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Abstract Urinary exfoliated tumor cells have emerged as promising biomarkers for predicting, diagnosing, and guiding therapy in bladder cancer. Several methodologies based on biological and physical differences between normal cells and malignant tumor cells have been developed over the past few years. However, these methods still did not have sufficient sensitivity or specificity. In this study, a remote analysis protocol was devised utilizing motion microscopy. This technique amplifies vibrations within a recorded video by re-rendering motions, thereby generating highly magnified visuals. This approach aims to detect dynamic motions that may not be perceptible to the human eye under normal observation. Remarkably, motion microscopy unveiled discernible fluctuations surrounding bladder malignant tumor cells, which we referred to herein as cellular trail. The cellular trails were predominantly evident at around 1 Hz in amplified video images, with a velocity of 22 μm/s. Moreover, cellular trails were observed regardless of whether they were in a non-Newtonian or Newtonian fluid environment. Significantly, this phenomenon was distinguishable even in urine samples. In conclusion, we suggest motion microscopy as an innovative approach for detecting urinary malignant tumors with potential clinical utility as a complementary tool to cytology.

Abstract It is necessary to verify whether nail fold capillaroscopy can be utilized for the early detection of breast cancer. To establish this technology, an animal model was developed, utilizing mice for nail fold observations. Nail fold capillaroscopy revealed a human-like anatomical pattern and facilitated the observation of cellular movement within blood vessels. Injection of MCF-7 or mammary fibroblasts in mice allowed the observation of cellular vibrations using motion microscopy from nail fold. We have named this technology ‘capillary cell motion microscopy.’ Intriguingly, we were able to identify distinct cellular vibrations in the MCF-7 group. Moreover, evaluating its effectiveness in mice with chemically induced cancer revealed higher sensitivity (81%-85%) compared to conventional methods (45%-68%). Capillary cell motion microscopy, operating at 0.5–1.5 Hz, provided clear distinction of tumor cells and demonstrated potential applicability in human subjects. While condition adjustments may be necessary, this method holds promise for noninvasive breast cancer detection through nail fold observations.

Abstract Owing to global warming and pollution concerns, reducing the environmental footprint of the textile and fashion industry has received considerable attention. Within this industry, the dyeing and finishing processes contribute significantly to greenhouse gas emissions and water pollution. This study introduces an innovative approach to address these challenges by leveraging digital twin technology to optimize the textile dyeing process. A smart analysis module was developed to continuously monitor and analyze the dyeing parameters in real time to implement control actions to automatically reduce the process duration. Integrated with this module, a digital twin of the dyeing machine enabled the real-time monitoring of energy consumption and process parameters. A case study comparing the traditional dyeing process with the optimized process was conducted. The results showed that dyeing time was reduced by ~ 17.5% without compromising dyeing quality. Energy consumption and greenhouse gas emissions were also reduced by ~ 12.1% when using the optimized process. This study offers a practical and sustainable option for textile dyeing, particularly for small and medium-sized enterprises.

Abstract Solute carrier family (SLC) transporters are expressed in the digestive system and play important roles in maintaining physiological functions in the body. In addition, SLC transporters act as oncoproteins or tumor-suppressor proteins during the development, progression, and metastasis of various digestive system cancers. SLC22A18, a member of the SLC22 gene family, is an orphan transporter with an unknown endogenous substrate. Previous study revealed that SLC22A18 is downregulated in colorectal cancer tissues and that it acts as a suppressor in colorectal cancer, although the effects of SLC22A18 variants on colon cancer cell proliferation, migration, and invasion are unknown. Therefore, in this study, we identified SLC22A18 variants found in multiple populations by searching public databases and determined the in vitro effects of these missense variations on transporter expression and cancer progression. Our results indicated that three missense SLC22A18 variants—p.Ala6Thr, p.Arg12Gln, and p.Arg86His—had significantly lower cell expression than the wild type, possibly owing to intracellular degradation. Furthermore, these three variants caused significantly higher proliferation, migration, and invasion of colon cancer cells than the wild type. Our findings suggest that missense variants of SLC22A18 can potentially serve as biomarkers or prognostic tools that enable clinicians to predict colorectal cancer progression.

Anomaly detection systems based on artificial intelligence (AI) have demonstrated high performance and efficiency in a wide range of applications such as power plants and smart factories. However, due to the inherent reliance of AI systems on the quality of training data, they still demonstrate poor performance in certain environments. Especially in hazardous facilities with constrained data collection, deploying these systems remains a challenge. In this paper, we propose Generative Anomaly Detection using Prototypical Networks (GAD-PN) designed to detect anomalies using only a limited number of normal samples. GAD-PN is a structure that integrates CycleGAN with Prototypical Networks (PNs), learning from metadata similar to the target environment. This approach enables the collection of data that are difficult to gather in real-world environments by using simulation or demonstration models, thus providing opportunities to learn a variety of environmental parameters under ideal and normal conditions. During the inference phase, PNs can classify normal and leak samples using only a small number of normal data from the target environment by prototypes that represent normal and abnormal features. We also complement the challenge of collecting anomaly data by generating anomaly data from normal data using CycleGAN trained on anomaly features. It can also be adapted to various environments that have similar anomalous scenarios, regardless of differences in environmental parameters. To validate the proposed structure, data were collected specifically targeting pipe leakage scenarios, which are significant problems in environments such as power plants. In addition, acoustic ultrasound signals were collected from the pipe nozzles in three different environments. As a result, the proposed model achieved a leak detection accuracy of over 90% in all environments, even with only a small number of normal data. This performance shows an average improvement of approximately 30% compared with traditional unsupervised learning models trained with a limited dataset.

Most textual analysis-based trading approaches in cryptocurrency (crypto) involve lexical, rule-based methods for extracting news sentiments. Furthermore, language models (LMs) are not always suitable for the crypto domain due to jargon that is not covered in general-purpose texts. This study answers the question of “Is it possible that the LMs can profit by effectively applying the sentiment score of the natural language processing task with chart score in the BTC trading system?” by focusing on the effectiveness of both scores, which significantly affect the profit of the trading system. We introduce CBITS: Cryptocurrency BERT Incorporated Trading System based on pre-trained LMs for Korean crypto sentiment analysis to aid Bitcoin (BTC) trading models. We pre-trained crypto-specific LMs, which are transformer encoder-based architectures. Along with our pre-trained LMs, we also present our custom fine-tuning dataset used to train our LMs on the BTC sentiment classifier and show that using sentiment scores along with BTC chart data boosts the performance of BTC trading models and also allows us to create a market-neutral trading strategy.

Abstract The ATP-binding cassette subfamily 4 (ABCA4), a transporter, is localized within the photoreceptors of the retina, and its genetic variants cause retinal dystrophy. Despite the clinical importance of the ABCA4 transporter, a few studies have investigated the function of each variant. In this study, we functionally characterized ABCA4 variants found in Korean patients with Stargardt disease or variants of the ABCA4 promoter region. We observed that four missense variants—p.Arg290Gln, p.Thr1117Ala, p.Cys1140Trp, and p.Asn1588Tyr—significantly decreased ABCA4 expression on the plasma membrane, which could be due to intracellular degradation. There are four major haplotypes in the ABCA4 proximal promoter. We observed that the H1 haplotype (c.-761C>A) indicated significantly increased luciferase activity compared to that of the wild-type, whereas the H3 haplotype (c.-1086A>C) indicated significantly decreased luciferase activity (P T in the H2 haplotype exhibited significantly increased luciferase activity compared with that of the wild-type. Two transcription factors, GATA-2 and HLF, were found to function as enhancers of ABCA4 transcription. Our findings suggest that ABCA4 variants in patients with Stargardt disease affect ABCA4 expression. Furthermore, common variants of the ABCA4 proximal promoter alter the ABCA4 transcriptional activity, which is regulated by GATA-2 and HLF transcription factors.

Vast amounts of dyeing wastewater released from the textile industry can not only cause water pollution but also have negative effects on the human body, such as skin irritation and respiratory diseases. Dye adsorption technology is necessary for the treatment of wastewater discharged from the dyeing industry and for environmental improvement. However, to remove dyeing wastewater, more energy and solvents are used to fabricate adsorbents, or excessive energy is used to filter dyeing wastewater out, resulting in more environmental pollution. Therefore, it is necessary to develop a method of filtering dyeing wastewater in a more environmentally friendly manner by minimizing the use of solvents and energy. In this study, we modified the surface of a textile substrate through UV irradiation to create a monomer capable of facilely bonding with dyes. Employing the UV photografting method, we were able to produce a dye adsorption filter in a more environmentally friendly manner, minimizing solvent usage and heat energy consumption required for absorbent synthesis. At a monomer concentration of 10%, the fabricated filter exhibited a dye removal efficiency of 97.34% after 24 h, all without the need for a pressure treatment or temperature increase. Moreover, it displayed an adsorption capacity of approximately 77.88 mg per 1 g of filter material.

The mixed work assignment technique was applied to the modular production concept to solve the apparel assembly line balancing problem. Specifically, an algorithm was implemented to generate workstations by first classifying tasks into modules through an analysis of the manufacturing process and assigning grouped tasks in the single task–multiple workers and multiple tasks–single worker assignment methods. Then, worker assignment was sequentially performed considering the skill level of the worker. A simulation of producing 100 men’s shirts was performed. Owing to line balancing, the total production time was considerably lower than that reported in previous studies. The enhanced performance was attributable to the fact that unlike previous studies that limited the apparel assembly line balancing problem to worker assignment, line balancing was performed through both task and worker assignment in this study. The results demonstrated that task assignment must be considered in the design stage in the apparel assembly line balancing problem.

Abstract Chronic myeloid leukemia is generally required bone marrow biopsy for diagnosis. Although examining peripheral blood is less invasive, it has not been fully validated as a routine diagnostic test due to suboptimal sensitivity. To overcome this limitation, a number of methodologies based on microfluidics have been developed for sorting circulating tumor cells from peripheral blood of patients with leukemia. In order to develop a more convenient method, we designed an analysis protocol using motion microscopy that amplifies cellular micro motions in a captured video by re-rendering pixels to generate extreme magnified visuals. Intriguingly, no fluctuations around leukemic myeloblasts were observed with a motion microscope at any wavelength of 0–10 Hz. However, use of 0.05% hyaluronic acid, one type of non-newtonian fluid, demonstrated fluctuations around leukemic myeloblasts under conditions of 25 μm/s and 0.5–1.5 Hz with a motion microscope. Thus, the non-invasive detection of leukemic myeloblasts can offer a valuable supplementary diagnostic tool for assessment of drug efficacy for monitoring patients with chronic myeloid leukemia.

Abstract Background Micro RNA of Marsupenaeus japonicas has been known to promote apoptosis of tumor cells. However, the detailed mechanisms are not well understood. Results Using tomographic microscope, which can detect the internal structure of cells, we observed breast tumor cells following treatment of the miRNA. Intriguingly, we found that mitochondria migrate to an adjacent tumor cells through a tunneling nanotube. To recapitulate this process, we engineered a microfluidic device through which mitochondria were transferred. We show that this mitochondrial transfer process released endonuclease G (Endo G) into tumor cells, which we referred to herein as unsealed mitochondria. Importantly, Endo G depleted mitochondria alone did not have tumoricidal effects. Moreover, unsealed mitochondria had synergistic apoptotic effects with subtoxic dose of doxorubicin thereby mitigating cardiotoxicity. Conclusions Together, we show that the mitochondrial transfer through microfluidics can provide potential novel strategies towards tumor cell death.

Abstract Tumor cells can respond to therapeutic agents by morphologic alternations including formation of tunneling nanotubes. Using tomographic microscope, which can detect the internal structure of cells, we found that mitochondria within breast tumor cells migrate to an adjacent tumor cell through a tunneling nanotube. To investigate the relationship between mitochondria and tunneling nanotubes, mitochondria were passed through a microfluidic device that mimick tunneling nanotubes. Mitochondria, through the microfluidic device, released endonuclease G (Endo G) into adjacent tumor cells, which we referred to herein as unsealed mitochondria. Although unsealed mitochondria did not induce cell death by themselves, they induced apoptosis of tumor cells in response to caspase‐3. Importantly, Endo G‐depleted mitochondria were ineffective as lethal agents. Moreover, unsealed mitochondria had synergistic apoptotic effects with doxorubicin in further increasing tumor cell death. Thus, we show that the mitochondria of microfluidics can provide novel strategies toward tumor cell death.

Abstract Background Since colon cancer stem cells (CSCs) play an important role in chemoresistance and in tumor recurrence and metastasis, targeting of CSCs has emerged as a sophisticated strategy for cancer therapy. α-mangostin (αM) has been confirmed to have antiproliferative and apoptotic effects on cancer cells. This study aimed to evaluate the selective inhibition of αM on CSCs in colorectal cancer (CRC) and the suppressive effect on 5-fluorouracil (5-FU)-induced CSCs. Methods The cell viability assay was performed to determine the optimal concentration of αM. A sphere forming assay and flow cytometry with CSC markers were carried out to evaluate the αM-mediated inhibition of CSCs. Western blot analysis and quantitative real-time PCR were performed to investigate the effects of αM on the Notch signaling pathway and colon CSCs. The in vivo anticancer efficacy of αM in combination with 5-FU was investigated using a xenograft mouse model. Results αM inhibited the cell viability and reduced the number of spheres in HT29 and SW620 cells. αM treatment decreased CSCs and suppressed the 5-FU-induced an increase in CSCs on flow cytometry. αM markedly suppressed Notch1, NICD1, and Hes1 in the Notch signaling pathway in a time- and dose-dependent manner. Moreover, αM attenuated CSC markers CD44 and CD133, in a manner similar to that upon DAPT treatment, in HT29 cells. In xenograft mice, the tumor and CSC makers were suppressed in the αM group and in the αM group with 5-FU treatment. Conclusion This study shows that low-dose αM inhibits CSCs in CRC and suppresses 5-FU–induced augmentation of CSCs via the Notch signaling pathway.

Cardiac tissue damage following ischemia leads to cardiomyocyte apoptosis and myocardial fibrosis. Epigallocatechin-3-gallate (EGCG), an active polyphenol flavonoid or catechin, exerts bioactivity in tissues with various diseases and protects ischemic myocardium; however, its association with the endothelial-to-mesenchymal transition (EndMT) is unknown. Human umbilical vein endothelial cells (HUVECs) pretreated with transforming growth factor β2 (TGF-β2) and interleukin 1β (IL-1β) were treated with EGCG to verify cellular function. In addition, EGCG is involved in RhoA GTPase transmission, resulting in reduced cell mobility, oxidative stress, and inflammation-related factors. A mouse myocardial infarction (MI) model was used to confirm the association between EGCG and EndMT in vivo. In the EGCG-treated group, ischemic tissue was regenerated by regulating proteins involved in the EndMT process, and cardioprotection was induced by positively regulating apoptosis and fibrosis of cardiomyocytes. Furthermore, EGCG can reactivate myocardial function due to EndMT inhibition. In summary, our findings confirm that EGCG is an impact activator controlling the cardiac EndMT process derived from ischemic conditions and suggest that supplementation with EGCG may be beneficial in the prevention of cardiovascular disease.

Abstract Apoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1β production and caspase-1 activation by IL-10 was reversed in BMDM from AIM −/− mice. Treatment of BMDM from both wild type (WT) and IL-10 −/− mice with recombinant AIM showed the inhibitory effects on IL-1β and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1β and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM −/− mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1β and IL-18 production.

A biologically-interpretable and robust metric that provides insight into one’s health status from a gut microbiome sample is an important clinical goal in current human microbiome research. Herein, the authors introduce a species-level index that predicts the likelihood of having a disease.

This study presents the direction of modeling and simulation (M&S) development, which is essential for high-tech armed forces, focusing on the Vision 2030 in Republic of Korea Army. In particular, in preparation for the Fourth Industrial Revolution, the army is doing its best to transform itself with cutting-edge science and technology. It is preparing for future warfare by promoting artificial intelligence (AI), a dronebot combat system, the warrior platform, and Army-Tiger 4.0 to increase the mobility, intelligence, and networking of infantry units. M&S is vital for accomplishing this advanced science and technology. In other words, it is an essential element of effective defense management, such as improving defense capabilities, enhancing military power, strengthening combat readiness posture, and training for future science. In particular, M&S is the best solution to overcome the difficult conditions of a limited budget and lack of resources by using more creative thinking methods along with cutting-edge technologies, such as AI, big data, virtual reality, and the Internet of things (IoT). The Republic of Korea Army recognizes its importance and intends to introduce and implement the 21-35 Army M&S development direction to present the vision and direction of the Army M&S for advanced science and technology force and to develop it continuously.

Abstract Background Yarrowia lipolytica, an oleaginous yeast, is a promising platform strain for production of biofuels and oleochemicals as it can accumulate a high level of lipids in response to nitrogen limitation. Accordingly, many metabolic engineering efforts have been made to develop engineered strains of Y. lipolytica with higher lipid yields. Genome-scale model of metabolism (GEM) is a powerful tool for identifying novel genetic designs for metabolic engineering. Several GEMs for Y. lipolytica have recently been developed; however, not many applications of the GEMs have been reported for actual metabolic engineering of Y. lipolytica. The major obstacle impeding the application of Y. lipolytica GEMs is the lack of proper methods for predicting phenotypes of the cells in the nitrogen-limited condition, or more specifically in the stationary phase of a batch culture. Results In this study, we showed that environmental version of minimization of metabolic adjustment (eMOMA) can be used for predicting metabolic flux distribution of Y. lipolytica under the nitrogen-limited condition and identifying metabolic engineering strategies to improve lipid production in Y. lipolytica. Several well-characterized overexpression targets, such as diglyceride acyltransferase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase, were successfully rediscovered by our eMOMA-based design method, showing the relevance of prediction results. Interestingly, the eMOMA-based design method also suggested non-intuitive knockout targets, and we experimentally validated the prediction with a mutant lacking YALI0F30745g, one of the predicted targets involved in one-carbon/methionine metabolism. The mutant accumulated 45% more lipids compared to the wild-type. Conclusion This study demonstrated that eMOMA is a powerful computational method for understanding and engineering the metabolism of Y. lipolytica and potentially other oleaginous microorganisms.

Signal transducer and activator of transcription 6 (STAT6) promotes an anti-inflammatory process by inducing the development of M2 macrophages. We investigated whether modulating STAT6 activity in macrophages using AS1517499, the specific STAT6 inhibitor, affects the restoration of homeostasis after an inflammatory insult by regulating PPARγ expression and activity. Administration of AS1517499 suppressed the enhanced STAT6 phosphorylation and nuclear translocation observed in peritoneal macrophages after zymosan injection. In addition, AS1517499 delayed resolution of acute inflammation as evidenced by enhanced secretion of pro-inflammatory cytokines, reduced secretion of anti-inflammatory cytokines in PLF and supernatants from peritoneal macrophages, and exaggerated neutrophil numbers and total protein levels in PLF. We demonstrate temporal increases in annexin A1 (AnxA1) protein and mRNA levels in peritoneal lavage fluid (PLF), peritoneal macrophages, and spleen in a murine model of zymosan-induced acute peritonitis. In vitro priming of mouse bone marrow-derived macrophages (BMDM) and peritoneal macrophages with AnxA1 induced STAT6 activation with enhanced PPARγ expression and activity. Using AS1517499, we demonstrate that inhibition of STAT6 activation delayed recovery of PPARγ expression and activity, as well as impaired efferocytosis. Taken together, these results suggest that activation of the STAT6 signaling pathway mediates PPARγ expression and activation in macrophages to resolve acute inflammation.

This study aims to develop the mechanical properties of the Al6Si2Cu aluminum alloy through the double-solution treatment. In addition to the Al matrix, large amounts of coarse eutectic Si, Al2Cu intermetallic, and Fe-rich phases were generated through thermo-calc simulation in agreement with the equilibrium phases. The eutectic Si phase is fragmented and spheroidized by the solution treatment as the heat treatment temperature and time increase. The Al2Cu intermetallic phase is dissolved into the Al matrix, resulting in an increase in both strength and elongation. The second-step solution temperature at 525 °C should be an optimum condition for enhancing the mechanical properties of the Al6Si2Cu aluminum alloy.

Shear stress (SS)-induced platelet activation is suggested as an essential mechanism of the acute coronary syndrome (ACS). We aimed to compare SS-induced thrombotic and thrombolytic activities among 3 treatment regimens in patients with ACS who underwent percutaneous coronary intervention (PCI). Patients were nonrandomly enrolled and treated with one of 3 regimens (TICA: ticagrelor 180 mg/d; RIVA: clopidogrel 75 mg/d and rivaroxaban 5 mg/d; CLP: clopidogrel 75 mg/d), administered in addition to aspirin (100 mg/d) for 30 days. The global thrombosis test was applied to measure SS-induced thrombotic (occlusion time [OT]) and thrombolytic activity (lysis time [LT]) at day 2 and 30. Aspirin reaction unit (ARU) and P2Y12 reaction unit (PRU) were simultaneously measured using VerifyNow. Group differences in the OT, LT, ARU, and PRU were evaluated. Seventy-five patients (25 patients in each group) finished 30 days of follow-up. Clinical and angiographic characteristics did not differ among the 3 groups, except ACS subtype and pre-PCI coronary flow. No major adverse cardiovascular events occurred in any group during follow-up. The OT and LT did not differ among the 3 groups at day 30 (OT: TICA, 447.2 ± 87.1 vs RIVA, 458.5 ± 70.3, vs CLP, 471.9 ± 90.7, LT: 1522.3 ± 426.5 vs 1734.6 ± 454.3 vs 1510.2 ± 593.9) despite significant differences in the PRU among the 3 groups. Shear stress–induced thrombotic and thrombolytic activities did not differ among the 3 investigated antithrombotic treatments.

ABSTRACT Colorectal adenomas are precancerous lesions of colorectal cancer (CRC) that offer a means of viewing the events key to early CRC development. A number of studies have investigated the changes and roles of gut microbiota in adenoma and carcinoma development, highlighting its impact on carcinogenesis. However, there has been less of a focus on the gut metabolome, which mediates interactions between the host and gut microbes. Here, we investigated metabolomic profiles of stool samples from patients with advanced adenoma (n = 102), matched controls (n = 102), and patients with CRC (n = 36). We found that several classes of bioactive lipids, including polyunsaturated fatty acids, secondary bile acids, and sphingolipids, were elevated in the adenoma patients compared to the controls. Most such metabolites showed directionally consistent changes in the CRC patients, suggesting that those changes may represent early events of carcinogenesis. We also examined gut microbiome-metabolome associations using gut microbiota profiles in these patients. We found remarkably strong overall associations between the microbiome and metabolome data and catalogued a list of robustly correlated pairs of bacterial taxa and metabolomic features which included signatures of adenoma. Our findings highlight the importance of gut metabolites, and potentially their interplay with gut microbes, in the early events of CRC pathogenesis. IMPORTANCE Colorectal adenomas are precursors of CRC. Recently, the gut microbiota, i.e., the collection of microbes residing in our gut, has been recognized as a key player in CRC development. There have been a number of gut microbiota profiling studies for colorectal adenoma and CRC; however, fewer studies have considered the gut metabolome, which serves as the chemical interface between the host and gut microbiota. Here, we conducted a gut metabolome profiling study of colorectal adenoma and CRC and analyzed the metabolomic profiles together with paired microbiota composition profiles. We found several chemical signatures of colorectal adenoma that were associated with some gut microbes and potentially indicative of future CRC. This study highlights potential early-driver metabolites in CRC pathogenesis and guides further targeted experiments and thus provides an important stepping stone toward developing better CRC prevention strategies.

Background: In order to ensure safer use of non-vitamin K antagonist oral anticoagulants (NOACs), continuously detecting unexpected adverse drug reactions (ADRs) after market approval is necessary. Methods: We performed disproportionality analysis to evaluate association between ADRs and NOACs including apixaban, dabigatran, and rivaroxaban using data from the Korea Institute of Drug Safety and Risk Management–Korea Adverse Event Reporting System database (KIDS-KD) between 2012 and 2016. There was no significant signal other than bleeding when considering quantity, signal strength, seriousness, and causality. In order to evaluate the NOAC reports about bleeding, we selected 62 WHO-ART diagnostic codes associated with bleeding. Among the 26 codes that referred to major bleeding, 18 codes referred to gastrointestinal bleeding and 8 were referred to intracranial bleeding. We evaluated the significance of the signals using reporting odds ratios (RORs) adjusted for age and sex. Results: Treatments with apixaban, dabigatran, and rivaroxaban were associated with 1989, 1668, and 2960 adverse events, respectively. Any type of bleeding with apixaban, dabigatran, rivaroxaban, and warfarin was reported in 174 (8.8%), 209 (12.5%), 523 (17.8%), and 620 (9.5%) events, respectively. For any bleeding, adjusted RORs of apixaban, dabigatran, and rivaroxaban were 0.99 [95% confidence interval (CI): 0.83–1.17], 1.47 (95% CI: 1.25–1.75), and 2.48 (95% CI: 2.16–2.84), respectively. With respect to major bleeding, the adjusted RORs of apixaban, dabigatran, and rivaroxaban were 1.08 (95% CI: 0.82–1.41), 1.46 (95% CI: 1.10–1.90), and 1.82 (95% CI: 1.43–2.32), respectively. Conclusion: Rivaroxaban might have stronger association with bleeding than apixaban and dabigatran.

Previously, we demonstrated that growth arrest-specific protein 6 (Gas6)/Axl or Mer signaling inhibited the transforming growth factor (TGF)-β1-induced epithelial−mesenchymal transition (EMT) in lung epithelial cells. Hepatocyte growth factor (HGF) has also been shown to inhibit TGF-β1-induced changes in EMT markers. Here, we examined whether Gas6 signaling can induce the production of HGF and c-Met in lung alveolar epithelial cells to mediate the inhibition of EMT and to inhibit the migration and invasion of epithelial cells. The inhibition of the RhoA/Rho kinase pathway, using either a RhoA-targeted small interfering RNA (siRNA) or the Rho kinase pharmacologic inhibitor Y27362, prevented the inhibition of TGF-β1-induced EMT in LA-4 cells and primary alveolar type II (AT II) epithelial cells. The c-Met antagonist PHA-665752 also blocked the anti-EMT effects associated with Gas6. Moreover, treatment with Y27362 or PHA-665752 prevented the Gas6-mediated inhibition of TGF-β1-induced migration and invasion. Our data provided evidence that the RhoA-dependent production of HGF and c-Met mediated the Gas6-induced inhibition of EMT, migration and invasion in lung alveolar epithelial cells. Thus, Gas6/Axl and Mer/RhoA signaling may be necessary for the maintenance of homeostasis in the alveolar epithelium, via HGF and c-Met.

IntroductionThe presence of late gadolinium enhancement (LGE) at the right ventricular insertion point (RVIP) on cardiac magnetic resonance (CMR) is generally believed to be nonspecific, but the clinical implication of this unique LGE pattern in patients with non-ischemic dilated cardiomyopathy (NICM) has not been elucidated.ObjectivesWe investigated the prognostic significance of RVIP-LGE in NICM patients.MethodsA total of 360 consecutive NICM patients referred for CMR (102 with no LGE, 50 with RVIP-LGE, 121 with left ventricular [LV]-LGE, and 87 with both an LV and RVIP-LGE) were studied. The primary endpoint was a composite of the all-cause death, hospitalization due to worsening of heart failure, and major arrhythmic events.ResultsDuring a mean follow-up of 45.2 ± 36.5 months, 149 (41.4%) patients (22 [21.6%] no LGE vs. 16 [32.0%] RVIP-LGE vs. 62 [51.2%] LV-LGE vs. 49 [56.3%] both LV and RVIP-LGE, P < 0.0001) reached the primary endpoint. A Kaplan Meier curve demonstrated that RVIP-LGE patients had an intermediate trend of an event free survival rate for the composite endpoint (log-rank P < 0.0001). In a multivariable Cox regression model, LV-LGE (P = 0.008) and both LV and RVIP-LGE (P = 0.003) were significantly associated with a worse outcome, whereas RVIP-LGE was not (P = 0.101). In addition, RVIP-LGE patients (n = 32) had a more favorable outcome compared to LV-LGE patients (n = 32) even after matching the extent of the LGE (median 3.4% [interquartile range, 3.1-3.8], 8 [25.0%] RVIP-LGE vs. 20 [62.5%] LV-LGE, P = 0.002).ConclusionsLGE confined to the RVIP among NICM patients did not significantly increase the risk of adverse cardiac events, and also showed a better outcome than the same extent of LGE located in the LV. Identification of this unique LGE distribution may help refine the current risk stratification.

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.