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The purpose of this study is to confirm the effect of the expanded marketing mix factors of hair shop on customer citizenship behavior. This study was attempted to verify through the mediating effect of perceived value and the moderating effect of personality type in this influence relationship. Data collection in this study distributed 310 questionnaires, and 271 copies were used for the final analysis. the main analysis results derived through data analysis are as follows. First, it was found that the expanded marketing mix had a significant effect on perceived value and customer citizenship behavior. Second, among the expanded marketing mix factors, People and Evidence factors had a positive effect in common on perceived value and customer citizenship behavior. Third, the perception of perceived value in the influence relationship between the expanded marketing mix and customer citizenship behavior shows a mediating effect. In addition, it was found that introverted personality had a positive (+) moderating effect on the path of increasing customer citizenship behavior. The results derived through this study would have helped the hair shop marketing plan and basic data acquisition. In other words, it's important to have an outgoing customer who directly requires the requirements, but paying more attention to less expressive introverts is more effective at boosting customer’s citizenship behavior.

Purpose: Recent studies have revealed that the expression of cancer-associated fibroblast (CAF) activation biomarkers in cancer cells is associated with clinical outcomes in patients with certain types of malignant tumors. However, whether the expression of CAF activation biomarkers affects the prognosis of colorectal cancer (CRC) has not been fully elucidated. This study aimed to evaluate the association between the expression of CAF activation biomarkers in cancer cells with cancer invasion and long-term oncological outcomes in patients with CRC.Methods: Cancer specimens obtained from 135 patients with stage I–III CRC were examined using immunohistochemical staining to evaluate the expression of fibroblast specific protein-1 (FSP-1), fibroblast activation protein α (FAPα), α-smooth muscle actin (α-SMA), and vimentin in cancer cells.Results: FSP-1 expression in cancer cells was significantly associated with lymphatic invasion, perineural invasion, tumor (T) status, and lymph node (N) status. FAPα expression in cancer cells was significantly associated with lymphatic invasion. On univariate and multivariate analyses, FSP-1 and α-SMA expression in cancer cells were associated with a short 10-year overall survival (OS) and high 10-year systemic recurrence (SR), respectively. Tumor budding was associated with a short 10-year OS. However, FAPα and vimentin did not contribute to the prognosis in this study.Conclusion: In this study, we found that FSP-1 expression in cancer cells was related to cancer invasion. Additionally, FSP-1 and α-SMA expression in cancer cells was associated with 10-year OS and SR, respectively. Therefore, these markers may be used as predictors of long-term oncological outcomes in patients with CRC.

4P mix(Product, Place, Promotion, Price) was mainly used as a marketing mix strategy for manufactured goods. However, in the service industry, in addition to this 4P mix, the need to add 3P mix (Physical Evicence, People, Process) has emerged due to its characteristics. These service marketing 7P mixes are applied and implemented in various ways to the beauty industry. This study was attempted based on these service marketing 7P mix elements. In other words, the purpose of this study is to verify which of the 7P mixes elements of service marketing for beauty industry affects the customer's preference behavior and experience satisfaction. Data collection for this study was conducted through a survey of people who have used beauty salon. Structural equation analysis was conducted using the statistical program AMOS & SPSS with the collected data. As a result of the test of this study hypothesis, it was found that ‘People’ factor had the highest positive effect on customers' preference behavior and experience satisfaction. In future studies, more extended research that can be variables that can effect on customer's preference behavior and experience satisfaction needs to be attempted.

The purpose of this study is to explore the influencing factors on customer loyalty in terms of service recovery in beauty service field. In a fiercely competitive environment, if a service failure fails to meet customer expectations and needs, what service recovery efforts can have an effective and positive effect on securing customer satisfaction and loyalty. To achieve the purpose of this study, the analysis was conducted based on the collected data of 271 consumers with experience using beauty services. As a result of the analysis, among the factors of recovery equities, the factors of handling equity and information equity showed a significant influence on recovery satisfaction. And service recovery satisfaction confirmed the role of service recovery as a mediator in the relationship between equity recognition and customer loyalty. This study is meaningful in that the equity of service recovery was set as an influence variable for customer loyalty. However, in order to expand the generalization of the results of this study, It seems necessary to balance the subjects and expand the influence variables in subsequent studies.

Background Coronary artery disease is a cardiovascular disease with a high mortality and mortality rate in modern society. Vascular stent insertion to restore blood flow is essential to treat this disease. A fully biodegradable vascular scaffold (BVS) is a vascular poly (L-lactic acid) (PLLA) stent that is receiving growing interest as this is biodegradable in the body and does not require secondary removal surgery. However, acidic byproducts composed of PLLA produced during the biodegradation of the BVS can induce an inflammatory response. Magnesium hydroxide, a basic inorganic particle, neutralizes the acidic byproducts of PLLA. Methods In this study, we investigated using a BVS coated with everolimus and surface-modified magnesium hydroxide that suppresses smooth muscle cell proliferation and protects endothelial cells, respectively. The various characteristics of the functional stent were evaluated using in vitro and in vivo analyses. Results The BVS was successfully prepared with evenly coated everolimus and surface-modified magnesium hydroxide. A neutral pH value was maintained by magnesium hydroxide during degradation, and everolimus was released for one month. The coated BVS effectively inhibited protein adsorption and platelet adhesion, demonstrating excellent blood compatibility. In vitro analysis showed that BVS protects endothelial cells with magnesium hydroxide and selectively inhibits smooth muscle cell proliferation via everolimus treatment. The functional BVS was inserted into porcine coronary arteries for 28 days, and the results demonstrated that the restenosis and inflammation greatly decreased and re-endothelialization was enhanced as compared to others. Conclusions This study provides new insights into the design of drug-incorporated BVS stent for coronary artery disease. Graphical Abstract

Background In clinical practice, one of the most important issues regarding the use of botulinum neurotoxin A (BoNT-A) is the proper storage conditions and the change in potency and quality over time after reconstitution. Objective This study aimed to investigate the change in potency and quality of reconstituted prabotulinumtoxin A (PraBoNT-A) over time when stored at different storage temperatures. Materials and methods ICR/CD-1 mice and PraBoNT-A were used for the mouse intraperitoneal lethal dose 50% (LD50) test. A thorough quality evaluation of the product was performed. Results All of the reconstituted PraBoNT-A stored at different temperatures met the evaluation criteria for the suggested limits of estimated potency and for the quality assessment at every evaluated time point. When the stability of reconstituted PraBoNT-A was evaluated by regression analysis, the shelf life of reconstituted PraBoNT-A was found to be 99.24, 73.80, and 16.34 weeks in the case of PraBoNT-A stored at freezing, refrigeration, or room temperatures, respectively. Conclusion Based on the results, the authors conclude that the efficacy and quality of the reconstituted PraBoNT-A product are not compromised at least for a certain period of time and that the shelf life of reconstituted PraBoNT-A is longest when stored at the freezing temperature.

The aim of this study was to evaluate temporal changes in coronary hemodynamic and physiological indexes in the non-infarct-related artery (IRA), which might be affected by adjacent infarcted myocardium, using an experimental animal model of acute myocardial infarction.There has been debate on the reliability of fractional flow reserve and resting pressure-derived indexes, including instantaneous wave-free ratio, in the non-IRA in patients with acute ST-segment elevation myocardial infarction.In Yorkshire swine, acute myocardial infarction was simulated with selective balloon occlusion at the left circumflex coronary artery as the IRA for 30 min. Non-IRA stenosis was created using bare-metal stent implantation in the left anterior descending coronary artery 4 weeks before the experiments. Serial changes in systemic hemodynamic status, coronary pressure, and Doppler-derived coronary flow velocity were measured in a nonoccluded left anterior descending coronary artery as the non-IRA from baseline, balloon occlusion of the left circumflex coronary artery, and 15 min after reperfusion of the left circumflex coronary artery.Among the 6 experimental subjects, the median diameter stenosis of the non-IRA was 33.9% (interquartile range: 21.7% to 46.1%). During balloon occlusion of the IRA, there were transient significant changes in both resting and hyperemic aortic pressure, distal coronary pressure, averaged peak velocity, transstenotic pressure gradient, and microvascular resistance of the non-IRA (p 0.020 for all). After reperfusion of the IRA, the resting averaged peak velocity (p = 0.002) and resting transstenotic pressure gradient (p = 0.004) were significantly increased and resting microvascular resistance (p = 0.004) was significantly decreased compared with their values in the baseline phase. However, the hyperemic averaged peak velocity (p = 0.479), hyperemic transstenotic pressure gradient (p = 0.778), and hyperemic microvascular resistance (p = 0.816) were not significantly different compared with those in the baseline phase. After reperfusion, fractional flow reserve in the non-IRA was not significantly different (0.94 ± 0.01 vs. 0.93 ± 0.01; p = 0.353), while coronary flow reserve (1.93 ± 0.07 vs. 1.36 ± 0.07; p = 0.025) and instantaneous wave-free ratio (0.97 ± 0.01 vs. 0.93 ± 0.01; p = 0.001) were significantly lower than baseline values.In a porcine model of acute myocardial infarction, occlusion of the IRA induced significant changes in systemic hemodynamic status and coronary circulatory indexes of the non-IRA. However, after reperfusion of the IRA, fractional flow reserve did not change significantly, whereas coronary flow reserve and instantaneous wave-free ratio showed significant changes compared with baseline values.

Objective Putaminal iron deposition is an important feature that helps differentiate multiple system atrophy with predominant parkinsonism (MSA-p) from Parkinson’s disease (PD). Most previous studies used visual inspection or quantitative methods with manual manipulation to perform this differentiation. We investigated the value of a new semiautomated diagnostic algorithm using 3T-MR susceptibility-weighted imaging for MSA-p.Methods This study included 26 MSA-p, 68 PD, and 41 normal control (NC) subjects. The algorithm was developed in 2 steps: 1) determine the image containing the remarkable putaminal margin and 2) calculate the phase-shift values, which reflect the iron concentration. The next step was to identify the best differentiating conditions among several combinations. The highest phaseshift value of each subject was used to assess the most effective diagnostic set.Results The raw phase-shift values were present along the lateral margin of the putamen in each group. It demonstrates an anterior- to-posterior gradient that was identified most frequently in MSA-p. The average of anterior 5 phase shift values were used for normalization. The highest area under the receiver operating characteristic curve (0.874, 80.8% sensitivity, and 86.7% specificity) of MSA-p versus PD was obtained under the combination of 3 or 4 vertical pixels and one dominant side when the normalization methods were applied. In the subanalysis for the MSA-p patients with a longer disease duration, the performance of the algorithm improved.Conclusion This algorithm detected the putaminal lateral margin well, provided insight into the iron distribution of the putaminal rim of MSA-p, and demonstrated good performance in differentiating MSA-p from PD.

In this study, a useful solution is proposed for assessing the safety of the ship’s hull damaged by grounding in Northern Sea Route (NSR) or Arctic sea. In particular, the residual ultimate longitu...

This study evaluated the effect of a novel triple drug-eluting stent containing antithrombotic abciximab, antioxidative alpha-lipoic acid (ALA), and antiproliferative sirolimus in a porcine model. The coronary arteries of pigs were randomized into three groups: triple drug-eluting stent (TES; n=10), sirolimus-eluting stent (SES; n=10), and bare metal stent (BMS; n=10). At 28 days after stent implantation, a histopathologic analysis was performed. There were no significant differences in the injury score. There were significant differences in the neointimal area (2.3±0.6 mm2 in TES vs. 2.5±0.88 mm2 in SES vs. 3.3±0.58 mm2 in BMS, p

Acute myocardial infarction (AMI) is considered the major cause of mortality in the world. Tremendous animal studies are performed to develop novel therapeutics, and this study aimed to induce porcine myocardial infarction model by using polyethylene terephthalate (PET). Coronary guidewire was placed in left anterior descending artery (LAD). The balloon angioplasty catheter was inserted at the back of the PET. The balloon catheter was carefully pushed forward, until the balloon marker was located in mid-LAD. Coronary angiography was performed pre- and post-occlusion at 28 days by C-arm. Histologic analysis of heart tissue was performed 28 days after inducing AMI. Thirty three pigs were anesthetized and underwent percutaneous coronary catheterization. All pigs were successfully embolized in mid-LAD by PET. Fifteen pigs died due to ventricular fibrillation during post-anesthetic recovery time, and overall experiment mortality was 45.5%. In 2,3,5- triphenyl tetrazolium chloride staining, gross finding of the ischemic heart lesion showed firm and white area of infarction associated with the apex and left ventricular posterior wall. Infarct on H&E-stained sections demonstrated a region without myocytes and rich with cardiomyocyte with atypical nuclei. Successful induction of AMI by using PET may provide the pathophysiological information of ischemic heart disease and improvement of therapy development for AMI.

Pigs are important experimental animals for cardiovascular research. Few porcine coronary atherosclerosis models have been developed; however, their induction requires more than six months. We developed a porcine coronary artery atherosclerosis model using nicotine injection with a balloon overdilation. A coronary balloon was placed in the porcine coronary artery and overdilated to induce a mechanical injury. Nicotine was administrated via intramuscular injection every day, and changes in the coronary artery were observed after four weeks. Coronary angiography revealed nicotine injection with a balloon overdilation group showed narrowing of the coronary artery at the injury site. The combination of balloon and nicotine significantly increased the intimal hyperplasia in optical coherence tomography analysis. Proliferated tunica media were noted in the nicotine injection with balloon overdilation groups and lack of collagen was observed in the tunica media at eight weeks. Quantitative analysis showed increased smooth muscle actin alpha (SMA), cluster of differentiation 68 (CD68), and Krüppel-like factor 4 (KLF4) in the nicotine injection with balloon overdilation groups. Immunohistochemistry results showed CD68-positive cells displayed SMA- and KLF4-positive reactivity in the border zone of the intimal hyperplasia. Our results show that nicotine injection with balloon overdilation can induce atherosclerotic lesions within one month, which can serve as an alternative pig animal model for the development of coronary stents.

Background: Titanium is commonly used in blood-exposed medical devices because it has superior blood compatibility. Mycophenolic acid inhibits the proliferation of vascular smooth muscle cells. This study examined the effect of a non-polymer TiO2 thin film–coated stent with mycophenolic acid in a porcine coronary overstretch restenosis model.Methods: Thirty coronary arteries in 15 pigs were randomized into three groups in which the coronary arteries were treated with a TiO2 film–coated stent with mycophenolic acid (NTM, n = 10), everolimus-eluting stent with biodegradable polymer (EES, n = 10), or TiO2 film–coated stent (NT, n = 10). A histopathologic analysis was performed 28 days after the stenting.Results: There were no significant intergroup differences in injury score, internal elastic lamina area, or inflammation score. Percent area stenosis was significantly smaller in the NTM and EES groups than in the NT group (36.1 ± 13.63% vs. 31.6 ± 7.74% vs. 45.5 ± 18.96%, respectively, p = 0.0003). Fibrin score was greater in the EES group than in the NTM and NT groups [2.0 (range, 2.0–2.0) vs. 1.0 (range, 1.0–1.75) vs. 1.0 (range, 1.0–1.0), respectively, p < 0.0001]. The in-stent occlusion rate measured by micro-computed tomography demonstrated similar percent area stenosis rates on histology analysis (36.1 ± 15.10% in NTM vs. 31.6 ± 8.89% in EES vs. 45.5 ± 17.26% in NT, p < 0.05).Conclusion: The NTM more effectively reduced neointima proliferation than the NT. Moreover, the inhibitory effect of NTM on smooth muscle cell proliferation was not inferior to that of the polymer-based EES with lower fibrin deposition in this porcine coronary restenosis model.

The recently identified molecule P7C3 has been highlighted in the field of pain research. We examined the effect of intrathecal P7C3 in tissue injury pain evoked by formalin injection and determined the role of the GABA system in the activity of P7C3 at the spinal level. Male Sprague-Dawley rats with intrathecal catheters implanted for experimental drug delivery were studied. The effects of intrathecal P7C3 and nicotinamide phosphoribosyltransferase (NAMPT) administered 10 min before the formalin injection were examined. Animals were pretreated with bicuculline, a GABA-A receptor antagonist; saclofen, a GABA-B receptor antagonist; L-allylglycine, a glutamic acid decarboxylase (GAD) blocker; and CHS 828, an NAMPT inhibitor; to observe involvement in the effects of P7C3. The effects of P7C3 alone and the mixture of P7C3 with GABA receptor antagonists on KCl-induced calcium transients were examined in rat dorsal root ganglion (DRG) neurons. The expression of GAD and the concentration of GABA in the spinal cord were evaluated. Intrathecal P7C3 and NAMPT produced an antinociceptive effect in the formalin test. Intrathecal bicuculline, saclofen, L-allylglycine, and CHS 828 reversed the antinociception of P7C3 in both phases. P7C3 decreased the KCl-induced calcium transients in DRG neurons. Both bicuculline and saclofen reversed the blocking effect of P7C3. The levels of GAD expression and GABA concentration decreased after formalin injection and were increased by P7C3. These results suggest that P7C3 increases GAD activity and then increases the GABA concentration in the spinal cord, which in turn may act on GABA receptors causing the antinociceptive effect against pain evoked by formalin injection.

Objectives: Clinical reproducibility of large animal models is important for developing new therapies for myocardial infarction (MI) and ischemic heart failure (IHF). This study aimed to induce MI and IHF in a swine model by using 3D bioprinted occluders to interrupt intravascular blood flow permanently. Methods: The 3D bioprinted occluder was placed in the proximal left anterior descending artery using a guide wire and a balloon catheter. Echocardiography was performed at the baseline, post MI (day 7-14), and at 28 days follow-up after the placement of the occluder to evaluate cardiac function. Quantitative coronary angiography was performed at baseline, post MI (immediately after the procedure) and at 42 days follow-up. Histopathology confirmed the deformation of the heart tissue and hypoxic damage.Results: Luminal diameter distal to the 3D bioprinted occluder was significantly reduced from the baseline to 42 days follow-up and left ventricular (LV) ejection fraction gradually decreased from the baseline to 28 days follow-up after the induction of MI. Tetrazolium staining showed firm and white area of the infarction in the LV apex and LV anterior wall. Hematoxylin and eosin stained section samples showed loss of normal architecture and morphology of myocytes in the LV myocardium. In addition, HIF-1 alpha was expressed in the ischemic myocardium area by immunohistochemistry staining. Conclusions: The customized occluder via 3D bioprinting technology could induce a stable, consistent and reproducible swine MI and IHF model.

Freezing of gait (FOG) is a commonly observed motor symptom for patients with Parkinson's disease (PD). The symptoms of FOG include reduced step lengths or motor blocks, even with an evident intention of walking. FOG should be monitored carefully because it not only lowers the patient's quality of life, but also significantly increases the risk of injury.In previous studies, patients had to wear several sensors on the body and another computing device was needed to run the FOG detection algorithm. Moreover, the features used in the algorithm were based on low-level and hand-crafted features. In this study, we propose a FOG detection system based on a smartphone, which can be placed in the patient's daily wear, with a novel convolutional neural network (CNN).The walking data of 32 PD patients were collected from the accelerometer and gyroscope embedded in the smartphone, located in the trouser pocket. The motion signals measured by the sensors were converted into the frequency domain and stacked into a 2D image for the CNN input. A specialized CNN model for FOG detection was determined through a validation process.We compared our performances with the results acquired by the previously reported settings. The proposed architecture discriminated the freezing events from the normal activities with an average sensitivity of 93.8% and a specificity of 90.1%.Using our methodology, the precise and continuous monitoring of freezing events with unconstrained sensing can assist patients in managing their chronic disease in daily life effectively.

Atherosclerotic plaques within the vasculature may eventually lead to heart failure. Currently, cardiac stenting is the most effective and least invasive approach to treat this disease. However, in-stent restenosis is a complex chronic side effect of stenting treatment. This study used coronary stents coated with stem cells secreting angiogenic growth factors via an inducible genome-editing system to reduce stent restenosis and induce re-endothelialization within the artery. The characteristics of the cells and their adhesion properties on the stents were confirmed, and the stents were transplanted into a swine model to evaluate restenosis and the potential therapeutic use of stents with stem cells. Restenosis was evaluated using optical coherence tomography (OCT), microcomputed tomography (mCT) and angiography, and re-endothelialization was evaluated by immunostaining after cardiac stent treatment. Compared to a bare metal stent (BMS) or a parental umbilical cord blood-derived mesenchymal stem cell (UCB-MSC)-coated stent, the stents with stem cells capable of the controlled release of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) successfully reduced restenosis within the stent and induced natural re-endothelialization. Furthermore, UCB-MSCs exhibited the ability to differentiate into endothelial cells in Matrigel, and HGF and VEGF improved this differentiation. Our study indicates that stents coated with UCB-MSCs secreting VEGF/HGF reduce the restenosis side effects of cardiac stenting with improved re-endothelialization.

Mechanosensitive ion channels have been suggested to be expressed in dental primary afferent (DPA) neurons to transduce the movement of dentinal fluid since the proposal of hydrodynamic theory. Piezo2, a mechanosensitive, rapidly inactivating (RI) ion channel, has been recently identified in dorsal root ganglion (DRG) neurons to mediate tactile transduction. Here, we examined the expression of Piezo2 in DPA neurons by in situ hybridization, single-cell reverse transcriptase polymerase chain reaction, and whole-cell patch-clamp recordings. DPA neurons with Piezo2 messenger RNA (mRNA) or Piezo2-like currents were further characterized based on their neurochemical and electrophysiological properties. Piezo2 mRNA was found mostly in medium- to large-sized DPA neurons, with the majority of these neurons also positive for Nav1.8, CGRP, and NF200, whereas only a minor population was positive for IB4 and peripherin. Whole-cell patch-clamp recordings revealed Piezo2-like, RI currents evoked by mechanical stimulation in a subpopulation of DPA neurons. RI currents were pharmacologically blocked by ruthenium red, a compound known to block Piezo2, and were also reduced by small interfering RNA-mediated Piezo2 knockdown. Piezo2-like currents were observed almost exclusively in IB4-negative DPA neurons, with the current amplitude larger in capsaicin-insensitive DPA neurons than the capsaicin-sensitive population. Our findings show that subpopulation of DPA neurons is indeed mechanically sensitive. Within this subpopulation of mechanosensitive DPA neurons, we have identified the Piezo2 ion channel as a potential transducer for mechanical stimuli, contributing to RI inward currents. Piezo2-positive DPA neurons were characterized as medium- to large-sized neurons with myelinated A-fibers, containing nociceptive peptidergic neurotransmitters.

Core body temperature is a reliable marker for circadian rhythm. As characteristics of the circadian body temperature rhythm change during diverse health problems, such as sleep disorder and depression, body temperature monitoring is often used in clinical diagnosis and treatment. However, the use of current thermometers in circadian rhythm monitoring is impractical in daily life. As heart rate is a physiological signal relevant to thermoregulation, we investigated the feasibility of heart rate monitoring in estimating circadian body temperature rhythm. Various heart rate parameters and core body temperature were simultaneously acquired in 21 healthy, ambulatory subjects during their routine life. The performance of regression analysis and the extended Kalman filter on daily body temperature and circadian indicator (mesor, amplitude, and acrophase) estimation were evaluated. For daily body temperature estimation, mean R-R interval (RRI), mean heart rate (MHR), or normalized MHR provided a mean root mean square error of approximately 0.40 °C in both techniques. The mesor estimation regression analysis showed better performance than the extended Kalman filter. However, the extended Kalman filter, combined with RRI or MHR, provided better accuracy in terms of amplitude and acrophase estimation. We suggest that this noninvasive and convenient method for estimating the circadian body temperature rhythm could reduce discomfort during body temperature monitoring in daily life. This, in turn, could facilitate more clinical studies based on circadian body temperature rhythm.

Background & Aims Prostaglandin E2 (PGE2) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE2 signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE2 function. Methods DLD-1 and SW480 colon cancer cell lines were transfected with vectors expressing transgenes or small hairpin RNAs and incubated with recombinant PGE2, with or without pharmacologic inhibitors of signaling proteins, and analyzed by immunoblot, immunofluorescence, quantitative reverse-transcription polymerase chain reaction, transcriptional reporter, and proliferation assays. Dextran sodium sulfate (DSS) was given to induce colitis in C57/BL6 (control) mice, as well as in mice with disruption of the hydroxyprostaglandin dehydrogenase 15 gene (15-PGDH–knockout mice), Yap1 gene (YAP-knockout mice), and double-knockout mice. Some mice also were given indomethacin to block PGE2 synthesis. 15-PGDH knockout mice were crossed with mice with intestine-specific disruption of the salvador family WW domain containing 1 gene (Sav1), which encodes an activator of Hippo signaling. We performed immunohistochemical analyses of colon biopsy samples from 26 patients with colitis-associated cancer and 51 age-and sex-matched patients with colorectal cancer (without colitis). Results Incubation of colon cancer cell lines with PGE2 led to phosphorylation of cyclic adenosine monophosphate–responsive element binding protein 1 and increased levels of YAP1 messenger RNA, protein, and YAP1 transcriptional activity. This led to increased transcription of the prostaglandin-endoperoxide synthase 2 gene (PTGS2 or cyclooxygenase 2) and prostaglandin E–receptor 4 gene (PTGER4 or EP4). Incubation with PGE2 promoted proliferation of colon cancer cell lines, but not cells with knockdown of YAP1. Control mice developed colitis after administration of DSS, but injection of PGE2 led to colon regeneration in these mice. However, YAP-knockout mice did not regenerate colon tissues and died soon after administration of DSS. 15-PGDH–knockout mice regenerated colon tissues more rapidly than control mice after withdrawal of DSS, and had faster recovery of body weight, colon length, and colitis histology scores. These effects were reversed by injection of indomethacin. SAV1-knockout or 15-PGDH–knockout mice did not develop spontaneous tumors after colitis induction, but SAV1/15-PGDH double-knockout mice developed polyps that eventually progressed to carcinoma in situ. Administration of indomethacin to these mice prevented spontaneous tumor formation. Levels of PGE2 correlated with those of YAP levels in human sporadic colorectal tumors and colitis-associated tumors. Conclusions PGE2 signaling increases the expression and transcriptional activities of YAP1, leading to increased expression of cyclooxygenase 2 and EP4 to activate a positive signaling loop. This pathway promotes proliferation of colon cancer cell lines and colon tissue regeneration in mice with colitis. Constitutive activation of this pathway led to formation of polyps and colon tumors in mice.

Inspired by the rolling mechanism of the proboscis of a butterfly, rollable electronics that can be rolled and unrolled to a great extent on demand are developed. Generally, electronic devices that are attached to various surfaces to acquire biosignals require mechanical flexibility and sufficient adhesive force. The rollable platform provides sufficient force that grips onto the entire target surface without destroying the target organ. To prove the versatility of our device not only in gripping and detecting biosignals from micro objects but also in performing a variety of functions, thin-film electronics including a heater, strain sensor and temperature sensor are constructed on the rollable platform, and it is confirmed that all the electronics operate normally in the rolled and unrolled states without breakdown. Then, micro bio-objects are gripped by using the rollable platform, and their tiny motions are successfully detected with the sensor on the platform. Furthermore, the detection of the pulse wave signals of swine under diverse experimental conditions is successfully conducted by rolling up the rollable system around the blood vessel of the swine, the result of which proves the feasibility of a rollable platform as a biomedical device. Rollable electronic devices inspired by butterflies have been fabricated by researchers in South Korea for biomedical applications. Bioelectronic devices can be attached to the body, either outside on the skin or inside on internal organs. They can then monitor and even help regulate the operation of the organ. Ensuring that bioelectronic components stay attached is tricky, particularly for tubular organs with a small radius of curvature, such as blood vessels. Gunhee Lee from the Seoul National University and co-workers constructed a thin-film electronic circuit that they could tightly roll and unroll on demand, in the same way a butterfly unfurls its proboscis, to grip the target organ with sufficient force. The viability of their device, which included a heater, strain and temperature sensor, was demonstrated by monitoring the femoral artery of a pig. Inspired by the rolling mechanism of the proboscis of a butterfly, a rollable electronics which can be rolled and unrolled on demand is developed. The rollable platform provides sufficient force which grips onto the entire target surface without destroying the target. Micro bio-objects are gripped by using the rollable platform and their tiny motions are successfully detected with the sensor on the platform. Furthermore, detecting pulse wave signals of the swine is successfully conducted by rolling up the rollable system around the blood vessel of swine, which result proves the feasibility of rollable platform as a biomedical device.

The aim of this study was to evaluate the effects of fimasartan/amlodipine fixed-dosed combination (F/A) on left ventricle (LV) systolic function and infarct size in the rat myocardial infarction (MI) model. We induced MI in 20 rats by ligation of the left anterior descending coronary artery and they were divided into two groups [MI group (n=10) vs. MI+F/A 10 mg/kg group (n=10)]. F/A was administered for 28 days between day-7 and day-35 in the MI+F/A group and echocardiography was performed at day-7 and at day-35 after the induction of MI. Picrosirius red staining was performed to confirm the fibrotic tissue and infarct size was measured using image analysis program for Image J. At the 35-day follow-up, the LV ejection fraction (EF) was significantly higher (38.10±3.92% vs. 29.86±4.56%, p

We evaluated the efficacy of fimasartan on perfusion defects and infarction size in an animal model of myocardial infarction (MI), with echocardiography and positron emission tomography (PET) using a 18F-labeled phosphonium cation (5-[18F]-fluoropentyl-triphenylphosphonium salt, [18F]FPTP) as a mitochondrial voltage sensor for myocardial imaging. We induced MI in 33 rats by ligation of the left coronary artery, and checked their cardiac PET image using [18F]FPTP for evaluation of myocardial perfusion. Rats were grouped into 3 groups according to their administered drugs: no drug (n=11), fimasartan 3 mg/kg (n=10), and fimasartan 10 mg/kg (n=12). Each designated drug was administered for 4 weeks, and follow-up PET and histologic examinations were done. In the PET analysis, a perfusion defect size was markedly improved in fimasartan 10 mg/kg group (35.9±7.0% to 28.4±6.9%, p

Tremor characteristics-amplitude and frequency components-are primary quantitative clinical factors for diagnosis and monitoring of tremors. Few studies have investigated how different patient's conditions affect tremor frequency characteristics in Parkinson's disease (PD). Here, we analyzed tremor characteristics under resting-state and stress-state conditions. Tremor was recorded using an accelerometer on the finger, under resting-state and stress-state (calculation task) conditions, during rest tremor and postural tremor. The changes of peak power, peak frequency, mean frequency, and distribution of power spectral density (PSD) of tremor were evaluated across conditions. Patients whose tremors were considered more than "mild" were selected, for both rest (n=67) and postural (n=25) tremor. Stress resulted in both greater peak powers and higher peak frequencies for rest tremor (p

A polymer-based coronary drug-eluting stent might induce inflammation and stent thrombosis of the vessel wall due to the presence of the polymer. Therefore, the purpose of this study was to compare synthetic poly lactic–glycolic acid (PLGA)-based tacrolimus (TCL)-eluting stents (PLGA-TES) and polymer-free TCL-eluting stents (PF-TES) in in vitro and in vivo models. The PF-TES was deposited with a TiO2 thin film onto a bare metal stent (BMS) using plasma-enhanced chemical vapor deposition (PECVD). The surface morphologies of the stents were investigated by scanning electron microscopy and energy dispersive X-ray spectroscopy methods. The effect of the drugs released from the stents on smooth muscle cell (SMC) proliferation and platelet adhesion were examined. Animal studies were performed with four study groups; 1) BMS, 2) N-TiO2, 3) PLGA-TES, and 4) PF-TES. Further, after 4 weeks of implantation, the vessels surrounding the stents were isolated and then subjected to various analyses. In this study, the stent was deposited with a very thin and uniform TiO2 film. The platelet adhesion on the TiO2 surfaces was less than that on the BMS surface. The drug was uniformly coated on the stent surface with a concentration of 1.184 μg/mm2. SMC proliferation was significantly inhibited in the TCL-eluting stent group (62.8 %, 42.3 %, n = 7, p

Background and objectives Antiarrhythmic effect of renal denervation (RDN) after acute myocardial infarction (AMI) remains unclear. The goal of this study was to evaluate the effect of RDN on ventricular arrhythmia (VA) after AMI in a porcine model. Methods Twenty pigs were randomly divided into 2 groups based on RDN (RDN, n=10; Sham, n=10). After implanting a loop recorder, AMI was induced by occlusion of the middle left anterior descending coronary artery. Catheter-based RDN was performed for each renal artery immediately after creating AMI. Sham procedure used the same method, but a radiofrequency current was not delivered. Electrocardiography was monitored for 1 hour to observe VA. One week later, the animals were euthanized and the loop recorder data were analyzed. Results Ventricular fibrillation event rate and the interval from AMI creation to first VA in acute phase were not different between the 2 groups. However, the incidence of premature ventricular complex (PVC) was lower in the RDN than in the Sham. Additionally, RDN inhibited prolongation of the corrected QT (QTc) interval after AMI. The frequency of non-sustained or sustained ventricular tachycardia, arrhythmic death was lower in the RDN group in the early period. Conclusions RDN reduced the incidence of PVC, inhibited prolongation of the QTc interval, and reduced VA in the early period following an AMI. These results suggest that RDN might be a therapeutic option in patients with electrical instability after AMI.

Tremor is a commonly observed symptom in patients of Parkinson's disease (PD), and accurate measurement of tremor severity is essential in prescribing appropriate treatment to relieve its symptoms. We propose a tremor assessment system based on the use of a convolutional neural network (CNN) to differentiate the severity of symptoms as measured in data collected from a wearable device. Tremor signals were recorded from 92 PD patients using a custom-developed device (SNUMAP) equipped with an accelerometer and gyroscope mounted on a wrist module. Neurologists assessed the tremor symptoms on the Unified Parkinson's Disease Rating Scale (UPDRS) from simultaneously recorded video footages. The measured data were transformed into the frequency domain and used to construct a two-dimensional image for training the network, and the CNN model was trained by convolving tremor signal images with kernels. The proposed CNN architecture was compared to previously studied machine learning algorithms and found to outperform them (accuracy = 0.85, linear weighted kappa = 0.85). More precise monitoring of PD tremor symptoms in daily life could be possible using our proposed method.

Objective: Cervical stabilization exercises are frequently to improve strength and endurance of cervical muscles. The purpose of this study was to identify changes in head repositioning accuracy (HRA) and neck proprioception through cervical stabilization exercises in healthy adults. Design: One group pretest-posttest design. Methods: Thirteen participants with no previous history of neck pain or injury to the cervical spine were recruited. HRA was measured by equipment including laser pointer, helmet, eye patch and marking pens. The distance between the spot where the beam had stopped and the center of the graph paper was measured three times with the averaged value used as the head repositioning accuracy. Neck proprioception was measured by a cervical range of motion device (CROM). Subjects wore the CROM tester and were to look straight ahead while bending his/her neck. Subjects were instructed to perform extension, lateral flexion and rotation, and the values were then measured and recorded. The measurements were performed pre-intervention, and after cervical stabilization exercise. Results: There was no significant difference on HRA after intervention. In addition, there was no significant difference on neck proprioception compared with pre-intervention. Conclusions: The present study did not identify any effect on HRA and neck proprioception of cervical stabilization exercise. Further investigations are required to elucidate this in old aged participants and patients with neck pain.

Motivation: Although clinical aspirations for new technology to accurately measure and diagnose Parkinsonian tremors exist, automatic scoring of tremor severity using machine learning approaches has not yet been employed. Objective: This study aims to maximize the scientific validity of automatic tremor-severity classification using machine learning algorithms to score Parkinsonian tremor severity in the same manner as the unified Parkinson's disease rating scale (UPDRS) used to rate scores in real clinical practice. Approach: Eighty-five PD patients perform four tasks for severity assessment of their resting, resting with mental stress, postural, and intention tremors. The tremor signals are measured using a wristwatch-type wearable device with an accelerometer and gyroscope. Displacement and angle signals are obtained by integrating the acceleration and angular-velocity signals. Nineteen features are extracted from each of the four tremor signals. The optimal feature configuration is decided using the wrapper feature selection algorithm or principal component analysis, and decision tree, support vector machine, discriminant analysis, and k-nearest neighbour algorithms are considered to develop an automatic scoring system for UPDRS prediction. The results are compared to UPDRS ratings assigned by two neurologists. Main results: The highest accuracies are 92.3%, 86.2%, 92.1%, and 89.2% for resting, resting with mental stress, postural, and intention tremors, respectively. The weighted Cohen's kappa values are 0.745, 0.635 and 0.633 for resting, resting with mental stress, and postural tremors (almost perfect agreement), and 0.570 for intention tremors (moderate). Significance: These results indicate the feasibility of the proposed system as a clinical decision tool for Parkinsonian tremor-severity automatic scoring.

Inflammation and thrombosis are linked to the use of polymer-based drug-eluting stents (DES). The aim of this study was to develop a polymer-free everolimus (EVL)-eluting stent using nitrogen-doped titanium dioxide (N-TiO2) and verify its efficacy by in vitro and in vivo assessment in a porcine coronary model. Various analytical approaches such as scanning electron microscopy and atomic force microscopy, electron spectroscopy, Fourier transform infrared spectrometry and contact angle measurement were employed for the characterization. As a part of biocompatibility assessment, platelet adhesion and smooth muscle cell (SMC) proliferation were examined. Bare metal stent (BMS), N-TiO2 stent, everolimus-eluting N-TiO2 (N-TiO2-EVL) stent, and commercialized EVL-eluting stent (EES) were randomly placed in forty coronary arteries in twenty pigs. After four weeks of implantation, the stents were subjected to histological and quantitative analysis. The N-TiO2 film used in this study was well coated without any cracks or peeling. Surface hydrophilicity (88.8% of angle decrement) could be associated with the decrease in surface roughness post N-TiO2 deposition (37.0%). The platelet adhesion on the N-TiO2 surfaces was less than that on the BMS surface. The proliferation of SMC was suppressed in the N-TiO2-EVL group (30.2%) but not in the BMS group. In the animal study, the percent area restenosis was significantly decreased in the N-TiO2-EVL group compared to that in the BMS group. The results (BMS; 47.0 ± 11.00%, N-TiO2-EVL; 31.7 ± 10.50%, and EES; 29.1 ± 11.21%, n = 10, p

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma.

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice. At the molecular level, activation of YAP/TAZ in the liver of Pten-/- Sav1-/- mice amplified AKT signaling through the upregulation of insulin receptor substrate 2 (IRS2) expression. Both ablation of YAP/TAZ and activation of the Hippo pathway could rescue these phenotypes. A high level of YAP/ TAZ expression was associated with a high level of IRS2 expression in human hepatocellular carcinoma (HCC). Moreover, treatment with the AKT inhibitor MK-2206 or knockout of IRS2 by AAV-Cas9 successfully repressed liver tumorigenesis in Pten-/- Sav1-/- mice. Thus, our findings suggest that Hippo signaling interacts with AKT signaling by regulating IRS2 expression to prevent NAFLD and liver cancer progression and provide evidence that impaired crosstalk between these 2 pathways accelerates NAFLD and liver cancer.

Sinomenium acutum has been used in traditional medicine to treat a painful disease such as rheumatic arthritis and neuralgia. Sinomenine, which is a main bioactive ingredient in Sinomenium acutum, has been reported to have an analgesic effect in diverse pain animal models. However little is known about the detailed mechanisms underlying peripheral analgesic effect of sinomenine. In the present study, we aimed to elucidate its cellular mechanism by using formalin-induced acute inflammatory pain model in mice. We found that intraperitoneal (i.p.) administration of sinomenine (50mg/kg) suppressed formalin-induced paw licking behavior in both the first and the second phase. Formalin-induced c-Fos protein expression was also suppressed by sinomenine (50mg/kg i.p.) in the superficial dorsal horn of spinal cord. Whole-cell patch-clamp recordings from small-sized dorsal root ganglion (DRG) neurons revealed that sinomenine reversibly increased the spike threshold and the threshold current intensity for evoking a single spike and decreased firing frequency of action potentials evoked in response to a long current pulse. Voltage-gated sodium currents (INa) were also significantly reduced by sinomenine in a dose-dependent manner (IC50=2.3±0.2mM). Finally, we confirmed that intraplantar application of sinomenine suppressed formalin-induced pain behavior only in the first phase, but not the second phase. Taken together, our results suggest that sinomenine has a peripheral analgesic effect by inhibiting INa.

The Republic of Korea (ROK) has emerged as a country of superior medical tourism in the last decade among the people of China, Japan, Southeast Asia, Russia and the Middle East for the plastic surgery or others requiring precision skills. Although the ROK’s medical tourism industry grew quantitatively in its revenue and the number of visitors, the report from the 2015 World Economic Forum concerning the competitiveness of ROK’s tourism including the medical tourism showed that its rank had dropped to 29th position, a drop of 4 places from 25th in 2013. Thus, it is about time to improve the situation by investigating the actual conditions of tours taken by the foreign tourists to establish new strategy, which is the main contribution of this research. As a research method, a big data analysis has been performed on the basis of machine learning and using R-studio. During the analysis process, there were some relevant regularities which were difficult to be found in the big data and based on these findings, we have attempted to find the solutions for the bad images that foreign visitors had shared in common. The result of the big data analysis showed that the their purpose of visit was different from each other depending on the age groups and the details of their experience of inconvenience varied as well.