Inactivation of VRK1 sensitizes ovarian cancer to PARP inhibition through regulating DNA-PK stability.

Ovarian cancer is the leading cause of gynecologic cancer death. Among the most innovative anti-cancer approaches, the genetic concept of synthetic lethality is that mutations in multiple genes work synergistically to effect cell death. Previous studies found that although vaccinia-related kinase-1 (VRK1) associates with DNA damage repair proteins, its underlying mechanisms remain unclear. Here, we found high VRK1 expression in ovarian tumors, and that VRK1 depletion can significantly promote apoptosis and cell cycle arrest. The effect of VRK1 knockdown on apoptosis was manifested by increased DNA damage, genomic instability, and apoptosis, and also blocked non-homologous end joining (NHEJ) by destabilizing DNA-PK. Further, we verified that VRK1 depletion enhanced sensitivity to a PARP inhibitor (PARPi), olaparib, promoting apoptosis through DNA damage, especially in ovarian cancer cell lines with high VRK1 expression. Proteins implicated in DNA damage responses are suitable targets for the development of new anti-cancer therapeutic strategies, and their combination could represent an alternative form of synthetic lethality. Therefore, normal protective DNA damage responses are impaired by combining olaparib with elimination of VRK1 and could be used to reduce drug dose and its associated toxicity. In summary, VRK1 represents both a potential biomarker for PARPi sensitivity, and a new DDR-associated therapeutic target, in ovarian cancer.

Degradation of AZGP1 suppresses apoptosis and facilitates cholangiocarcinoma tumorigenesis via TRIM25.

Alpha-2-Glycoprotein 1, Zinc-binding (AZGP1, ZAG) is a secreted protein that is synthesized by adipocytes and epithelial cells; it is downregulated in several malignancies such as breast, prostate, liver and lung cancers. However, its function remains unclear in cholangiocarcinoma (CCA). Here, we evaluated the impact AZGP1 in CCA using Gene Expression Omnibus (GEO) and GEPIA. In addition, we analysed AZGP1 expression using quantitative reverse transcription PCR and western blotting. Expression of AZGP1 was nearly deficient in CCA patients and cell lines and was associated with poor prognosis. AZGP1 overexpression upregulated apoptosis markers. Co-immunoprecipitation experiments showed that AZGP1 interacts with tripartite motif-containing protein 25 (TRIM25), and tissue microarray and bioinformatic analysis showed that AZGP1 is negatively correlated with TRIM25 expression in CCA. Thereafter, TRIM25 knockdown led to AZGP1 upregulation and induced cancer cell apoptosis. TRIM25 targets AZGP1 for degradation by catalysing its ubiquitination. AZGP1 overexpression significantly suppressed tumour growth in a xenograft mouse model. This study findings suggest that AZGP1 is a potential therapeutic target or a diagnostic biomarker for treating patients with CCA.

Clinical impact of pancreatic steatosis measured by CT on the risk of post-ERCP pancreatitis: a multicenter prospective trial.

BACKGROUND AND AIMS: Pancreatic steatosis (PS) may be a risk factor for acute pancreatitis. Whether it is also a risk factor for post-ERCP pancreatitis (PEP) has not been evaluated. This study aimed to determine the impact of PS on PEP development. METHODS: This multicenter prospective trial enrolled 786 consecutive patients who underwent contrast-enhanced abdominal CT and subsequent first-time ERCP. PS was evaluated based on pancreatic attenuation on unenhanced CT images. The risk of PS for the development of PEP was evaluated using a logistic regression model. RESULTS: Of 527 patients included in the study, 157 (29.8%) had PS and 370 (70.2%) did not. At 24 hours after ERCP, there was a significant difference in the PEP identified in 22 patients (14.0%) in the PS group and 23 patients (6.2%) in the "no PS" (NPS) group (P = .017). Diabetes and hypertension were more common in the PS group than in the NPS group; no differences in dyslipidemia were found. Patients with PS had a higher risk for the development of PEP than those with NPS (odds ratio, 2.09; 95% confidence interval, 1.08-4.03). No other variables were identified as risk factors for PEP. CONCLUSIONS: PS is a significant risk factor for PEP for which preventive measures should be considered. Standardized measurement protocols to assess PS by CT are needed. (Clinical trial registration number: KCT0006068.).

Evaluation on the Sex-Specific Association Between Cigarette Smoke Exposure and Inflammation Markers-C-Reactive Protein and White Blood Cell Count.

INTRODUCTION: Cigarette smoke increases peripheral white blood cell (WBC) count. However, the dose-dependent association between smoking and C-reactive protein (CRP), an important inflammatory marker, has been reported as inconsistent. AIMS AND METHODS: Here, we evaluated the associations between smoking and CRP using both smoking questionnaires and urine cotinine as exposure markers. The Korea National Health and Nutrition Examination Survey data were used for analyzing the associations. Multiple regression analyses were performed to examine the associations between cigarette smoke exposure, as assessed by questionnaires and urine cotinine, and health effects, as measured by CRP and WBC count, controlling for potential confounders. The confounders, including age, sex, body mass index, blood pressure, cholesterol, glucose, alanine aminotransferase, and uric acid, were selected a priori based on the literature. RESULTS: A total of 11 435 participants were included for analysis. For the exposure-response relationship, the results indicated a significant increase in CRP levels in male smokers compared to male nonsmokers (p = .002), whereas no significant increase was found in female smokers compared to female nonsmokers (p = .680). For the dose-response relationship, a significant positive association was observed between urine cotinine and CRP in male smokers (p = .018), whereas no significant association was found in female smokers (p = .508). WBC count consistently showed significant exposure-response and dose-response relationships in both sexes. CONCLUSIONS: WBC count was found to be a consistent effect marker of cigarette smoke exposure, while the association between CRP level and smoking was inconsistent and varied by sex. The sex-specific response to cigarette smoke exposure warrants further exploration in future studies. IMPLICATIONS: Cigarette smoke exposure is known to increase inflammation and has been thought to increase CRP, a significant inflammation marker. However, recent studies have reported conflicting results regarding the dose-dependent association between cigarette smoke exposure and CRP. This study found that the association between smoking and CRP is inconsistent and varies by sex, showing significant exposure response in men but not in women. Furthermore, the study suggests that WBC count is a more consistent marker for cigarette smoke exposure.

In Silico and In Vitro multiple analysis approach for screening naturally derived ligands for red seabream aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AHR) is a key ligand-dependent transcription factor that mediates the toxic effects of compounds such as dioxin. Recently, natural ligands of AHR, including flavonoids, have been attracting physiological and toxicological attention as they have been reported to regulate major biological functions such as inflammation and anti-cancer by reducing the toxic effects of dioxin. Additionally, it is known that natural AHR ligands can accumulate in wildlife tissues, such as fish. However, studies in fish have investigated only a few ligands in experimental fish species, and the AHR response of marine fish to natural AHR ligands of various other structures has not been thoroughly investigated. To explore various natural AHR ligands in marine fish, which make up the most fish, it is necessary to develop new screening methods that consider the specificity of marine fish. In this study, we investigated the response of natural ligands by constructing in vitro and in silico experimental systems using red seabream as a model species. We attempted to develop a new predictive model to screen potential ligands that can induce transcriptional activation of red seabream AHR1 and AHR2 (rsAHR1 and rsAHR2). This was achieved through multiple analyses using in silico/ in vitro data and Tox21 big data. First, we constructed an in vitro reporter gene assay of rsAHR1 and rsAHR2 and measured the response of 10 representatives natural AHR ligands in COS-7 cells. The results showed that FICZ, Genistein, Daidzein, I3C, DIM, Quercetin and Baicalin induced the transcriptional activity of rsAHR1 and rsAHR2, while Resveratrol and Retinol did not induce the transcriptional activity of rsAHR isoforms. Comparing the EC50 values of the respective compounds in rsAHR1 and rsAHR2, FICZ, Genistein, and Daidzein exhibited similar isoform responses, but I3C, Baicalin, DIM and Quercetin show the isoform-specific responses. These results suggest that natural AHR ligands have specific profiling and transcriptional activity for each rsAHR isoform. In silico analysis, we constructed homology models of the ligand binding domains (LBDs) of rsAHR1 and rsAHR2 and calculated the docking energies (U_dock values) of natural ligands with measured in vitro transcriptional activity and dioxins reported in previous studies. The results showed a significant correlation (R2=0.74(rsAHR1), R2=0.83(rsAHR2)) between docking energy and transcriptional activity (EC50) value, suggesting that the homology model of rsAHR1 and rsAHR2 can be utilized to predict the potential transactivation of ligands. To broaden the applicability of the homology model to diverse compound structures and validate the correlation with transcriptional activity, we conducted additional analyses utilizing Tox21 big data. We calculated the docking energy values for 1860 chemicals in both rsAHR1 and rsAHR2, which were tested for transcriptional activation in Tox21 data against human AHR. By comparing the U_dock energy values between 775 active compounds and 1085 inactive compounds, a significant difference (p<0.001) was observed between the U_dock energy values in the two groups, suggesting that the U_dock value can be applied to distinguish the activation of compounds. Furthermore, we observed a significant correlation (R2=0.45) between the AC50 of Tox21 database and U_dock values of human AHR model. In conclusion, we calculated equations to translate the results of an in silico prediction model for ligand screening of rsAHR1 and rsAHR2 transactivation. This ligand screening model can be a powerful tool to quantitatively estimate AHR transactivation of major marine agents to which red seabream may be exposed. The study introduces a new screening approach for potential natural AHR ligands in marine fish, based on homology model-docking energy values of rsAHR1 and rsAHR2, with implications for future agonist development and applications bridging in silico and in vitro data.

Endovascular Treatment of Traumatic Vascular Injuries in the Head and Neck Region.

Background and Objectives: Traumatic vascular injuries of the head and neck pose significant treatment challenges due to the complex anatomy, diverse clinical presentation, and mostly emergent nature. Endovascular treatment increasingly complements traditional surgical approaches. This study aimed to report our 10-year experience in treating traumatic vascular injuries of the head and neck with endovascular therapy and to determine the effectiveness of endovascular treatment. Materials and Methods: A retrospective analysis of 21 patients treated for head and neck vascular injuries between May 2011 and April 2021 was performed. Patients' medical histories, clinical presentations, imaging findings, treatment materials, and clinical outcomes were reviewed. Treatments included stenting, coil embolization, and other endovascular techniques focused on hemostasis and preservation of the parent vessel. Results: The most common injuries involved the internal maxillary artery branches (n = 11), followed by the common or internal carotid artery (n = 6), vertebral artery (n = 3), and others. Endovascular treatment achieved successful hemostasis in all but one case. In five of six carotid artery injuries and two of three vertebral artery injuries, we achieved successful hemostasis while preserving the parent vessel using covered and bare stents, respectively. Conclusions: Endovascular therapy might be a useful treatment modality for traumatic vascular injuries in the head and neck region, offering efficacy, safety, and a minimally invasive approach.

Cholecystectomy Increases the Risk of Type 2 Diabetes in the Korean Population: Data From the National Health Insurance Cooperation Health Checkup 2010-2017.

OBJECTIVE: This study assessed whether cholecystectomy is a risk factor for newly developed type 2 diabetes mellitus (T2DM) in the Korean population. BACKGROUND: There is a lack of evidence that cholecystectomy is independently associated with insulin resistance and T2DM. METHODS: This study included all patients aged more than 20 years who had undergone cholecystectomy from 2010 to 2015 (n=55,166) and age-matched and sex-matched control subjects without cholecystectomy (n=110,332) using the National Health Insurance Service database. They were followed up until the date of newly developed T2DM or study end and the incidence of T2DM was traced over a maximum observation period of 7 years. RESULTS: Overall, 55,166 patients who underwent cholecystectomy and 110,332 age-matched and sex-matched controls were followed up for ∼4.7 years, during which, incident T2DM occurred in 5982 (3.61%) patients. Cholecystectomy was associated with 20% higher risk of T2DM after adjustment for all covariates. The cumulative incidence of T2DM also significantly increased in the cholecystectomy group for ∼7 years ( P <0.001). The adjusted hazard ratio (HR) for T2DM was the highest in the group with both cholecystectomy and obesity using the control without both cholecystectomy and obesity as a reference [HR=1.41, 95% confidence interval (CI): 1.29-1.56]. The group with cholecystectomy without obesity showed the comparable risk of incident T2DM compared with the group without cholecystectomy with obesity (HR=1.29, 95% CI: 1.20-1.40 for cholecystectomy without obesity and HR=1.24, 95% CI: 1.14-1.36 for control with obesity). CONCLUSIONS: These results provide evidence that cholecystectomy is associated with an increased risk of newly developed T2DM in the Korean population. Further research is required to elucidate the mechanism of the association between cholecystectomy and incident diabetes.

DGG-300273, a novel WNT/ß-catenin inhibitor, induces apoptotic cell death by activating ROS-BIM signaling in a Wnt-dependent manner in colon cancer cells.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/ß-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/ß-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/ß-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study.

National-scale investigation of dual nitrate isotopes and chloride ion in South Korea: Nitrate source apportionment for stream water.

Nitrate sources in surface water have been identified using dual-isotope compositions of nitrate with various tools to efficiently manage the water quality at the local scale. Correlation between Cl and NO3 has also been used to identify NO3. In this study, we assess the reliability of the dual-isotope approach and Cl in terms of nitrate source apportionment. To this end, we collected stream water samples throughout South Korea to estimate nitrate sources in streams and determine whether the land-use pattern was closely related to nitrate sources. The δ15N-NO3 ranging from -1.3 to 14.8‰ showed a spatial distribution that was lower in mountain ranges (<7‰) than plain areas (>8‰). The Cl concentration in this national-scale distribution was also assessed. The relationship between the proportion of Cl and δ15N-NO3 classifies nitrate sources into areas characterized by three land-use patterns: (1) agricultural and business areas, (2) forests in highlands, and (3) lowland forests, of which (1) had proportions of Cl >50%, while (2) and (3) were <50%. The samples in (3) showed δ15N-NO3 values > 6‰, similar to those of (1). Deuterium excess of samples was negatively correlated (R2 = 0.53) with δ15N-NO3, accounting for the fact that δ15N-NO3 reflected land-use patterns. Samples were dominantly affected by agriculture-derived sources and domestic sewage showed NO3/Cl of <0.4 and δ15N-NO3 of >6‰. These results suggest that nitrate source apportionment should be comprehensively evaluated considering the dual-isotope approach, land-use patterns, and Cl proportions.

Evaluation of Temporal Trends of Lead Exposure in Korean Workers Using Workplace Monitoring Data.

BACKGROUND: Lead, which is widely used in various industrial settings, is a major health hazard for manufacturing workers. Therefore, control of lead exposure has been implemented in an effort to prevent lead-related health problems. In this study, our aim was to evaluate temporal trends in occupational lead exposure in Korean lead workers using data from monitoring of workplace exposure. METHODS: A nationwide work environment monitoring database, data from a work environment monitoring institution, and data extracted from a review paper were utilized. Different versions of standard industrial classification codes were aligned with the 10th Korean Standard Industrial Classification, which is generally consistent with the 4th revision of the International Standard Industrial Classification. The multiple data sources were combined and temporal trends over the period from 1994-2021 were estimated. In addition, separate estimation of temporal trends in the storage battery manufacturing industry over the period from 1987-2021 was also performed. RESULTS: A total of 444,296 personal airborne lead measurements were used for the estimation process. The temporal trends in occupational exposure to lead declined by -6% annually over the study period. In particular, levels of lead exposure in the storage battery manufacturing industry showed a steeper decline of -12% annually. CONCLUSIONS: Findings of our study showed that occupational exposure to lead declined over the period from 1994 to 2021 in Korea. However, adverse effects of exposure to lead on health should be regarded with caution. The results will be useful in conduct of epidemiological studies examining lead-related effects on health.

Spatial investigation of water quality and estimation of groundwater pollution along the main stream in the Geum River Basin, Korea.

This study aims to identify spatially water quality distribution of groundwater and surface water in reservoirs, and comprehensively to address possible influencing factors. The concentration of NO3 in the reservoirs along the main stream of the Geum River was generally lower than that in groundwater. The pollution level of the reservoir, especially the particulate pollutant SS, clearly showed seasonal variations and increased significantly downstream. The H-3 concentration of the groundwater was high in the plains and low in the mountain areas, indicating a difference in residence time between the two regions. The hydrochemical properties and factor loading values of the principal components indicated that the major factors were water‒rock interactions and residence time, but a positive correlation of K-NO3 and Mg-Cl showed the influence of agricultural activities. The main groundwater pollutants were likely to be contributed by agricultural activities at upstream and seawater intrusion at downstream. The sensitive redox species uranium in the groundwater of this region existed as the uranyl ion, and it showed a positive correlation with HCO3, pH, and Ca. The results emphasize the importance of monitoring both tributaries and groundwater together in order to effectively manage the water quality of the Geum River basin.

Modulation of Solvation Structure and Electrode Work Function by an Ultrathin Layer of Polymer of Intrinsic Microporosity in Zinc Ion Batteries.

Zinc ion batteries are promising candidates for large-scale energy storage systems. However, they suffer from the critical problems of insufficient cycling stability due to internal short-circuiting by zinc dendrites and zinc metal orphaning. In this work, a polymer of intrinsic microporosity (PIM-1) is reported as an ion regulating layer and an interface modulator, which promotes a uniform Zn plating and stripping process. According to spectroscopic analyses and computational calculations, PIM-1 enhances the reaction kinetics of a Zn metal electrode by altering the solvation structure of Zn2+ ions and increasing the work function of the Zn surface. As a result, the PIM-1 coating significantly improves the cyclability (1700 h at 0.5 mA cm-2 ) and Coulombic efficiency (99.6% at 3 mA cm-2 ) of the Zn/Zn2+ redox reaction. Moreover, the PIM-1 coated Zn operates for more than 200 h at 70% Zn utilization even under 10 mA cm-2 and 110 h at 95% Zn utilization of the Zn metal electrode. A Zn||V2 O5 full cell employing the PIM-1 layer exhibits seven times longer cycle life compared to the cell using bare Zn. The findings in this report demonstrate the potential of microporous materials as a key ingredient in the design of reversible Zn electrodes.

Tunable Ti3C2Tx MXene-Derived TiO2 Nanocrystals at Controlled pH and Temperature.

While two-dimensional (2D) Ti3C2Tx MXene in aqueous dispersions spontaneously oxidizes into titanium dioxide (TiO2) nanocrystals, the crystallization mechanism has not been comprehensively understood and the resultant crystal structures are not controlled among three representative polymorphs: anatase, rutile, and brookite. In this study, such control on the lattice structures and domain sizes of the MXene-derived TiO2 crystallites is demonstrated by means of the oxidation conditions, pH, and temperature (3.0-11.0 and 20-100 °C, respectively). It is observed that the formation of anatase phase is preferred against rutile phase in more basic and hotter oxidizing solutions, and even 100% anatase can be obtained at pH 11.0 and 100 °C. At lower pH and temperature, the portion of rutile phase increases such that it reaches ∼70% at pH 3 and 20 °C. Under certain circumstances, small portion of brookite phase is also observed. Smaller domain sizes of both anatase and rutile phases are observed in more basic oxidizing solutions and at lower temperatures. Based on these experimental results, we propose the crystallization mechanism in which the oxidative dissociation of Ti3C2Tx first produces Ti ions as the intermediate state, and they bind to abundant oxygen in the aqueous dispersions, and nucleate and crystallize into TiO2.

Low insertion of cystic duct increases risk for common bile duct stone recurrence.

BACKGROUND: Common bile duct (CBD) stone is one of the most frequent biliary diseases. Recurrence after the complete removal of CBD stones is high, and we aim to evaluate the rate and risk factors for symptomatic recurrence of CBD stones after endoscopic retrograde cholangiopancreatography (ERCP). METHODS: We, retrospectively, reviewed the database of patients who underwent ERCP for CBD stones and subsequent cholecystectomy between January 2015 and December 2017 at a tertiary hospital. The recurrence of symptomatic CBD stones was defined as the presence of a CBD stone with related symptoms at least 6 months after the ERCP procedure. The primary outcomes were recurrence of symptomatic CBD stones and its risk factors. RESULTS: Among the 362 enrolled patients, 60 experienced a symptomatic recurrence of CBD stones between 6 months and 5 years after the procedure. The mean duration of follow-up was 32.3 ± 8.1 months. The patients with recurrences were older and had a longer follow-up duration. Low insertion of the cystic duct (HR = 2.893, p = 0.016), distal CBD angulation (HR = 1.015, p = 0.034), maximum CBD diameter (HR = 1.070, p = 0.012), number of ERCP sessions at first admission (HR = 1.558, p = 0.032), and cannulation time (HR = 1.030, p = 0.008) were the independent risk factors for symptomatic recurrent CBD stones. CONCLUSIONS: Patients with risk factors, especially those with low cystic duct insertion, are more prone to symptomatic recurrent CBD stones and should be followed more carefully.

Polyacrylonitrile-based carbon nanofibers as a matrix for laser desorption/ionization time-of-flight mass spectrometric analysis of small molecules under both positive and negative ionization modes.

Carbon fiber (CNF), prepared by carbonization of electrospun polyacrylonitrile (PAN) fibers, is systematically investigated as a mediator to replace conventional organic matrices for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-MS). CNF exhibits a high salt tolerance, sensitivity, and resolution for organic matrix-free laser desorption/ionization time-of-flight mass spectrometry (LDI-MS) analysis of various analytes under both positive and negative ionization modes. Especially, saccharides, a neutral molecule having low negative ionization efficiency, are successfully detected with CNF. Taken together, this study clearly demonstrates CNF is a promising material to develop an efficient and universal platform for LDI-MS analysis regardless of preferential ionization modes of analytes. Graphical abstract.

Ursodeoxycholic acid shows antineoplastic effects in bile duct cancer cells via apoptosis induction; p53 activation; and EGFR-ERK, COX-2, and PI3K-AKT pathway inhibition.

Unlike in normal cells, ursodeoxycholic acid (UDCA) causes apoptosis rather than protection in cancer cells. Aim of this study was to demonstrate whether UDCA actually inhibits proliferation and induces apoptosis in bile duct cancer cells; the effect of UDCA on the expression of COX-2, PI3K/AKT, ERK, and EGFR; how UDCA affects cancer cell invasiveness and metastasis, since these effects are not established in bile duct cancer cells. SNU-245 cells (human extrahepatic bile duct cancer cells) were cultured. MTT assays were performed to evaluate the effect of UDCA on the cell proliferation. A cell death detection enzyme-linked immunosorbent assay and a caspase-3 activity assay were used to determine apoptosis. Western blot analysis measured expression levels of various proteins. The invasiveness of the cancer cells was evaluated by invasion assay. In cultured bile duct cancer cells, UDCA suppressed cell proliferation in bile duct cancer cells by inducing apoptosis and p53 activation, blocking deoxycholic acid (DCA)-induced activated EGFR-ERK signaling and COX-2, inhibiting DCA-induced activated PI3K-AKT signaling, and suppressing the invasiveness of bile duct cancer cells. In addition, a MEK inhibitor impaired UDCA-induced apoptosis in bile duct cancer cells. UDCA has antineoplastic and apoptotic effects in bile duct cancer cells. Thus, UDCA could be a chemopreventive agent in patients with a high risk of cancer, and/or a therapeutic option that enhances other chemotherapeutics.

Role of p53 in transcriptional repression of SVCT2.

SVCT2, Sodium-dependent Vitamin C Transporter 2, uniquely transports ascorbic acid (also known as vitamin C and ascorbate) into all types of cells. Vitamin C is an essential nutrient that must be obtained through the diet and plasma levels are tightly regulated by transporter activity. Vitamin C plays an important role in antioxidant defenses and is a cofactor for many enzymes that enable hormone synthesis, oxygen sensing, collagen synthesis and epigenetic pathways. Although SVCT2 has various functions, regulation of its expression/activity remains poorly understood. We found a p53-binding site, within the SVCT2 promoter, using a transcription factor binding-site prediction tool. In this study, we show that p53 can directly repress SVCT2 transcription by binding a proximal- (~-185 to -171 bp) and a distal- (~-1800 to -1787 bp) p53-responsive element (PRE), Chromatin immunoprecipitation assays showed that PRE-bound p53 interacts with the corepressor-histone deacetylase 3 (HDAC3), resulting in deacetylation of histones Ac-H4, at the proximal promoter, resulting in transcriptional silencing of SVCT2. Overall, our data suggests that p53 is a potent transcriptional repressor of SVCT2, a critical transporter of diet-derived ascorbic acid, across the plasma membranes of numerous essential tissue cell types.

Identification of risk factors for obstructive cholecystitis following placement of biliary stent in unresectable malignant biliary obstruction: a 5-year retrospective analysis in single center.

BACKGROUND: The risk factors for acute cholecystitis following biliary stent placement in patients with malignant biliary obstruction (MBO) have not been identified. We determined these risk factors and the efficacy of endoscopic ultrasound (EUS)-guided gallbladder drainage (GBD) as treatment. METHODS: We retrospectively analyzed patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for MBO from October 2013 to September 2018, and those with unresectable MBO with intact gallbladder (GB) were enrolled. RESULTS: Acute cholecystitis occurred in 30 (15.7%) of 191 patients who underwent biliary stent placement for unresectable MBO. Logistic regression analysis confirmed that biliary stent across the orifice of the cystic duct (OCD) (odds ratio [OR] 6.02, 95% confidence interval [CI] 1.43-25.41, P = 0.015), GB opacification during ERCP (OR 13.07, 95% CI 4.22-40.50; P < 0.0001), and self-expandable metal stent (SEMS) (OR 14.19, 95% CI 4.36-46.18; P < 0.0001) were independent risk factors for cholecystitis. Subgroup analysis of patients who only underwent SEMS placement showed that biliary stent across the OCD and GB opacification were significant risk factors. Among the 25 patients who underwent EUS-GBD, the technical and clinical success rates were 100% and 96%, respectively. CONCLUSIONS: Biliary stent across the OCD, GB opacification, and SEMS were established as potential risk factors for post-ERCP cholecystitis. Thus, the strategy of using shorter stent length and avoiding unnecessary contrast injection could be a reasonable treatment option for selected patients with high risk of cholecystitis. Furthermore, EUS-GBD is not only safe and reliable for acute cholecystitis, but it also improves quality of life.

Effects of tris(2-chloroethyl) phosphate exposure on chicken embryos in a shell-less incubation system.

Tris(2-chloroethyl) phosphate (TCEP) is an organophosphate flame retardant that used in textiles, industrial materials, and furniture to delay the spread of fire after ignition. TCEP has been detected in the tissues and eggs of fish and birds. However, there are no studies regarding the effects of TCEP on avian embryos. In the present study, we investigated the developmental toxicity of TCEP exposure on chicken embryos in a shell-less incubation system, which enables in situ observation. Chicken embryos were treated with graded doses of TCEP (50, 250, and 500 nmol/g egg) on incubation day 0. The survival rate, morphological biometrics, heart rate, and length and branch number of extraembryonic blood vessels were measured on incubation days 3-9. Survival rates were reduced from incubation day 3 and were significantly decreased until day 9. Body length, head + bill length and eye diameter were significantly reduced by TCEP exposure. Regarding skeletal effects, spine length was decreased in a dose-dependent manner on day 9. Body weight on day 9 significantly reduced in all TCEP treatment groups. These results suggest that TCEP exposure to >50 nmol/g egg retards development in chicken embryos. TCEP exposure to 500 nmol/g egg significantly increased heart weight to body weight ratio in the embryos. More than 250 nmol/g egg of TCEP significantly reduced the heart rate of embryos in the early developmental stage. The formation of extraembryonic blood vessels and the number of erythrocytes were significantly reduced even with 50 nmol/g egg of TCEP. These findings suggest that TCEP exposure specifically affects the cardiovascular system in chicken embryos, which leads to developmental delay. The results of this study also demonstrate that the shell-less incubation system can be used to continuously monitor the effects of chemicals on developing avian embryos.

Traffic Sign Recognition Evaluation for Senior Adults Using EEG Signals.

Elderly people are not likely to recognize road signs due to low cognitive ability and presbyopia. In our study, three shapes of traffic symbols (circles, squares, and triangles) which are most commonly used in road driving were used to evaluate the elderly drivers' recognition. When traffic signs are randomly shown in HUD (head-up display), subjects compare them with the symbol displayed outside of the vehicle. In this test, we conducted a Go/Nogo test and determined the differences in ERP (event-related potential) data between correct and incorrect answers of EEG signals. As a result, the wrong answer rate for the elderly was 1.5 times higher than for the youths. All generation groups had a delay of 20-30 ms of P300 with incorrect answers. In order to achieve clearer differentiation, ERP data were modeled with unsupervised machine learning and supervised deep learning. The young group's correct/incorrect data were classified well using unsupervised machine learning with no pre-processing, but the elderly group's data were not. On the other hand, the elderly group's data were classified with a high accuracy of 75% using supervised deep learning with simple signal processing. Our results can be used as a basis for the implementation of a personalized safe driving system for the elderly.