice signals could differentiate subjects with laryngeal cancer from those of healthy subjects with higher diagnostic properties than those performed by the four volunteers.11Ysciescopu

Dimethylfumarate suppresses adipogenic differentiation in 3T3-L1 preadipocytes through inhibition of STAT3 activity.

The excessive accumulation of adipocytes contributes to the development of obesity and obesity-related diseases. The interactions of several transcription factors, such as C/EBPβ, PPARγ, C/EBPα, Nrf2, and STAT3, are required for adipogenic differentiation. Dimethylfumarate (DMF), an immune modulator and antioxidant, may function as an inhibitor of STAT3 and an activator of Nrf2. This study examined whether DMF inhibits adipogenic differentiation of 3T3-L1 preadipocytes by inhibiting STAT3 or activating Nrf2. DMF suppressed 3T3-L1 preadipocyte differentiation to mature adipocytes in a dose-dependent manner as determined by Oil Red O staining. The mRNA and protein levels of adipogenic genes, including C/EBPβ, C/EBPα, PPARγ, SREBP-1c, FAS, and aP2, were significantly lower in DMF-treated 3T3-L1 preadipocytes. Suppression of adipogenic differentiation by DMF treatment resulted primarily from inhibition of the early stages of differentiation. DMF inhibits clonal expansion during adipogenic differentiation through induction of a G1 cell cycle arrest. Additionally, DMF regulates cell cycle-related proteins, such as p21, pRb, and cyclin D. DMF treatment markedly inhibited differentiation medium-induced STAT3 phosphorylation and inhibited STAT3 transcriptional activation of a reporter construct composed of four synthetic STAT3-response elements. Moreover, inhibition of endogenous Nrf2 activity using a dominant negative Nrf2 did not abolish the DMF-induced inhibition of adipogenic differentiation of 3T3-L1 preadipocytes. In summary, DMF is a negative regulator of adipogenic differentiation based on its regulation of adipogenic transcription factors and cell cycle proteins. This negative regulation by DMF is mediated by STAT3 inhibition, but is unlikely to involve Nrf2 activation

Dimethylfumarate attenuates restenosis after acute vascular injury by cell-specific and Nrf2-dependent mechanisms

Excessive proliferation of vascular smooth muscle cells (VSMCs) and incomplete re-endothelialization is a major clinical problem limiting the long-term efficacy of percutaneous coronary angioplasty. We tested if dimethylfumarate (DMF), an anti-psoriasis drug, could inhibit abnormal vascular remodeling via NF−E2-related factor 2 (Nrf2)-NAD(P)H quinone oxidoreductase 1 (NQO1) activity. DMF significantly attenuated neointimal hyperplasia induced by balloon injury in rat carotid arteries via suppression of the G1 to S phase transition resulting from induction of p21 protein in VSMCs. Initially, DMF increased p21 protein stability through an enhancement in Nrf2 activity without an increase in p21 mRNA. Later on, DMF stimulated p21 mRNA expression through a process dependent on p53 activity. However, heme oxygenase-1 (HO-1) or NQO1 activity, well-known target genes induced by Nrf2, were dispensable for the DMF induction of p21 protein and the effect on the VSMC proliferation. Likewise, DMF protected endothelial cells from TNF-α-induced apoptosis and the dysfunction characterized by decreased eNOS expression. With knock-down of Nrf2 or NQO1, DMF failed to prevent TNF-α-induced cell apoptosis and decreased eNOS expression. Also, CD31 expression, an endothelial specific marker, was restored in vivo by DMF. In conclusion, DMF prevented abnormal proliferation in VSMCs by G1 cell cycle arrest via p21 upregulation driven by Nrf2 and p53 activity, and had a beneficial effect on TNF-α-induced apoptosis and dysfunction in endothelial cells through Nrf2–NQO1 activity suggesting that DMF might be a therapeutic drug for patients with vascular disease