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Circadian disruption often arises prior to the onset of typical motor deficits in patients with Parkinson's disease (PD). It remains unclear whether such a prevalent non-motor manifestation would contribute to the progression of PD. Diffusible oligomeric alpha-synuclein (O-αSyn) is perceived as the most toxic and rapid-transmitted species in the early stages of PD. Exploring the factors that influence the spread and toxicity of O-αSyn should be helpful for developing effective interventions for the disease. The aim of this study was to explore the effects of circadian disruption on PD pathology and parkinsonism-like behaviors in a novel mouse model induced by O-αSyn. We discovered that O-αSyn could enter the brain rapidly following intranasal administration, resulting in the formation of nitrated-αSyn pathology and non-motor symptoms of the mice. Meanwhile, circadian disruption exacerbated the burden of nitrated-αSyn pathology and accelerated the loss of dopaminergic neurons in O-αSyn-treated mice. Subsequent experiments demonstrated that circadian disruption might act via promoting nitrative stress and neuroinflammation. These findings could highlight the circadian rhythms as a potential diagnostic and therapeutic target in early-stage PD., (© 2024. The Author(s).)

Study Objectives: Mounting evidence indicated the correlation between sleep and cerebral small vessel disease (CSVD). However, little is known about the exact causality between poor sleep and white matter injury, a typical signature of CSVD, as well as the underlying mechanisms., Methods: Spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats were subjected to sleep fragmentation (SF) for 16 weeks. The effects of chronic sleep disruption on the deep white matter and cognitive performance were observed., Results: SHR were validated as a rat model for CSVD. Fragmented sleep induced strain-dependent white matter abnormalities, characterized by reduced myelin integrity, impaired oligodendrocytes precursor cells (OPC) maturation and pro-inflammatory microglial polarization. Partially reversible phenotypes of OPC and microglia were observed in parallel following sleep recovery., Conclusions: Long-term SF-induced pathological effects on the deep white matter in a rat model of CSVD. The pro-inflammatory microglial activation and the block of OPC maturation may be involved in the mechanisms linking sleep to white matter injury., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate the diagnostic accuracy and safety of using magnetically guided capsule endoscopy with a detachable string (ds-MCE) for detecting and grading oesophagogastric varices in adults with cirrhosis., Design: Prospective multicentre diagnostic accuracy study., Setting: 14 medical centres in China., Participants: 607 adults (>18 years) with cirrhosis recruited between 7 January 2021 and 25 August 2022. Participants underwent ds-MCE (index test), followed by oesophagogastroduodenoscopy (OGD, reference test) within 48 hours. The participants were divided into development and validation cohorts in a ratio of 2:1., Main Outcome Measures: The primary outcomes were the sensitivity and specificity of ds-MCE in detecting oesophagogastric varices compared with OGD. Secondary outcomes included the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices and the diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices., Results: ds-MCE and OGD examinations were completed in 582 (95.9%) of the 607 participants. Using OGD as the reference standard, ds-MCE had a sensitivity of 97.5% (95% confidence interval 95.5% to 98.7%) and specificity of 97.8% (94.4% to 99.1%) for detecting oesophagogastric varices (both P<0.001 compared with a prespecified 85% threshold). When using the optimal 18% threshold for luminal circumference of the oesophagus derived from the development cohort (n=393), the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices in the validation cohort (n=189) were 95.8% (89.7% to 98.4%) and 94.7% (88.2% to 97.7%), respectively. The diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices was 96.3% (92.6% to 98.2%), 96.9% (95.2% to 98.0%), and 96.7% (95.0% to 97.9%), respectively. Two serious adverse events occurred with OGD but none with ds-MCE., Conclusion: The findings of this study suggest that ds-MCE is a highly accurate and safe diagnostic tool for detecting and grading oesophagogastric varices and is a promising alternative to OGD for screening and surveillance of oesophagogastric varices in patients with cirrhosis., Trial Registration: ClinicalTrials.gov NCT03748563., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the “Ten Thousand Plan”-National High-Level Talents Special Support Plan and Shanghai Municipal Hospital Emerging Frontier Technology Joint Project for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: The Zhongshan colorectal endoscopic submucosal dissection (CR-ESD) score model was proposed to grade the technical difficulty of CR-ESD. The objective of this study was to prospectively validate and update the score model., Methods: A multicenter prospective cohort analysis of CR-ESD was conducted. Individual data on patients, lesions, and outcomes of CR-ESD were used to validate the original model and further refine the difficulty of the prediction model. Data were randomly divided into discovery and internal validation cohorts. A multivariate Cox regression analysis was conducted on the discovery cohort to develop an updated risk-scoring system, which was then validated., Results: Five hundred forty-eight patients with 565 colorectal lesions treated by ESD from 4 hospitals were included. In the prospective validation cohort, the area under the receiver-operating characteristic (ROC) curve for the original model was .707. Six risk factors were identified and assigned point values: tumor size (2 points for 30-50 mm, 3 points for ≥50 mm), at least two-thirds circumference of the lesion (3 points), tumor location in the cecum (2 points) or flexure (2 points), laterally spreading tumor-nongranular lesions (1 point), preceding biopsy sampling (1 point), and NBI International Colorectal Endoscopic type 3 (3 points). The updated model had an area under the ROC curve of .738 in the discovery cohort and of .782 in the validation cohort. Cases were categorized into easy (score = 0-1), intermediate (score = 2-3), difficult (score = 4-6), and very difficult (score ≥7) groups. Satisfactory discrimination and calibration were observed., Conclusions: The original model achieved an acceptable level of prediction in the prospective cohort. The updated model exhibited superior performance and can be used in place of the previous version. (Clinical trial registration number: ChiCTR2100047087.)., Competing Interests: Disclosure All authors disclosed no financial relationships. Research support for this study (Y-S Zhong and B Li) was provided by the National Natural Science Foundation of China (grant nos. 82273025 and 82203460), the Science and Technology Commission Foundation of Shanghai Municipality (grant nos. 22XD1402200 and 22JC1403003), and China Postdoctoral Science Foundation (grant nos. 2022TQ0070 and 2022M710759)., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objectives: Laser lithotripsy under fluoroscopic guidance is difficult to perform and risky due to its invisibility. In this study we aimed to investigate the efficacy and safety of a novel endoscopic auxiliary system (NEAS)-assisted lithotripsy under fluoroscopy for treating difficult common bile duct (CBD) stones., Methods: Patients with difficult CBD stones who were treated with NEAS-assisted laser lithotripsy (NEAS group) or conventional mechanical lithotripsy (ML) under fluoroscopy (ML group) were retrospectively evaluated. The primary outcome was the complete stone clearance rate and the secondary outcomes included operation time, complications, and medical cost., Results: Seventeen patients were treated with NEAS-assisted laser lithotripsy and 144 patients underwent ML. Using the propensity score matching analysis, 17 pairs of cases treated with NEAS-assisted lithotripsy and ML were included. Patients in the NEAS group showed a higher stone clearance rate than the ML group (94.1% vs 58.8%, P = 0.039), as well as shorter operation time (41.9 min vs 49.4 min, P < 0.001) and lower medical cost (USD 4607 vs USD 5014, P < 0.001). There was no significant difference in the complication rate between the two groups (5.9% vs 17.6%, P = 0.601)., Conclusion: NEAS-assisted fluoroscopy-guided laser lithotripsy is feasible and safe, which may be a promising technique in fluoroscopy-guided laser lithotripsy for difficult CBD stones., (© 2023 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Gastric cancer (GC) is one of most common cancers worldwide. Several studies have suggested that Rab31 functions as a membrane vesicle transport regulator; however, the mechanism by which RAB31 regulates exosome secretion and promotes metastasis remains to be clarified., Methods: We examined the expression of RAB31 protein and mRNA in GC tissue samples via immunohistochemistry and reverse transcription-polymerase chain reaction assays, respectively. We elucidated the function of RAB31 in GC cells by constructing a cell model and a pulmonary metastatic model of GC with overexpression of RAB31. Protein mass spectrometry was used to identify the exosomal protein., Results: RAB31 expression increased at both the protein and mRNA levels with the development of GC. Cells overexpressing RAB31 showed an enhanced ability to migrate in both the in vitro cell model and the pulmonary metastatic model of GC. Exosome nanoparticle tracking analysis and electron microscopy revealed that the both the number and size of the exosomes secreted by GC cells were reduced when RAB31 expression was depleted. Injection of exosomes derived from RAB31 overexpressing cells promoted pulmonary metastasis in vivo. Analysis of the exosomal proteins revealed that PSMA1 was overexpressed in GC tissue in accordance with RAB31 expression. PSMA1 overexpression was highly associated with poor prognosis of GC patients., Conclusion: Our findings revealed a key role for RAB31 in GC metastasis through regulation of exosome secretion., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N-terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD-deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS-induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co-cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS., (© 2022 Wiley-VCH GmbH.)

Programmed death ligand 1 (PD-L1) is not only an important molecule in mediating tumor immune escape, but also regulates inflammation development. Here we showed that PD-L1 was upregulated on neutrophils in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Neutrophil specific knockout of PD-L1 reduced lung injury in ARDS model induced by intratracheal LPS injection. The level of NET release was reduced and autophagy is elevated by PD-L1 knockout in ARDS neutrophils both in vivo and in vitro . Inhibition of autophagy could reverse the inhibitory effect of PD-L1 knockout on NET release. PD-L1 interacted with p85 subunit of PI3K at the endoplasmic reticulum (ER) in neutrophils from ARDS patients, activating the PI3K/Akt/mTOR pathway. An extrinsic neutralizing antibody against PD-L1 showed a protective effect against ARDS. Together, PD-L1 maintains the release of NETs by regulating autophagy through the PI3K/Akt/mTOR pathway in ARDS. Anti-PD-L1 therapy may be a promising measure in treating ARDS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Xie, Zhao, Li, Liu, Guo, Meng, Wan, Bian, Deng and Wang.)

Background: This study sought to identify candidate biomarkers associated with gastric cancer (GC) prognosis based on an integrated bioinformatics analysis., Methods: First, the GSE54129 and GSE79973 data sets were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) identified between the 2 data sets were screened using the limma software package in R, and the intersection DEGs were obtained by a Venn analysis. Subsequently, gene clustering and a functional analysis were performed to explore the roles of the DEGs. The protein-protein interaction (PPI) network of the genes in clusters was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins. A survival analysis evaluated the associations between the candidate genes and the overall survival of GC patients. A drug-gene interaction analysis and an external data set analysis were conducted using The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD) data set to validate the prognostic genes., Results: We extracted 421 intersection DEGs from the 2 GEO data sets. There were 5 gene clusters, and the functional analysis revealed that they were mainly associated with the extracellular matrix-receptor interaction pathway. The PPI interaction analysis identified the top 36 hub genes. The survival analysis revealed that 7 upregulated genes [i.e., platelet-derived growth factor receptor beta ( PDGFRB ), angiopoietin 2 ( ANGPT2 ), vascular endothelial growth factor C ( VEGFC ), collagen type IV alpha 2 chain ( COL4A2 ), collagen type IV alpha 1 chain ( COL4A1 ), thrombospondin 1 ( THBS1 ), and fibronectin 1 ( FN1 )] were associated with the survival prognosis of GC patients. The 20 drug-gene interaction pairs among the 4 genes and 18 drugs were obtained. Finally, TCGA-STAD data set was used to validate the expression levels of COL4A1, PDGFRB , and FN1 ., Conclusions: We found that 7 upregulated genes (i.e., PDGFRB, ANGPT2, VEGFC, COL4A2, COL4A1, THBS1 , and FN1 ) were promising markers of prognosis in GC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-651/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that affects 1%-2% of the population over 60 years old. Immune response dysfunction in the brain contributes to the occurrence and development of PD. This study aimed to uncover the potential diagnostic genes for PD and characterize the immune cell infiltrates., Methods: We downloaded the microarray data of patients with PD samples from the Gene Expression Omnibus (GEO) database. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify the modules linked to PD in the GSE20163 dataset. Meanwhile, differentially expressed genes (DEGs) between the healthy control samples and PD samples were also identified. Then the PD-related genes were integrated based on the genes in the key module and DEGs. Functional enrichment analysis was used to explore the molecular mechanisms of these PD-related genes. Protein-protein interaction (PPI) network and least absolute shrinkage and selection operator (LASSO) analysis were used to further screen candidate genes for PD. Gene set enrichment analysis (GSEA) was applied to explore the biological functions of these candidate genes. The infiltration of immune cells was detected by single-sample gene set enrichment analysis (ssGSEA) algorithm in the GSE20163 dataset, and Pearson analysis was used to investigate the correlation of candidate genes with immune cells and immune checkpoint proteins. The expression of candidate genes in clinical samples was verified by qPCR., Results: Altogether, we found a unique gene module related to PD, where 109 DEGs were identified in the GSE20163 dataset. Following these results, we screened 68 genes associated with PD. Gene Expression Omnibus (GEO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that these genes were markedly enriched in the pathway of synthesis and transport of neurons. Three candidate genes (SLC18A2, CALB1, and SYNGR3) were further identified in PD patients through PPI network and LASSO analysis. The receiver operating characteristic (ROC) curve indicated that the three candidate genes had a good performance in distinguishing the PD samples from healthy control samples. The proportions of the aDC, DC, NK CD56dim cells, and follicular helper T cells (TFH) were obviously different between the healthy control and PD samples. Moreover, CTLA4, LAG3, CEACAM1, and CD27 were highly expressed in the PD group. GSEA analysis for candidate genes revealed that they were all closely related to the neurogenic disease. Additionally, the three candidate genes were all strongly correlated with the above immune cells and immune checkpoint proteins. The qPCR results validated the expression differences of SLC18A2 and SYNGR3 in the clinical PD and control samples., Conclusion: The three candidate genes may be a useful tool for diagnosing PD patients. These findings provide a reference for exploring new therapeutic targets and strategies for PD treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Unraveling the photogenerated exciton dynamics of π-stacked molecular aggregates is of great importance for both fundamental studies and industrial applications. Among various π-stacked molecular aggregates, perylene tetracarboxylic acid bisimide (PBI) based aggregates are regarded as one of the prototypes due to their inherent high fluorescence quantum yield and excellent photostability and flexibility in controlling intermolecular forces via chemical modifications. However, the exciton dynamics of these PBI based aggregates remain elusive up to now. In this work, we have first employed LR-TDDFT-based nonadiabatic dynamics simulations and static electronic structure calculations to investigate the ultrafast exciton dynamics of a newly synthesized perylene bisimide quadruple (PBQ) π-stack. Upon photoexcitation, the S 6 to S 10 states are the most likely populated excited states, which can be regarded as a combination of local excited (LE) excitons and charge transfer (CT) excitons of those four PBI chromophores. Then, the excited PBQ π-stack relaxes ultrafast to the lowest lying excited S 1 state within 500 fs, which is accompanied by the complicated exciton conversion as well as exciton localization/delocalization dynamics. In short, the initially populated hybrid LE and CT excitons convert to the LE excitons of B/C and A/D, in which the LE excitons of B/C contribute the most (∼0.44) while the LE excitons of A/D also have minor contributions (0.21), indicating the formation of the localized excimer state. We use the notations A/B/C/D here to represent the four PBI fragments of PBQ π-stacks along the direction perpendicular to the PBI molecular plane. Additionally, using a recently defined root mean square deviation (RMSD) of electron and hole spatial distributions along three Cartesian coordinates, we could investigate the exciton localization/delocalization dynamics in a quantitative way. Our simulation results indicate that the photoinduced electrons and holes of the PBQ π-stack exhibit an ultrafast localization(∼10 fs)-delocalization(∼60 fs)-localization(∼200 fs) dynamics, during which both LE and CT excitons play crucial roles. Our present work is not only consistent with previous experimental studies, but also provides more detailed insights into the relevant processes, which might be useful for the future design of PBI based optoelectronic devices with improved performances.

Objective: To investigate the incidence of primary gallbladder and biliary tract cancer, mortality and disability-adjusted life years (DALY) of the global burden from 1990 to 2017., Methods: Data of 195 countries and territories from 1990 to 2017 were extracted from the Global Health Data Exchange. The age-standardized incidence rate (ASIR) and estimated annual percentage change (EAPC) were employed to quantify trends in the incidence of primary gallbladder and biliary tract cancer. The age-standardized death rate (ASDR), age-standardized DALY and their corresponding EAPC were used to evaluate mortality trends., Results: The global incidence of primary gallbladder and biliary tract cancer rose by 75.9% from 119 900 cases in 1990 to 210 900 cases in 2017. The highest ASIR was observed in Chile (10.8 per 100 000 in 2017), followed by Japan and South Korea. Regions with the highest social development index (SDI) quintile also had the highest death cases associated with primary gallbladder and biliary tract cancer in 2017 (60 100, 95% UI 55 800-62 700). A high body mass index (BMI) was found to be closely related to age-standardized deaths and age-standardized DALY in most of the regions analyzed., Conclusions: Primary gallbladder and biliary tract cancer remains a serious threat to global public health, especially in high-SDI countries. The ASDR and age-standardized DALY decreased from 1990 to 2017. A high BMI may be associated with this cancer burden., (© 2022 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

A type III polyketide synthase (SfuPKS1) from the edible seaweed Sargassum fusiforme was molecularly cloned and biochemically characterized. The recombinant SfuPKS1 catalyzed the condensation of fatty acyl-CoA with two or three malonyl-CoA using lactone-type intramolecular cyclization to produce tri- and/or tetraketides. Moreover, it can also utilize phenylpropanoyl-CoA to synthesize phloroglucinol derivatives through Claisen-type cyclization, exhibiting broad substrate and catalysis specificity. Furthermore, the catalytic efficiency ( k cat / K M ) for acetyl-CoA was 11.8-fold higher than that for 4-coumaroyl-CoA. A pathway for the synthesis of naringenin involving SfuPKS1 was also constructed in Escherichia coli by recombinant means, resulting in 4.9 mg of naringenin per liter.

Objectives: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with Roux-en-Y reconstruction after total gastrectomy is difficult to be performed using routine tools. The aim of this study was to evaluate the feasibility and safety of cap-assisted routine adult colonoscope (CARAC) for ERCP in these patients., Methods: Sixteen consecutive patients with indications of ERCP who had previously undergone total gastrectomy with Roux-en-Y reconstruction at two tertiary care endoscopy centers were identified. All ERCP procedures were carried out by using CARAC. The success rate of reaching the papilla, biliary cannulation and procedure-related adverse events were analyzed., Results: The papilla was successful reached in 11 (68.8%) of the 16 cases, and biliary cannulation was subsequently reached in eight (72.7%) of the 11 cases. The procedures succeeded in three patients by using a percutaneous-endoscopic rendezvous procedure after failed cannulation. Overall clinical success was achieved in 11 (68.8%) of 16 patients. Procedure-related mild acute pancreatitis was observed in 25.0% (4/16) of the cases and mild cholangitis in 18.8% (3/16). No serious adverse events were reported., Conclusions: CARAC for therapeutic ERCP is safe and effective in treating patients with Roux-en-Y reconstruction after total gastrectomy., (© 2021 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background and Aims: TP53-induced glycolysis and apoptosis regulator (TIGAR) is now characterized as a fructose-2,6-bisphosphatase to reduce glycolysis and protect against oxidative stress. Recent studies have demonstrated that TIGAR is associated with cardiovascular disease. However, little is known about its role in atherosclerogenesis. In this study, we aimed to investigate the effect of TIGAR on atherosclerosis and explore the underlying molecular mechanism., Methods: The Gene Expression Omnibus (GEO) datasets were used to analyze the differential expression of relative proteins. THP-1-derived macrophages were used as an in vitro model and apolipoprotein E-deficient (Apoe -/ - ) mice were used as an in vivo model. [ 3 H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Both qPCR and Western blot were used to evaluate the mRNA and protein expression, respectively. Lentiviral vectors were used to disturb the expression of TIGAR in vitro and in vivo. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaques in Apoe -/ - mice fed a Western diet. Conventional assay kits were used to measure the levels of reactive oxygen species (ROS), plasma lipid profiles and 27-hydroxycholesterol (27-HC)., Results: Our results showed that TIGAR is increased upon the formation of macrophage foam cells and atherosclerosis. TIGAR knockdown markedly promoted lipid accumulation in macrophages. Silencing of TIGAR impaired cholesterol efflux and down-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity, but did not influence cholesterol uptake by macrophages. Additionally, this inhibitory effect of TIGAR deficiency on cholesterol metabolism was mediated through the ROS/CYP27A1 pathway. In vivo experiments revealed that TIGAR deficiency decreased the levels of ABCA1 and ABCG1 in plaques and aorta and impaired the capacity of RCT, thereby leading to the progression of atherosclerosis in Apoe -/ - mice., Conclusions: TIGAR mitigates the development of atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the ROS/CYP27A1/LXRα pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: The purpose of this study was to explore the role of long noncoding RNA (lncRNA) prostate cancer antigen 3 (PCA3) in atherosclerosis and the underlying mechanism., Methods: The Gene Expression Omnibus (GEO) datasets were used to divide differentially expressed lncRNAs, microRNAs (miRNAs), and mRNAs. The expression of PCA3, miR-140-5p, RFX7 and ABCA1 were determined by qPCR or Western blot in ox-LDL-treated macrophages. Macrophage lipid accumulation s was evaluated using the Oil Red O staining and high-performance liquid chromatography. Target relationships among PCA3, miR-140-5p, RFX7, and ABCA1 promoter area were validated via dual-luciferase reporter gene assay or chromatin immunoprecipitation assay. The apoE -/- mouse model in vivo was designed to evaluate the effect of PCA3 on the reverse cholesterol transport (RCT) and atherosclerosis., Results: PCA3 was down-regulated in foam cells, whereas miR-140-5p was highly expressed. Overexpression of PCA3 promoted ABCA1-mediated cholesterol efflux and reduced lipid accumulation in macrophages. Besides, RFX7 bound to the ABCA1 promoter and increased ABCA1 expression. Targeted relationships and interactions on the expression between miR-140-5p and PCA3 or RFX7 were elucidated. PCA3 up-regulated ABCA1 expression by binding to miR-140-5p to up-regulate RFX7 and ABCA1 expression in macrophages. PCA3 promoted RCT and impeded the progression of atherosclerosis by sponging miR-140-5p in apoE -/- mice. Meanwhile, miR-140-5p also inhibit ABCA1 expression via downregulation of RFX7 to impede RCT and aggravate atherosclerosis., Conclusions: lncRNA PCA3 promotes ABCA1-mediated cholesterol efflux to inhibit atherosclerosis through sponging miR-140-5p and up-regulating RFX7., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aromatic imides are a class of attractive organic materials with inherently electroactive groups and large π electron-deficient scaffolds, which hold potential as electrode materials for organic secondary batteries (OSBs). However, the undecorated aromatic imides are usually plagued by low capacity, high solubility in electrolyte, and poor electronic/ionic conductivity. Molecular engineering has been demonstrated to be an effective strategy to address unsatisfying characteristics of the aromatic imides, thereby expanding their scope for applications in OSBs. In this review, the recent research progress in modulation of the capacity, dissolution, and electronic/ionic conductivity of aromatic imides for organic lithium batteries, organic sodium batteries, and redox flow batteries are summarized. In addition, the challenge and prospective of aromatic imides in organic secondary battery applications are also discussed., (© 2021 Wiley-VCH GmbH.)

Abstract: Lipid metabolism disorder and inflammatory response are considered to be the major causes of atherosclerogenesis. Astragalin, the most important functional component of flavonoid obtained from persimmon leaves, has the hypolipidemic effects. However, it is unknown, how astragalin protects against atherosclerosis. The aim of this study was to observe the effects of astragalin on cholesterol efflux and inflammatory response and to explore the underlying mechanisms. Our results showed that astragalin upregulated the expression of ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), promoted cholesterol efflux, and suppressed foam cell formation. Inhibition of the PPARγ/LXRα pathway abrogated the promotive effects of astragalin on both transporter expression and cholesterol efflux. In addition, treatment of astragalin markedly decreased the secretion of inflammatory factors, including interleukin 6, monocyte chemotactic protein 1, tumor necrosis factor α, and interleukin 1β. Mechanistically, astragalin upregulated ABCA1 and ABCG1 expression, which in turn reduced TLR4 surface levels and inhibited NF-κB nuclear translocation. Consistently, astragalin reduced atherosclerotic plaque area in apoE-/- mice. Taken together, these findings suggest that astragalin protects against atherosclerosis by promoting ABCA1- and ABCG1-mediated cholesterol efflux and inhibiting proinflammatory mediator release., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

In this retrospective study we assessed the efficacy and safety of tocilizumab in patients with critical or severe coronavirus disease 2019 (COVID-19). We enrolled 181 patients admitted to Huoshenshan Hospital (Wuhan, China) with confirmed COVID-19 between January 2020 and February 2020. Ninety-two patients were treated with tocilizumab, and 89 patients were treated conventionally. We analyzed the clinical manifestations, changes in CT scan images, and laboratory tests before and after tocilizumab treatment, and compared these results with the conventionally treated group. A significant reduction in the level of C-reactive protein was observed 1 week after tocilizumab administration. In some cases this meant the end of the IL-6-related cytokine storm. In addition, tocilizumab relieved fever, cough, and shortness of breath with no reported adverse drug reactions. These findings suggest tocilizumab improves clinical outcomes and is effective for treatment of patients with critical or severe COVID-19. However, future clinical trials are needed to better understand the impact of tocilizumab interference with IL-6 and provide a therapeutic strategy for treatment of COVID-19.

Background: Effective endoscopic management is fundamental for the treatment of extrahepatic cholangiocarcinoma (ECC). However, current biliary stents that are widely used in clinical practice showed no antitumor effect. Drug-eluting stents (DESs) may achieve a combination of local chemotherapy and biliary drainage to prolong stent patency and improve prognosis., Aim: To develop novel DESs coated with gemcitabine (GEM) and cisplatin (CIS)-coloaded nanofilms that can maintain the continuous and long-term release of antitumor agents in the bile duct to inhibit tumor growth and reduce systemic toxicity., Methods: Stents coated with different drug-eluting components were prepared by the mixed electrospinning method, with poly-L-lactide-caprolactone (PLCL) as the drug-loaded nanofiber membrane and GEM and/or CIS as the antitumor agents. Four different DESs were manufactured with four drug-loading ratios (5%, 10%, 15%, and 20%), including bare-loaded (PLCL-0), single-drug-loaded (PLCL-GEM and PLCL-CIS), and dual-drug-loaded (PLCL-GC) stents. The drug release property, antitumor activity, and biocompatibility were evaluated in vitro and in vivo to confirm the feasibility and efficacy of this novel DES for ECC., Results: The in vitro drug release study showed the stable, continuous release of both GEM and CIS, which was sustained for over 30 d without an obvious initial burst, and a higher drug-loaded content induced a lower release rate. The drug-loading ratio of 10% was used for further experiments due to its ideal inhibitory efficiency and relatively low toxicity. All drug-loaded nanofilms effectively inhibited the growth of EGI-1 cells in vitro and the tumor xenografts of nude mice in vivo ; in addition, the dual-loaded nanofilm (PLCL-GC) had a significantly better effect than the single-drug-loaded nanofilms ( P < 0.05). No significant differences in the serological analysis ( P > 0.05) or histopathological changes were observed between the single-loaded and drug-loaded nanofilms after stent placement in the normal porcine biliary tract., Conclusion: This novel PLCL-GEM and CIS-eluting stent maintains continuous, stable drug release locally and inhibits tumor growth effectively in vitro and in vivo . It can also be used safely in normal porcine bile ducts. We anticipate that it might be considered an alternative strategy for the palliative therapy of ECC patients., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: Fargesin mainly functions in the improvement of lipid metabolism and the inhibition of inflammation, but the role of fargesin in atherogenesis and the molecular mechanisms have not been defined. We aimed to explore if and how fargesin affects atherosclerosis by regulating lipid metabolism and inflammatory response., Methods and Results: ApoE -/- mice were fed a high-fat diet to form atherosclerotic plaques and then administrated with fargesin or saline via gavage. Oil Red O, HE and Masson staining were performed to assess atherosclerostic plaques in apoE -/- mice. [ 3 H] labeled cholesterol was used to detect cholesterol efflux and reverse cholesterol transport (RCT) efficiency. Enzymatic methods were performed to analyze plasma lipid profile in apoE -/- mice. Immunohistochemistry was used to analyze macrophage infiltration. THP-1-derived macrophages were incubated with fargesin or not. Both Western blot and qRT-PCR were applied to detect target gene expression. Oil Red O staining was applied to examine lipid accumulation in THP-1-derived macrophages. ELISA and qRT-PCR were used to examine the levels of inflammatory mediotors. We found that fargesin reduced atherosclerotic lesions by elevating efficiency of RCT and decreasing inflammatory response via upregulation of ABCA1 and ABCG1 expression in apoE -/- mice. Further, fargesin reduced lipid accumulation in THP-1-derived macrophages. Besides, fargesin increased phosphorylation of CEBPα in Ser21 and then upregulated LXRα, ABCA1 and ABCG1 expression in THP-1-derived macrophages. In addition, fargesin could reduce ox-LDL-induced inflammatory response by inactivation of the TLR4/NF-κB pathway., Conclusion: These results suggest that fargesin inhibits atherosclerosis by promoting RCT process and reducing inflammatory response via CEBPα S21 /LXRα and TLR4/NF-κB pathways, respectively., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To evaluate whether patients with malignant biliary obstruction (MBO) benefit from balloon dilation before the placement of a self-expanding metal stent (SEMS) for palliative biliary drainage., Methods: Consecutive patients who underwent endoscopic retrograde cholangiopancreatography with SEMS placement for palliative management of MBO were retrospectively included. Comparative analyses of serum bilirubin levels, post-procedural adverse events, stent patency time, stent dysfunction, and patient survival were performed between the dilation and non-dilation groups., Results: A total of 221 patients underwent palliative endoscopic SEMS implantation for MBO from January 2014 to June 2018. Dilation significantly improved the percentage of serum bilirubin improvement (37.0% vs 14.3%, P = 0.001), with a decreasing trend in the incidence of post-procedural cholangitis (2.5% vs 7.8%, P = 0.075), while the rates of other complications such as pancreatitis and bleeding were not increased. The patency time of SEMS and patient survival did not significantly differ between patients with and without dilation. Patients had endoscopic nasobiliary drainage (ENBD) but not dilation showed similar short-term outcomes as patients underwent dilation but without ENBD., Conclusions: Dilation with a small-caliber balloon catheter before the placement of SEMS is a safe and effective approach for MBO. Balloon dilation may improve the short-term efficacy of SEMS placement, while long-term outcomes are not obviously affected. The short-term effect of stricture dilation may be achieved by ENBD. Further studies are needed to confirm our results., (© 2020 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

CXC chemokine ligand 12 (CXCL12) is a member of the CXC chemokine family and mainly acts on cell chemotaxis. CXCL12 also elicits a proatherogenic role, but the molecular mechanisms have not been fully defined yet. We aimed to reveal if and how CXCL12 promoted atherosclerosis via regulating lipid metabolism. In vitro, our data showed that CXCL12 could reduce ABCA1 expression, and it mediated cholesterol efflux from THP-1-derived macrophages to apoA-I. Data from the luciferase reporter gene and chromatin immunoprecipitation assays revealed that transcription factor 21 (TCF21) stimulated the transcription of ABCA1 via binding to its promoter region, which was repressed by CXCL12. We found that CXCL12 increased the levels of phosphorylated glycogen synthase kinase 3β (GSK3β) and the phosphorylation of β-catenin at the Thr120 position. Inactivation of GSK3β or β-catenin increased the expression of TCF21 and ABCA1. Further, knockdown or inhibition of CXC chemokine receptor 4 (CXCR4) blocked the effects of CXCL12 on TCF21 and ABCA1 expression and the phosphorylation of GSK3β and β-catenin. In vivo, the overexpression of CXCL12 in Apoe -/- mice via lentivirus enlarged the atherosclerotic lesion area and increased macrophage infiltration in atherosclerotic plaques. We further found that the overexpression of CXCL12 reduced the efficiency of reverse cholesterol transport and plasma HDL-C levels, decreased ABCA1 expression in the aorta and mouse peritoneal macrophages (MPMs), and suppressed cholesterol efflux from MPMs to apoA-I in Apoe -/- mice. Collectively, these findings suggest that CXCL12 interacts with CXCR4 and then activates the GSK-3β/β-catenin T120 /TCF21 signaling pathway to inhibit ABCA1-dependent cholesterol efflux from macrophages and aggravate atherosclerosis. Targeting CXCL12 may be a novel and promising strategy for the prevention and treatment of atherosclerotic cardiovascular diseases., (Copyright © 2019 Gao et al.)

Background: Although in vitro culture system has been optimized in the past few decades, the problem of few or no high quality embryos has been still not completely solved. Accordingly, fully understanding the regulatory mechanism of pre-implantation embryonic development would be beneficial to further optimize the in vitro embryo culture system. Recent studies have found the expression of c-kit in mouse embryo and its promotion effects on mouse embryonic development. However, it is unclear the expression, the role and the related molecular regulatory mechanism of c-kit in human pre-implantation embryo development. Therefore, the present study is to determine whether c-kit is expressed in human pre-implantation embryos, and to investigate the possible regulatory mechanism of c-kit signaling in the process of embryonic development., Methods: The present study includes human immature oocytes and three pronucleus (3PN) embryos collected from 768 women (28-32 ages) undergoing IVF, and normal 2PN embryos collected from ICR mice. Samples were distributed randomly into three different experimental groups: SCF group: G-1™ (medium for culture of embryos from the pro-nucleate stage to day 3) or G-2™ (medium for culture of embryos from day3 to blastocyst stage) + HSA (Human serum album) solution + rhSCF; SCF + imanitib (c-kit inhibitor) group: G-1™ or G-2™ + HSA solution + rhSCF + imanitib; SCF + U0126 (MEK/ERK inhibitor) group: G-1™ or G-2™ + HSA solution + rhSCF + U0126; Control group: G-1™ or G-2™ + HSA solution + PBS; The rate of good quality embryos at day 3, blastulation at day 6 and good quality blastulation at day 6 were analysis. RT-PCR, western blot and immunofluorescence staining were applied to detect the target genes and proteins in samples collected from human or mice, respectively., Results: c-kit was expressed ubiquitously in all human immature oocytes, 3PN embryos and 3PN blastocysts. In the experiment of human 3PN embryos, compared with other groups, SCF group showed obviously higher rate of good quality at day 3, better rate of blastocyst formation at day 6 and higher rate of good quality blastocyst formation at day 6. Furthermore, we observed a higher ETV5 expression in SCF group than that in other groups. Similar results were also found in animal experiment. Interestingly, we also found a higher phosphorylation level of MEK/ERK signal molecule in mice embryos from SCF group than those from other groups. Moreover, inhibition of MEK/ERK signaling would remarkably impeded the mice embryonic development, which might be due to the reduced ETV5 expression., Conclusions: The present study firstly revealed that c-kit signaling might promote the human pre-implantation embryonic development and blastocyst formation by up-regulating the expression of ETV5 via MEK/ERK pathway. Our findings provide a new idea for optimizing the in vitro embryo culture condition during ART program, which is beneficial to obtain high quality embryos for infertile patients.

Background: The treatment of difficult common bile duct stones (CBDS) remains a big challenge around the world. Biliary stenting is a widely accepted rescue method in patients with failed stone extraction under endoscopic retrograde cholangiopancreatography. Fully covered self-expanding metal stent (FCSEMS) has gained increasing attention in the management of difficult CBDS., Aim: To manufacture a drug-eluting FCSEMS, which can achieve controlled release of stone-dissolving agents and speed up the dissolution of CBDS., Methods: Customized covered nitinol stents were adopted. Sodium cholate (SC) and disodium ethylene diamine tetraacetic acid (EDTA disodium, EDTA for short) were used as stone-dissolving agents. Three different types of drug-eluting stents were manufactured by dip coating (Stent I), coaxial electrospinning (Stent II), and dip coating combined with electrospinning (Stent III), respectively. The drug-release behavior and stone-dissolving efficacy of these stents were evaluated in vitro to sort out the best manufacturing method. And the selected stone-dissolving stents were further put into porcine CBD to evaluate their biosecurity., Results: Stent I and Stent II had obvious burst release of drugs in the first 5 d while Stent III presented controlled and sustainable drug release for 30 d. In still buffer, the final stone mass-loss rate of each group was 5.19% ± 0.69% for naked FCSEMS, 20.37% ± 2.13% for Stent I, 24.57% ± 1.45% for Stent II, and 33.72% ± 0.67% for Stent III. In flowing bile, the final stone mass-loss rate of each group was 5.87% ± 0.25% for naked FCSEMS, 6.36% ± 0.48% for Stent I, 6.38% ± 0.37% for Stent II, and 8.15% ± 0.27% for Stent III. Stent III caused the most stone mass-loss no matter in still buffer or in flowing bile, which was significantly higher than those of other groups ( P < 0.05). In vivo , Stent III made no difference from naked FCSEMS in serological analysis ( P > 0.05) and histopathological examination ( P > 0.05)., Conclusion: The novel SC and EDTA-eluting FCSEMS is efficient in diminishing CBDS in vitro . When conventional endoscopic techniques fail to remove difficult CBDS, SC and EDTA-eluting FCSEMS implantation may be considered a promising alternative., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this article.

Fc receptor common γ signaling chain (FcRγ), a common subunit shared by Fc receptors (FcγRI, III, IV, FcαRI, and FcεRI), is an important immune regulator both in innate and adaptive immunity. Previous studies have shown that FcRγ was a potential target of inflammatory diseases, whereas the role of FcRγ in sepsis has been poorly understood. In this study, we found that deficiency of FcRγ resulted in increased survival in lipopolysaccharide (LPS)/D-galactosamine and E. coli-induced sepsis in mice. This protective effect was characterized by decreased TNF-α, IL-6, and IL-10. Further experiments in bone marrow-derived macrophages (BMDMs) in vitro also showed that FcRγ deficiency resulted in decreased production of TNF-α, IL-6, and IL-10 upon LPS stimulation. The mechanism study showed that FcRγ was physiologically associated with toll-like receptor 4 (TLR4), and tyrosine phosphorylation of FcRγ mediated TLR4 signaling pathway, followed by increased ERK phosphorylation upon LPS stimulation. Our results suggest that FcRγ might be a potential therapeutic target of sepsis.

Background: Tissue sampling for biliary stricture is important for differential diagnosis and further treatment. The aim of this study was to assess a novel dilation catheter-guided mini-forceps biopsy (DCMB) method in the diagnosis of malignant biliary strictures., Methods: 42 patients with malignant biliary stricture who underwent both brush cytology and DCMB during endoscopic retrograde cholangiopancreatography between October 2014 and November 2015 were retrospectively included. During DCMB, the mini biopsy forceps was introduced into the biliary stricture through the dilation catheter, and then the position and direction of the forceps were adjusted to obtain tissue samples., Results: The positive rate of DCMB was significantly higher than that of brush cytology (81.0 % [34/42] vs. 38.1 % [16/42]; P  < 0.001). No severe complications occurred; three patients (7.1 %) experienced mild procedure-related acute pancreatitis., Conclusions: The novel DCMB technique was a practical, safe, efficient, and low-costing method for diagnosing malignant biliary stricture with a high accuracy rate., Competing Interests: None, (© Georg Thieme Verlag KG Stuttgart · New York.)

The determination of pesticide residues is an indispensable task in controlling food safety and environment protection. Carbendazim is one of the extensive uses of pesticides in the agricultural industry. In this study, a simple method utilizing syringe filter has been applied as electrospray ionization emitter for mass spectrometric identification and quantification of carbendazim in complex matrices including soil, natural water, and fruit juice samples, which contain many insoluble materials. With online syringe filter of the complex samples, most of insoluble materials such as soil were excluded in spray ionization process due to the filter effect, and analytes were subsequently sprayed out from syringe needle for mass spectrometric detection. The pore sizes of filters and diameters of syringe needles also were investigated. The analytical performances, including the linear range (1-200 ng·mL -1 ), limit of detection (0.2-0.6 ng·mL -1 , S/N > 3), limit of quantitation (3.5-8.6 ng·mL -1 , S/N > 10), reproducibility (6.4%-12.5%, n = 6), and recoveries (72.1%-91.0%, n = 6) were well acceptable for direct analysis of raw samples. Matrix effect for detection of carbendazim in soil samples also was experimentally investigated. This study demonstrated that syringe filter needle coupled with electrospray ionization mass spectrometry is a simple, efficient, and sensitive method for detection of pesticide residues in water, soil, and fruit juice for risk assessment., (Copyright © 2018 John Wiley & Sons, Ltd.)

Polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants with carcinogenic effect raising worldwide concerns. Hydroxylated PAHs (OH-PAHs) could be formed in the body as metabolites of PAHs in human urine samples and thus considered as biomarkers of PAH exposure. In this study, five OH-PAHs including 3-phenanthrol, 1-naphthol, 2-hydroxy fluorene, 1-hydroxprene and 6-hydroxy chrysene in human urine samples were selectively enriched by C18 solid-phase microextraction (SPME), then SPME fiber was connected high voltage and then was inserted into a glass-capillary to elute and ionize the analytes for mass spectrometric (MS) detection. The coupling of SPME-MS showed excellent analytical performance for detection of urinary OH-PAHs under optimal conditions, providing an easy operation for rapid detection of a single sample within minutes. By use of internal standard (i.e., 2-hydroxy fluorene-d9), the limit of detection (LOD) and limit of quantitation (LOQ) of OH-PAHs were found to be less than 0.05 ng L -1 level (S/N > 3) and less than 0.1 ng L -1 level (S/N > 10), respectively. The dynamic ranges of five OH-PAHs were found to be a range at 0.1-5.0 ng L -1 with excellent coefficient (R 2  > 0.99). This method also showed good precisions (intra-day: 3.4-5.5%, inter-day: 7.0-9.8%, n = 5) and good accuracy (85.3-95.3%, n = 5). Moreover, ion suppression and matrix effect in detection of OH-PAHs in urine were also investigated. Human urine samples collected from 12 volunteers including 6 non-smokers and 6 smokers have been successfully analyzed, it was found that individual OH-PAHs in smokers were higher than in non-smokers. This study demonstrated that SPME coupled with glass-capillary nanoESI-MS is a sensitive method for rapid detection of urinary OH-PAHs for health risk assessment of PAHs exposure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Endoscopic ultrasonography-guided drainage has been established as a good treatment modality in the management of walled-off pancreatic necrosis, but the unmanageable infection of postoperation is still a thorny problem due to the poor drainage ability for solid necrotic debris only through transmural stent and nasocystic catheter., Aims: Introduce a novel therapeutic method, namely endoscopic ultrasonography-guided drainage combined with cyclic irrigation technique in managing patients with walled-off pancreatic necrosis., Methods: 18 patients with severe acute pancreatitis complicated with walled-off pancreatic necrosis received treatment with endoscopic ultrasonography-guided drainage combined with cyclic irrigation were involved in this retrospective study., Results: 17 of 18 patients with walled-off pancreatic necrosis were treated by this new therapeutic method. Subsequent surgery was performed in 1 case due to uncontrolled infection, complications such as perforation, bleeding or multiple organ failure were not observed. Treatment success rate was high (16 in 17, 94.12%)., Conclusion: Endoscopic ultrasonography-guided drainage combined with cyclic irrigation is an effective treatment option for symptomatic walled-off pancreatic necrosis to facilitate drainage and obviate the need for subsequent surgery or endoscopic necrosectomy., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the outcomes of endoscopic balloon dilation and metal stent placement in patients with achalasia., Methods: The patients with newly diagnosed achalasia between July 2001 and December 2011 were retrospectively studied. A total of 88 patients underwent either balloon dilation (n = 41) or metal stent placement (n = 47), their global symptom score and esophageal kinetics index were determined before, one week after and one month after the treatment. All the patients were followed up in the Outpatient Clinics or with a telephone interview every 6 months., Results: There were significant improvements in the global symptom scores and esophageal kinetics indices in all patients. No major complications were encountered in either group. There were no significant differences with regard to overall treatment failure or long-term outcome., Conclusion: Balloon dilation and removable stents can effectively relieve clinical manifestations in patients with achalasia., (© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Traditional macroscopic and microscopic identification methods of medicinal materials are economical and practical, but usually experience-based due to few chemical supports. Here histochemical evaluation on bioactive components of Coptidis Rhizoma (CR) in anatomic sections using laser microdissection and liquid chromatography-mass spectrometry (LMD-LC-MS) was developed to correlate the inner quality and outer features of materials from different growing areas. Results of a total 33 peaks representing potential different alkaloids were detected and 8 common peaks were identified as the major alkaloids, namely magnoflorine, thalifendine, columbamine, epiberberine, jatrorrhizine, coptisine, palmatine, and berberine. Six major alkaloids were quantified in the top and middle sections of raw materials and in their tissues and cells at the same time. Histochemical analyses showed consistent results with direct determination in raw materials and explained the reason why top sections of all samples contained higher contents of alkaloids by giving out attributions of each alkaloid in different anatomic sections. Besides, results manifested the distribution and accumulation rules of alkaloids in diverse tissues and cells of CR. This study demonstrates an effective and scientific way to correlate bioactive components and morphological features of medicinal materials, which is beneficial to future research, agriculture and application., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objectives: To analyse anti-D alloimmunisation in pregnant women with D-elute (DEL) phenotype in China, for developing a predictive model to evaluate whether a person with the DEL phenotype can receive RhD-positive blood., Background: Alloanti-D acquired by pregnancy or transfusion is one of the major causes of both haemolytic disease among newborns and haemolytic transfusion reactions. To date, there is little data available about the antigenic properties and immunogenicity of extremely weak D variants known as DEL., Methods: RHD genotyping and D epitope mapping were performed using gene sequencing and comprehensive immunohaematological methods, respectively. DEL pregnant women carrying an RhD-positive fetus were tested for the presence of alloanti-D., Results: A total of 130 of 142 (91·5%) pregnant women with a DEL phenotype were confirmed to carry the RHD (K409K) allele. Among 12 DEL women who appeared to have RHD-CE-D hybrid alleles, there were 1 RHD-CE (4-7)-D, 7 RHD-CE(4-9)-D, and 4 RHD-CE (2-5)-D alleles. Alloanti-D antibodies were detected in 6 of 142 DEL women, and all the six women had the partial DEL phenotype., Conclusion: The data indicate that partial DEL women appear at risk of alloimmunization to the D antigen. RhD immune globulin prophylaxis is necessary for partial DEL women. Partial DEL patients should receive only RhD-negative RBCs, whereas DEL patients with complete expression of antigen can safely receive RhD-positive RBCs., (© 2015 British Blood Transfusion Society.)

Background and Study Aim: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most common complication of ERCP. Somatostatin may inhibit pancreatic secretion and has been tested for PEP prophylaxis. However, the results of previous studies are inconsistent. The aim of the current study was to investigate whether somatostatin can reduce the incidence of PEP., Patients and Methods: The study was a multicenter, open-label, randomized controlled trial. A total of 908 patients with normal amylase levels who were undergoing ERCP were randomized to receive somatostatin 250 μg bolus injection before ERCP and 250 μg/hour intravenous infusion for 11 hours after ERCP (somatostatin group) or no somatostatin treatments (control group). The incidences of PEP and hyperamylasemia were compared in the two groups., Results: The full analysis set included 900 patients (445 in the somatostatin group, 455 in the control group). PEP developed in 34 patients (7.5 %) in the control group (95 % confidence interval [CI] 5.4 % - 10.3 %) and in 18 patients (4.0 %) in the somatostatin group (95 %CI 2.6 % - 6.3 %; P = 0.03). Hyperamylasemia occurred in 46 patients (10.1 %) in the control group (95 %CI 7.7 % - 13.2 %) and in 27 patients (6.1 %) in the somatostatin group (95 %CI 4.2 % - 8.7 %; P = 0.03). No perforation or death occurred during the study., Conclusions: This study showed that somatostatin was effective and safe for the prevention of PEP and hyperamylasemia in ERCP patients.(ClinicalTrials.gov number, NCT01431781)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Study Aim: We previously reported on a plastic stent that was coated with ethylenediaminetetraacetic acid (EDTA) and sodium cholate, which dissolved common bile duct (CBD) stones ex vivo. The aim of this study was to investigate the safety and efficacy of such stents on biliary stones in a live porcine model., Methods: Stents without coating or with degradable membranes containing 0 % or 50 % EDTA and sodium cholate were inserted together with human CBD stones into the porcine CBD. Serum laboratory variables, histological examinations of the bile duct, and the weight change in stones were compared during and after stent placement for 6 months., Results: A total of 16 pigs were included (5 no coating, 5 0 % coating, 6 50 % coating). Biliary stones showed decreased weight in all groups; however, stones in the group with 50 % coated stents showed a greater reduction in weight compared with the no coating and the 0 % coating groups (269 ± 66 mg vs. 179 ± 51 mg [P = 0.09]; 269 ± 66 mg vs. 156 ± 26 mg [P = 0.01], respectively)., Conclusions: The plastic stent coated with 50 % agent enhanced CBD stone dissolution in vivo and may be a promising tool for patients with difficult biliary stones., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Recent studies have shown that neutrophils may display an antigen-presenting function and inhibit lymphocyte proliferation by expressing programmed cell death 1 ligand 1 (PD-L1). The current study was performed to investigate the effect of neutrophils and their pathophysiological significance during sepsis., Methods: Neutrophil PD-L1 expression was determined in both septic mice (n = 6) and patients (n = 41). Neutrophils from septic mice were subtyped into PD-L1 and PD-L1 populations to determine their phenotypes and functions. Septic neutrophils were cocultured with lymphocytes to observe the effect of septic neutrophils on lymphocyte apoptosis., Results: The PD-L1 level on neutrophils from septic mice was significantly up-regulated (21.41 ± 4.76%). This level increased with the progression of sepsis and the migration of neutrophils from the bone marrow to the blood and peritoneal cavity. The percentages of CD11a, CD62L, and C-C chemokine receptor type 2 were lower, whereas the percentages of CD16 and CD64 were higher on PD-L1 neutrophils than on PD-L1 neutrophils. The migratory capacity of PD-L1 neutrophils was compromised. Septic neutrophils induced lymphocyte apoptosis via a contact mechanism, and this process could be reversed by anti-PD-L1 antibody. PD-L1 was also up-regulated on neutrophils from patients with severe sepsis (14.6% [3.75%, 42.1%]). The levels were negatively correlated with the monocyte human leukocyte antigen-DR level and positively correlated with the severity of septic patients. Neutrophil PD-L1 was a predictor for the prognosis of severe sepsis, with an area of 0.74 under the receiver operating curve., Conclusions: PD-L1 is up-regulated on neutrophils during sepsis, which may be related to sepsis-induced immunosuppression.

The differentiation of vascular smooth muscle cells (VSMCs), which are exposed to mechanical stretch in vivo, plays an important role in vascular remodeling during hypertension. Here, we demonstrated the mechanobiological roles of large conductance calcium and voltage-activated potassium (BK) channels in this process. In comparison with 5% stretch (physiological), 15% stretch (pathological) induced the de-differentiation of VSMCs, resulting in significantly decreased expressions of VSMC markers, i.e., α-actin, calponin and SM22. The activity of BK channels, assessed by patch clamp recording, was significantly increased by 15% stretch and was accompanied by an increased alternative splicing of BK channel α-subunit at the stress axis-regulated exons (STREX). Furthermore, transfection of whole BK or STREX-deleted BK plasmids revealed that STREX was important for BK channels to sense mechanical stretch. Using thapsigargin (TG) which induces endoplasmic reticulum (ER) stress, and xbp1-targeted siRNA transfection which blocks ER stress, the results revealed that ER stress was contribute to stretch-induced alternative splicing of STREX. Our results suggested that during hypertension, pathological stretch may induce the ER stress in VSMCs, which affects the alternative splicing and activity of BK channels, and subsequently modulates VSMC differentiation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Endothelium-derived molecules may be predictive to organ injury. Heat shock protein (HSP) A12B is mainly located in endothelial cells, which can be detected in the plasma of septic patients. Whether it is correlated with prognosis of sepsis remains unclear., Methods: Extracellular HSPA12B (eHSPA12B) was determined in plasma of septic mice at 6 h, 12 h, 24 h and 48 h after cecal ligation and puncture (CLP). It was also detected in plasma of patients with severe sepsis, sepsis, systemic inflammatory response syndrome and healthy volunteers. The predictive value for prognosis of severe sepsis was assessed by receiver operating curve (ROC) and Cox regression analyses., Results: eHSPA12B was elevated in plasma of CLP mice at 6 h and peaked at 24 h after surgery. A total of 118 subjects were included in the clinical section, including 66 patients with severe sepsis, 21 patients with sepsis, 16 patients with SIRS and 15 volunteers. Plasma eHSPA12B was significantly higher in patients with severe sepsis than in patients with sepsis, SIRS and volunteers. The level of eHSPA12B was also higher in non-survivals than survivals with severe sepsis. The area under the curve (AUC) of eHSPA12B in predicting death among patients with severe sepsis was 0.782 (0.654-0.909) in ROC analysis, much higher than that of IL-6 and IL-10. Cox regression analysis showed that cardiovascular diseases, IL-6 and eHSPA12B were risk factors for mortality in patients with severe sepsis. Survival curve demonstrated a strikingly significant difference between 28-day survival rates of patients with an eHSPA12B lower or not lower than 1.466 ng/ml., Conclusions: Plasma eHSPA12B is elevated in both septic mice and patients. It may be a good predictor for poor outcome in patients with severe sepsis.

Objective: We aimed to determine the efficacy and safety of endoscopic nasobiliary drainage (ENBD) with or without endoscopic sphincterotomy (EST) for temporary biliary decompression in patients with acute obstructive cholangitis., Methods: In total, 72 patients with acute obstructive cholangitis were prospectively randomized to undergo emergency ENBD with EST (EST group, n = 36) or without EST (non-EST group, n = 36). The clinical outcomes and complications between the two groups were compared., Results: Endoscopic nasobiliary decompression was successful in all 72 patients. Four patients underwent a second endoscopic retrograde cholangiopancreatography (ERCP) to replace the nasobiliary catheter due to blockage (one in the EST group and two in the non-EST group) or migration (one in the EST group). The mean serum γ-glutamyltransferase and total bilirubin levels after treatment were significantly higher in the non-EST group than in the EST group (P < 0.05). However, no significant differences were observed for other parameters evaluated. The total complication rate was similar between the two groups (EST 25.0% vs non-EST 19.4%). Although hemorrhage occurred more frequently in the EST group and acute pancreatitis in the non-EST group, these differences were not significant., Conclusions: EST is helpful and safe for biliary drainage while ENBD without EST is the first choice for acute cholangitis. EST may increase the efficacy of ENBD in patients with papillary inflammatory stricture and thick bile., (© 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Metal stents may represent an alternative therapy in the treatment of achalasia. We therefore evaluated the effectiveness of retrievable, fully covered metal stents in patients with achalasia. Fifty-nine patients with achalasia were treated with retrievable, fully covered metal stents. Symptoms using a global symptom score (0-10), lower esophageal sphincter (LES) resting pressure, LES relaxation, and simultaneous contraction of the esophagus were analyzed before and 1 week and 1 month after intervention. Complications and treatment outcomes were followed up at 6, 12, 18, and 24 months postoperatively. Stent placement was successful, and clinical symptoms resolved (P < 0.01) in all patients. Regurgitation, dysphagia and chest pain improved significantly (all P < 0.01). Therapy improved LES resting pressure (51.4 ± 9.7 mmHg pretherapy vs. 20.9 ± 8.1 mmHg post-therapy), LES relaxation (58.1 ± 17.1% pretherapy vs. 84.5 ± 18.9% post-therapy), and simultaneous contraction of the esophagus (36.1 ± 8.6% pretherapy vs. 69.4 ± 23.1% post-therapy) 1 month after stent placement (all P < 0.01). The cumulative clinical remission rates 6, 12, 18, 24, 30, and 36 months after stent removal were 90.9%, 81.8%, 76.4%, 69.1%, 65.5%, and 49.1%, respectively. All patients tolerated stent placement. Twelve patients (25.5%) complained of substernal pain and five (10.6%) had substernal burning. Stents migrated in four patients (8.5%). Insertion of retrievable, fully covered metal stents is an effective and safe treatment in patients with achalasia., (© 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Background: Temporary plastic stent insertion has been considered a safe and effective bridge therapy for difficult common bile duct (CBD) stones. Infusing chemicals to directly dissolve stones through the bile duct might also be effective. However, there are no studies on the efficacy of the combination of these 2 approaches., Objective: To investigate the efficacy of a novel ethylenediaminetetraacetic acid (EDTA) and sodium cholate-eluting plastic stent on biliary stones., Design: Ex vivo model by using different doses of active ingredient., Setting and Interventions: An ex vivo bile duct model perfused with porcine bile was created. Stents coated with degradable membranes containing various concentrations of EDTA and sodium cholate were placed in the model with CBD stones., Main Outcome Measurements: The change in the weight of stents and stones was measured every week during perfusion until the coated membranes were completely biodegraded., Results: The time that the stents required to be fully degraded and the efficiency of stone dissolution were positively correlated with the percentage of EDTA and sodium cholate in the stent membrane. However, the 50% EDTA and sodium cholate stents achieved the greatest percentage of stone weight loss when the drugs were completely released., Limitations: Ex vivo study., Conclusions: The EDTA and sodium cholate-eluting plastic stent effectively dissolved CBD stones and has prospect in the therapy for patients with difficult CBD stones., (Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Intercellular adhesion molecule-1 (ICAM-1) is a key adhesion molecule mediating neutrophil migration and infiltration during sepsis. But its role in the outcome of sepsis remains contradictory. The current study was performed to investigate the role of anti-ICAM-1 antibody in the outcome of polymicrobial sepsis and sepsis-induced immune disturbance. Effect of anti-ICAM-1 antibody on outcome of sepsis induced by cecal ligation and puncture (CLP) was evaluated by the survival analysis, bacterial clearance, and lung injury. Its influence on neutrophil migration and infiltration, as well as lymphocyte status, in thymus and spleen was also investigated. The results demonstrated that ICAM-1 mRNA was upregulated in lung, thymus, and spleen of CLP mice. Anti-ICAM-1 antibody improved survival and bacterial clearance in CLP mice and attenuated lung injury. Migration of neutrophils to peritoneal cavity was enhanced while their infiltration into lung, thymus, and spleen was hampered by ICAM-1 blockade. Anti-ICAM-1 antibody also prevented sepsis-induced apoptosis in thymus and spleen. Positive costimulatory molecules including CD28, CD80, and CD86 were upregulated, while negative costimulatory molecules including PD-1 and PD-L1 were downregulated following anti-ICAM-1 antibody administration. In conclusion, ICAM-1 blockade may improve outcome of sepsis. The rationale may include the modulated neutrophil migration and the reversed immunosuppression.

Objective: To explore the in vitro inhibitive effect and underlying mechanisms of Brucea Javanica oil emulsion (BJOE) on human papilloma virus (HPV) type 16 infected cells., Methods: The HPV16 E61E7 immortalized human ectocervical Ect1/E6E7 cell line and the CaSki cell line were selected as the in vitro models of premalignant cervical lesion and cervical cancer respectively. After treated with BJOE at different concentrations (5, 10, 20, and 40 microg/mL) at the operation time points (24, 48, and 72 h), the effects of BJOE on proliferative activities were measured by MTT assay. The morphologic changes of cell apoptosis stained with Hochest 33,258 were observed by fluorescence microscope. The effect on the cell apoptosis rate was analyzed by Annexin V-FITC/PI double-labeled flow cytometry. The mRNA expressions of HPV16 E6 and E7 were determined by semi-quantitative RT-PCR. The protein expressions of HPV16 E6, E7 oncogene, and specifically interacted p53, Rb antioncogene were stained by immunocytochemical staining (Elivison two-step procedure)., Results: (1) The proliferative activities of the Ect1/E6E7 cell and the CaSki cell treated with BJOE at different concentrations (5, 10, 20, and 40 p g/mL) at the operation time points (24, 48, and 72 h) were obviously inhibited, showing dose- and time-dependent manners (P <0.05). (2) Typical changes of apoptosis were observed in both HPV 16 positive cell lines after treated with BJOE. The cell apoptosis rates increased markedly after being cultured with BJOE at different concentrations (5, 10, and 20 microg/mL) for 48 h (P < 0.05). (3) After treated with BJOE at different concentrations (5, 10, and 20 microg/mL) for 48 h, the HPV16 E6 and E7 mRNA relative expressions in both HPV 16 positive cell lines decreased significantly (P < 0.05). (4) After treated with BJOE at different concentrations (5, 10, and 20 microg/ mL), the expressions of HPV16 E6, E7, and mutant p53 protein decreased gradually (P < 0.05), while the Rb protein expression increased gradually (P < 0.05)., Conclusions: BJOE showed obvious in vitro inhibitory effects on HPV type 16 infected cells. Its underlying mechanisms might be possibly associated with down-regulating expressions of HPV16 E6 and E7 oncogenes.

Background: Endoscopic retrograde biliary drainage (ERBD) using a plastic stent is suggested to be as effective as endoscopic nasobiliary drainage (ENBD) with a nasobiliary catheter for temporary biliary drainage in acute obstructive cholangitis. However, there are few studies that have compared the two methods. We therefore compared the safety and effectiveness of endoscopic biliary decompression by nasobiliary catheter versus plastic stent placement in these patients., Methods: A total of 94 screened patients with acute obstructive cholangitis were randomised to undergo emergency endoscopic biliary drainage with ENBD (n = 47) or ERBD (n = 47). Clinical outcomes and adverse events were compared., Results: Patient backgrounds were similar in the two groups. Endoscopic biliary drainage was successfully achieved in all patients. Eleven patients underwent unscheduled endoscopic retrograde cholangiopancreatography (ERCP) to replace the nasobiliary catheter, 10 due to a catheter (1 in the ENBD group) or stent (9 in the ERBD group) blockage and 1 due to catheter migration. Clinical manifestations were similar, however, there was a significantly lower patient discomfort score in the ERBD group (p <0.05). The mean serum gamma-glutamyltransferase and total bilirubin concentrations after ERCP were significantly higher in the ERBD than ENBD group (p <0.001). Complication rates were similar in the ENBD and ERBD groups. However, the incidence rate of blockage in ERBD was statistically higher than ENBD (p = 0.015)., Conclusions: Endoscopic biliary decompression is an effective treatment for patients with acute obstructive cholangitis. In contrast to other studies, we found an increased rate of blockage in the ERBD group and a greater decrease in liver enzyme levels in the ENBD group.

Background: Intrasphincteric injection of botulinum toxin (BTX) and removable self-expanding metal stents (SEMS) have both been used for the treatment of achalasia., Aim: To compare the effectiveness and long-term outcome of SEMS placement and BTX injection in patients with achalasia., Methods: A total of 110 patients with newly diagnosed achalasia were enrolled in the study between July 2003 and December 2009. The patients received either BTX injection (n = 51) or SEMS placement (n = 59). Clinical symptoms, objective parameters, and long-term clinical outcomes were evaluated after 7 and 30 days and then every 6 months until withdrawal from the study. The mean duration of follow-up was 28 months (range 10-36 months)., Results: Improvements in global symptom and dysphagia scores and in basal lower esophageal sphincter pressure were significantly more marked in the SEMS group than in the BTX group (all P < 0.05). After 12 months, the remission rate in the SEMS group (81.28 %) was statistically significantly higher than that in the BTX group (64.58; P < 0.05). At 36 months, the remission rates in the two groups were 49.1 and. 4.2 %, respectively (P < 0.01). The symptom-free interval was 831 ± 46 days in the SEMS group and 522 ± 42 days in the BTX group (P < 0.01). No side effects were reported with BTX treatment. In the SEMS group there were 13 episodes of chest pain, nine cases of regurgitation, and four stent migrations. No serious complications occurred., Conclusion: Removable SEMS was associated with better long-term outcomes than BTX injection in patients with achalasia.

The mol-ecule of the title compound, C22H23NO3S, adopts an E conformation about the C=C bond. The dihedral angle between the benzene rings is 23.79 (5)°. In the crystal, pairs of N-H⋯O hydrogen bonds link the mol-ecules, forming inversion dimers. The terminal butyl group is disordered over two sets of sites in a 0.559 (6):0.441 (6) ratio.

MicroRNAs (miRs) are known to have an important role in modulating vascular biology. MiR21 was found to be involved in the pathogenesis of proliferative vascular disease. The role of miR21 in endothelial cells (ECs) has well studied in vitro, but the study in vivo remains to be elucidated. In this study, miR21 endothelial-specific knockout mice were generated by Cre/LoxP system. Compared with wild-type mice, the miR21 deletion in ECs resulted in structural and functional remodeling of aorta significantly, such as diastolic pressure dropping, maximal tension depression, endothelium-dependent relaxation impairment, an increase of opening angles and wall-thickness/inner diameter ratio, and compliance decrease, in the miR21 endothelial-specific knockout mice. Furthermore, the miR21 deletion in ECs induced down-regulation of collagen I, collagen III and elastin mRNA and proteins, as well as up-regulation of Smad7 and down-regulation of Smad2/5 in the aorta of miR21 endothelial-specific knockout mice. CTGF and downstream MMP/TIMP changes were also identified to mediate vascular remodeling. The results showed that miR21 is identified as a critical molecule to modulate vascular remodeling, which will help to understand the role of miR21 in vascular biology and the pathogenesis of vascular diseases.