Biomolecular condensates regulate cellular electrochemical equilibria.

Control of the electrochemical environment in living cells is typically attributed to ion channels. Here, we show that the formation of biomolecular condensates can modulate the electrochemical environment in bacterial cells, which affects cellular processes globally. Condensate formation generates an electric potential gradient, which directly affects the electrochemical properties of a cell, including cytoplasmic pH and membrane potential. Condensate formation also amplifies cell-cell variability of their electrochemical properties due to passive environmental effect. The modulation of the electrochemical equilibria further controls cell-environment interactions, thus directly influencing bacterial survival under antibiotic stress. The condensate-mediated shift in intracellular electrochemical equilibria drives a change of the global gene expression profile. Our work reveals the biochemical functions of condensates, which extend beyond the functions of biomolecules driving and participating in condensate formation, and uncovers a role of condensates in regulating global cellular physiology.

NDRG2 acts as a negative regulator of the progression of small-cell lung cancer through the modulation of the PTEN-AKT-mTOR signalling cascade.

N-myc downstream-regulated gene 2 (NDRG2) has been recognised as a negative regulator of the progression of numerous tumours, yet its specific role in small-cell lung carcinoma (SCLC) is not fully understood. The purpose of the current study was to investigate the biological role and mechanism of NDRG2 in SCLC. Initial investigation using the Gene Expression Omnibus (GEO) dataset revealed marked downregulation of NDRG2 transcripts in SCLC. The decreased abundance of NDRG2 in SCLC was verified by examining clinical specimens. Increasing NDRG2 expression in SCLC cell lines caused significant changes in cell proliferation, cell cycle progression, colony formation, and chemosensitivity. NDRG2 overexpression decreased the levels of phosphorylated PTEN, AKT and mTOR. In PTEN-depleted SCLC cells, the upregulation of NDRG2 did not result in any noticeable impact on AKT or mTOR activation. Additionally, the reactivation of AKT reversed the antitumour effects of NDRG2 in SCLC cells. Notably, increasing NDRG2 expression retarded the growth of SCLC cell-derived xenografts in vivo. In conclusion, NDRG2 serves as an inhibitor of SCLC, and its cancer-inhibiting effects are achieved through the suppression of AKT/mTOR via the activation of PTEN. This work suggests that NDRG2 is a potential druggable target for SCLC treatment.

Zinc finger protein 367 exerts a cancer-promoting role in small cell lung cancer by influencing the CIT/LATS2/YAP signaling cascade.

A remarkable cancer-related role of zinc finger protein 367 (ZNF367) has been demonstrated in multiple malignancies. However, whether ZNF367 has a role in small-cell lung cancer (SCLC) remains unexplored. The purpose of this work was to explore the potential role and mechanism of ZNF367 in SCLC. In silico analysis using the Gene Expression Omnibus (GEO) dataset revealed high levels of the ZNF367 transcript in SCLC. Examination of clinical tissues confirmed the significant abundance of ZNF367 in SCLC tissues compared with adjacent non-malignant tissues. The genetic depletion of ZNF367 in SCLC cells led to remarkable alterations in cell proliferation, the cell cycle, colony formation and chemosensitivity. Mechanistically, ZNF367 was shown to regulate the activation of yes-associated protein (YAP) associated with the up-regulation of phosphorylated large tumour suppressor kinase 2 (LATS2). Further investigation revealed that ZNF367 affected the LATS2-YAP cascade by regulating the expression of citron kinase (CIT). Re-expression of constitutively active YAP diminished the tumour-inhibiting function of ZNF367 depletion. Xenograft experiments confirmed the tumour-inhibiting effect of ZNF367 depletion in vivo. In summary, our results demonstrate that the inhibition of ZNF367 displays anticancer effects in SCLC by inhibiting YAP activation, suggesting it as a potential druggable oncogenic target.

MAFT-SO: A novel multi-atlas fusion template based on spatial overlap for ASD diagnosis.

Autism spectrum disorder (ASD) is a common neurological condition. Early diagnosis and treatment are essential for enhancing the life quality of individuals with ASD. However, most existing studies either focus solely on the brain networks of subjects within a single atlas or merely employ simple matrix concatenation to represent the fusion of multi-atlas. These approaches neglected the natural spatial overlap that exists between brain regions across multi-atlas and did not fully capture the comprehensive information of brain regions under different atlases. To tackle this weakness, in this paper, we propose a novel multi-atlas fusion template based on spatial overlap degree of brain regions, which aims to obtain a comprehensive representation of brain networks. Specifically, we formally define a measurement of the spatial overlap among brain regions across different atlases, named spatial overlap degree. Then, we fuse the multi-atlas to obtain brain networks of each subject based on spatial overlap. Finally, the GCN is used to perform the final classification. The experimental results on Autism Brain Imaging Data Exchange (ABIDE) demonstrate that our proposed method achieved an accuracy of 0.757. Overall, our method outperforms SOTA methods in ASD/TC classification.

Hyperactivation of p53 contributes to mitotic catastrophe in podocytes through regulation of the Wee1/CDK1/cyclin B1 axis.

Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.

Cyclophilin D Contributes to Airway Epithelial Mitochondrial Damage in Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Airway epithelial mitochondrial injury is an important pathogenesis of chronic obstructive pulmonary disease (COPD). Cyclophilin D (CypD) is a component of mitochondrial permeability transition pore and related to mitochondrial damage. However, the role of CypD in airway epithelial mitochondrial injury and COPD pathogenesis remains unclear. METHODS: CypD expression in human airway epithelium was determined by immunohistochemistry, and mitochondrial structure of airway epithelial cell was observed under the transmission electron microscopy. The expression of CypD signaling pathway in cigarette smoke extract (CSE)-treated airway epithelial cells was measured by real-time PCR and Western-blot. CSE-induced damage of airway epithelial cell and mitochondria was further studied. RESULTS: Immunohistochemistry and transmission electron microscopy analysis revealed that CypD expression in airway epithelium was significantly increased associated with notable airway epithelial mitochondrial structure damage in the patients with COPD. The mRNA and protein expression of CypD was significantly increased in concentration- and time-dependent manners when airway epithelial cells were treated with CSE. CypD siRNA pretreatment significantly suppressed the increases of CypD and Bax expression, and reduced the decline of Bcl-2 expression in 7.5% CSE-treated airway epithelial cells. Furthermore, CypD silencing significantly attenuated mitochondrial damage and cell apoptosis, and increased cell viability when airway epithelial cells were stimulated with 7.5% CSE. CONCLUSION: These data suggest that CypD signaling pathway is involved in the pathogenesis of COPD and provide a potential therapeutic target for COPD.

Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer.

Rationale: The current molecular classification of small-cell lung cancer (SCLC) on the basis of the expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. Objectives: To refine the current SCLC classification with epigenomic profiles and to identify features of the redefined SCLC subtypes. Methods: We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9)-mediated deletion. NKX2-1-specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox; Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized. Measurements and Main Results: We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. In addition, we found that maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aα subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.

Risk factors of pancreatitis after endoscopic retrograde cholangiopancreatography in patients with biliary tract diseases.

BACKGROUND: To investigate the risk factors of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in patients with biliary tract diseases. METHODS: We retrospectively analyzed the clinical data of 480 patients who underwent ERCP for biliary tract diseases at the Affiliated Zhongshan Hospital of Dalian University from October 2011 to October 2016. The patients were divided into a study group (n = 75, with PEP) and a control group (n = 405, without PEP) based on whether they developed post-ERCP pancreatitis (PEP), and their clinical baseline data and intraoperative conditions were retrieved and compared. Then, factors associated with PEP were analyzed using logistic regression model, based on which a nomogram prediction model was constructed. The receiver operating characteristic (ROC) curve and calibration curve were used to evaluate the performance of the prediction model. RESULTS: Significant differences in age, sex, history of pancreatitis, history of choledocholithiasis, pancreatic duct imaging, pancreatic sphincterotomy, difficult cannulation, multiple cannulation attempts and juxtapapillary duodenal diverticula were observed between the two groups. Multivariate logistic regression analysis showed that age less than 60 years (OR, 0.477; 95% CI, 0.26-0.855), female sex (OR, 2.162; 95% CI, 1.220-3.831), history of pancreatitis (OR, 2.567; 95% CI, 1.218-5.410), history of choledocholithiasis (OR, 2.062; 95% CI, 1.162-3.658), pancreatic sphincterotomy (OR, 2.387; 95% CI, 1.298-4.390), pancreatic duct imaging (OR, 4.429; 95% CI, 1.481-13.242), multiple cannulation attempts (OR, 2.327; 95% CI, 1.205-4.493), difficult cannulation (OR, 2.421; 95% CI, 1.143-5.128), and JPD (OR, 2.002; 95% CI, 1.125-3.564) were independent risk factors for PEP. The nomogram for predicting the occurrence of PEP demonstrated an area under the ROC curve (AUC) of 0.787, and the calibration curves of the model showed good consistency between the predicted and actual probability of PEP. CONCLUSION: Our results showed that age less than 60 years, female sex, history of pancreatitis, history of choledocholithiasis, pancreatic sphincterotomy, pancreatic duct imaging, multiple cannulation attempts, difficult cannulation and juxtapapillary duodenal diverticula were independent risk factors for PEP. In addition, the established nomogram demonstrated promising clinical efficacy in predicting PEP risk in patients who underwent ERCP for biliary tract diseases.

Serum exosomal proteomics analysis of lung adenocarcinoma to discover new tumor markers.

BACKGROUND: Among the most aggressive and rapidly lethal types of lung cancer, lung adenocarcinoma is the most common type. Exosomes, as a hot area, play an influential role in cancer. By using proteomics analysis, we aimed to identify potential markers of lung adenocarcinoma in serum. METHODS: In our study, we used the ultracentrifugation method to isolate serum exosomes. The Liquid chromatography-mass spectrometry (LC-MS) and bioinformatics analysis were used to identify potential serum exosomal proteins with altered expression among patients with advanced lung adenocarcinoma, early lung adenocarcinoma, and healthy controls. A western blot (WB) was performed to confirm the above differential expression levels in a separate serum sample-isolated exosome, and immunohistochemistry (IHC) staining was conducted to detect expression levels of the above differential proteins of serum exosomes in lung adenocarcinoma tissues and adjacent tissues. Furthermore, we compared different expression models of the above differential proteins in serum and exosomes. RESULT: According to the ITGAM (Integrin alpha M chain) and CLU (Clusterin) were differentially expressed in serum exosomes among different groups as well as tumor tissues and adjacent tissues. ITGAM was significantly and specifically enriched in exosomes. As compared to serum, CLU did not appear to be significantly enriched in exosomes. ITGAM and CLU were identified as serum exosomal protein markers of lung adenocarcinoma. CONCLUSIONS: This study can provide novel ideas and a research basis for targeting lung adenocarcinoma treatment as a preliminary study.

New injury severity score (NISS) outperforms injury severity score (ISS) in the evaluation of severe blunt trauma patients.

PURPOSE: The injury severity score (ISS) and new injury severity score (NISS) have been widely used in trauma evaluation. However, which scoring system is better in trauma outcome prediction is still disputed. The purpose of this study is to evaluate the value of the two scoring systems in predicting trauma outcomes, including mortality, intensive care unit (ICU) admission and ICU length of stay. METHODS: The data were collected retrospectively from three hospitals in Zhejiang province, China. The comparisons of NISS and ISS in predicting outcomes were performed by using receiver operator characteristic (ROC) curves and Hosmer-Lemeshow statistics. RESULTS: A total of 1825 blunt trauma patients were enrolled in our study. Finally, 1243 patients were admitted to ICU, and 215 patients died before discharge. The ISS and NISS were equivalent in predicting mortality (area under ORC curve [AUC]: 0.886 vs. 0.887, p = 0.9113). But for the patients with ISS ≥25, NISS showed better performance in predicting mortality. NISS was also significantly better than ISS in predicting ICU admission and prolonged ICU length of stay. CONCLUSION: NISS outperforms ISS in predicting the outcomes for severe blunt trauma and can be an essential supplement of ISS. Considering the convenience of NISS in calculation, it is advantageous to promote NISS in China's primary hospitals.

Circular RNA SMARCA5 suppressed non-small cell lung cancer progression by regulating miR-670-5p/RBM24 axis.

Circular RNAs (circRNAs) have good stability and long half-life in blood and other body fluid, and possess regulatory effects on various biological processes as miRNA/RNA-binding protein sponges, or by competing endogenous RNA, indicating their great potential as biomarkers or targets of cancer therapy. In this study, we mainly explored the role and mechanism of circular RNA SMARCA5 (circsSMARCA5) in non-small cell lung cancer (NSCLC). Quantitative RT-PCR was applied to measure the expression levels of genes, and then, the relationships among circsSMARCA5, microRNA-670-5p (miR-670-5p), and RBM24 were further analyzed. Animal and cell experiments were performed to explore the functions of circsSMARCA5 in NSCLC cells. The results showed that circsSMARCA5 was expressed at low level in NSCLC tissues and cells, while miR-670-5p had high level in NSCLC tissues. Dual luciferase reporter assay verified that miR-670-5p was the target of circsSMARCA5, and RBM24 has the binding site of miR-670-5p. Further analysis showed that circsSMARCA5 could negatively regulate miR-670-5p and had positive relationship with RBM24. Moreover, circsSMARCA5 obviously inhibited tumor growth in vivo, reduced cell proliferation and increased cell apoptosis in vitro, while miR-670-5p mimic or RBM24 knockdown could reverse these effects. Thus, circsSMARCA5 may serve as an NSCLC suppressor by regulating the miR-670-5p/RBM24 axis, and it may have the potential to be a biomarker or therapeutic target for NSCLC.

Developing a Multi-Element Sensor to Non-Destructively Monitor Several Fundamental Parameters Related to Concrete Durability.

A design scheme of multi-element sensor which included electrical resistivity probes, multiple Cl- selective electrodes, and a steel corrosion monitoring system was proposed in this work. Embedding this multi-element sensor in concrete enables the real-time and non-destructive monitoring of internal electrical resistivity, free Cl- (Clf) contents in the concrete pore solution at different depths, and steel corrosion parameters. Based on the monitoring data obtained by the multi-element sensor, the freezing-thawing (F-T) damage degree, the Clf diffusion coefficient, the quantitative relation between F-T damage degree and Clf diffusion coefficient, the initiation period of steel corrosion, and the critical content related to steel corrosion are determined. To conclude, the multi-element sensor provides key durability parameters for the establishment of the Clf diffusion model, the assessment of health condition, and the prediction of service life of concrete under the coexistence of the F-T cycle and Cl-.

Jaundice caused by protrusion of a hepatic cyst into common bile duct that was resolved by choledochoscopic needle-knife electrotomy: a case report.

BACKGROUD: Hepatic cysts are the most frequent, innocuous, space-occupying lesions of the liver. The majority of solitary liver cysts are nonsymptomatic. When liver cysts reach a large size, there are some complications, including infection, rupture, spontaneous hemorrhage, obstructive jaundice, and neoplastic degeneration. Percutaneous aspiration, fenestration, hepatic resection, and liver transplantation have been proposed for symptomatic patients. CASE PRESENTATION: In this case report, we describe a 41-year-old woman who presented with persistent liver dysfunction, indolent xanthochromia, and skin itching for 3 months. After a series of tests, she has a 5.0 × 5.3 cm hepatic cyst with many separations in the left medial liver lobe. The obstructive jaundice was caused by a large pedunculated lump protruding into the common bile duct from the left hepatic duct. She was treated with laparotomy and this lump was completely removed from the root by choledochoscopic needle-knife electrotomy with a good clinical response. Postoperative pathology of the lump suggested a hepatic cyst wall without heterocysts or tumor cells. CONCLUSION: Hepatic cyst wall protruding into the common bile duct can form capsular lump and result in indolent jaundice. Choledochoscopic high-frequency needle-knife electrotomy could be considered as a simple, safe and effective complementary approach for benign mass on the bile duct wall.

The modified pancreatic stent system for prevention of post-ERCP pancreatitis: a case-control study.

BACKGROUND: Prophylactic pancreatic stents after endoscopic retrograde cholangiopancreatography (ERCP) can help prevent post-ERCP pancreatitis. However most of the pancreatic stents need to be removed by another ERCP. The aim of this observational study was to investigate the feasibility and effectiveness of the modified pancreatic stent system for prevention of post-ERCP pancreatitis. METHODS: From November 2013 to November 2015, a total of 230 patients who had prophylactic pancreatic stent placed for prevention of post-ERCP pancreatitis at a single institution were identified and stratified. In this case-control design, 150 patients received an ordinary pancreatic stent, and 80 patients received the modified pancreatic stent. The main outcome measures were the difficulty level and complications of pancreatic stent placement and extraction between the two groups. RESULTS: In ordinary group, the average time of pancreatic stent and nasal biliary drainage placement was 3.5 ± 0.6 min. There were 13 cases of stent proximal migration (8.7%), 20 cases of stent spontaneous abscission (13.3%), 5 cases of acute pancreatitis (3.3%) (2 cases for stent abscission) and 7 cases of hyperamylasemia (4.7%) after ERCP. One hundred thirty patients received extra duodenoscope (86.7%) to remove the stent, and 4 cases had acute pancreatitis and 5 patients had hyperamylasemia after removing the proximal migratory stents. In modified group, the average time of pancreatic stent system placement was 4.9 ± 0.7 min, but there was only one case of stent abscission (1.3%), 2 cases of acute pancreatitis (2.5%) and 3 cases of hyperamylasemia (3.8%). The new pancreatic stents were removed directly under x-ray without complication. CONCLUSIONS: The modified pancreatic stent system has the same effect of preventing post-ERCP pancreatitis, lower rate of stents proximal migration and spontaneous abscission, and the advantage of easier removed compared with ordinary pancreatic stent.

Choledochoscopic high-frequency needle-knife electrotomy for treatment of anastomotic strictures after Roux-en-Y hepaticojejunostomy.

BACKGROUND: Anastomotic stricture is a complex and substantial complication following Roux-en-Y hepaticojejunostomy. Initially, endoscopic and percutaneous approaches are often attempted, but the gold standard remains surgical biliary reconstruction, especially for refractory stricture. However, this solution leaves much room for improvement, due to the challenging nature of the biliary reconstruction procedure, in which anastomotic stricture may still occur. AIMS: To investigate the feasibility and effectiveness of choledochoscopic high-frequency needle-knife electrotomy as an intervention in the treatment of anastomotic strictures following Roux-en-Y hepaticojejunostomy. METHODS: From February 2010 to October 2014, clinical data was collected and retrospectively compared for patients who underwent balloon dilation or/and choledochoscopic high-frequency needle-knife electrotomy for the treatment of anastomotic strictures after Roux-en-Y hepaticojejunostomy. RESULTS: A total of 38 patients underwent successful choledochoscopic treatment and all the anastomotic strictures were removed successfully, 19 of which were treated with electrotomy, 7 with balloon dilation, and 12 with both electrotomy and balloon dilation. Among these groups,the average operating times were 6.9 ± 2.4 min,10.1 ± 6.8 min, and 20.2 ± 13.5 min, respectively. The average stent supporting times were 6.3 ± 0.7 months, 6.5 ± 0.6 months, and 6.1 ± 0.4 respectively. The mean follow-up after stent removal was 42.1 ± 27.4 months, and in 26.3 % (5/19), 28.5 % (2/7) and 16.7 % (2/12) of cases, recurrent anastomotic stricture occurred. Of these 9 total patients with recurrent anastomotic, two patients were successfully rescued by full-covered self-expanding removable metal stents and 7 patients by electrotomy combined with balloon dilation. CONCLUSIONS: Choledochoscopic high-frequency needle-knife electrotomy is both feasible and safe in the treatment of anastomotic stricture after Roux-en-Y hepaticojejunostomy, with a similar long-term outcome to balloon dilation in treating anastomotic stricture after Roux-en-Y hepaticojejunostomy. A combination of choledochoscopic electrotomy concurrent with balloon dilation should be recommended based on the low rate of recurrence.

Wnt agonist stimulates liver regeneration after small-for-size liver transplantation in rats.

AIM: Liver regeneration is inhibited in small-for-size grafts, which plays a role in the failure of partial liver grafts after transplantation. The Wnt/ß-catenin signaling pathway plays a critical role in liver development, regeneration and homeostasis. In this study, we investigated whether pharmacological activation of Wnt signaling improves liver regeneration after small-for-size liver transplantation. METHODS: The livers of male Sprague-Dawley rats were reduced to approximately 50% and 30% of their original sizes and transplanted. A Wnt agonist (2-amino-4-[3,4-[methylenedioxy]benzylamino]-6-[3-methoxyphenyl] pyrimidine], 5 mg/kg bodyweight) or an equal volume of vehicle was administrated i.p. into the donor 1 h before the transplantation. Tissue and blood samples were collected at various times after transplantation, and a survival study was performed. RESULTS: Hepatic expression of active ß-catenin and its downstream target gene Axin2 were decreased in 30% of liver grafts after transplantation while the Wnt agonist increased their expression similar to the 50% liver grafts. The Wnt agonist reversed inhibition of cyclin D1 expression and adenosine triphosphate production in the 30% liver grafts compared with the 50% grafts. The Wnt agonist also attenuated hepatocellular injury and increased the hepatocyte proliferation response, liver regeneration rate and survival after transplantation of the 30% liver graft. CONCLUSION: Activation of Wnt/ß-catenin signaling in liver grafts by pharmacological pretreatment can accelerate regeneration in a partial liver transplant model.

The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A.

BACKGROUND: miR-126 is a key regulator of oncogenic processes. It is functionally linked to cellular proliferation, survival and migration. Vascular endothelial growth factor A (VEGF-A), which is regarded as a tumorgenesis activator, could directly target miR-126 in several tumors. However, the mechanism in esophageal cancer remains unclear. METHODS AND RESULTS: In this study, the expression of miR-126 and VEGF-A were assessed in esophageal cancer tissues and esophageal cancer cell lines. We found that miR-126 has significantly lower expression in esophageal cancer tissues and esophageal cancer cell lines than in healthy tissues, while the expression of VEGF-A is high. Luciferase reporter assays were performed to investigate the relationship between VEGF-A and miR-126. We confirmed that VEGF-A is a target for miR-126. Furthermore, the proliferation of esophageal cancer cells with miR-126 overexpression and miR-126 knockdown was monitored using the MTT assay. The results showed that miR-126 could inhibit esophageal cancer cell proliferation in vitro. The effect of miR-126 was also detected in BALB/c nude mice with transplanted esophageal cancer cells. In vivo study showed that tumor growth was significantly suppressed by miR-126 overexpression. CONCLUSIONS: We believe that restoring miR-126 levels may be a promising therapeutic approach in cases of esophageal cancer.

Choledochoscopic high-frequency needle-knife electrotomy as an effective treatment for intrahepatic biliary strictures.

BACKGROUND AND AIM: Hepatolithiasis is associated with the presence of intrahepatic biliary strictures, and balloon dilatation is the main approach. However, this method is difficult to implement if the bile duct distal to the stricture is blocked by stones. Therefore, alternative methods need to be explored to effectively treat hepatolithiasis. The aim of this study is to investigate the feasibility and effectiveness of choledochoscopic high-frequency needle-knife electrotomy for the treatment of intrahepatic biliary strictures. METHODS: Clinical data of 58 patients suffering from intrahepatic bile duct strictures from January 2011 to January 2013 were retrospectively analyzed. Choledochoscopic electrotomy was used to resolve the strictures. RESULTS: One hundred thirty-four sites of intrahepatic bile duct strictures were discovered. The average operating time of electrotomy is 5.6 min (range, 1 ∼ 15 min). Structured bile duct tissue bleeding occurred in eight sites (8/134, 6.0%) but were resolved by endoscopic high-frequency electric cautery. After the operations, 14 cases of cholangitis (14/58, 24.1%), three cases of delayed hemobilia, one case of liver abscess (1/58, 1.7%), and seven cases of stenting exodus (7/58, 12.1%) were observed despite conservative treatment and stenting reset. The average supporting time was 7.0 months (6 ∼ 9 months). No abnormal bile duct structure or presence of stone was found according to choledochoscopy. The follow-up period ranged from 12 to 48 months. Hepatolithiasis recurred in five (5/58, 8.6%) patients, and the cumulative recurrent probability of intrahepatic bile duct stricture was 5.2% (7/134). CONCLUSIONS: Choledochoscopic high-frequency needle-knife electrotomy could be considered as a simple, safe, and effective complementary approach for treating intrahepatic biliary strictures.

[Prevention and treatment of complications for full-covered self-expanding removable metal stents in malignant obstructive jaundice].

OBJECTIVE: To explore the prevention and treatment of complications for full-covered self-expanding removable metal stents (FCSERMS) in malignant obstructive jaundice. METHODS: The clinical data were analyzed retrospectively for 45 cases undergoing endoscopic biliary FCSERMS drainage for malignant obstructive jaundice from May 2012 to March 2014. RESULTS: Among them, 45 cases were successful one time. The parameters of liver function improved significantly with a jaundice efficiency of 91.1%. There were 4 dead cases. Among 19 cases of early complications, hyperamylasemia (n = 8), acute mild pancreatitis (n = 4), acute cholecystitis (n = 2) and hemobilia (n = 1) recovered after conservative treatments. Acute suppurative cholecystitis (n = 2) and acute obstructive suppurative cholangitis (n = 2) were cured by percutaneous transhepatic cholangial drainage (PTCD) and percutaneous transhepatic gallbladder drainage (PTGBD). And late complications of obstructive jaundice (n = 3), acute suppurative cholecystitis (n = 4), acute cholangitis (n = 2), hepatophyma (n = 2) and acute pancreatitis (n = 1) were cured by endoscopic retrograde cholangiopancreatography (ERCP), PTCD and PTGBD. CONCLUSION: Various complications are associated with FCSERMS in malignant obstructive jaundice.However, positive and effective prevention and proper treatment reduce the incidence of complications.

Spleen derived monocytes regulate pulmonary vascular permeability in Hepatopulmonary syndrome through the OSM-FGF/FGFR1 signaling.

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS.