Practice patterns in endoscopic treatment for gastric varices: A Chinese survey.

OBJECTIVES: Gastric varices (GV), a common complication of liver cirrhosis, often cause serious consequences. However, the management of GV remains debated. In this study we aimed to explore the practice patterns of Chinese practitioners in GV treatment and discuss whether these patterns conform to the guidelines in China and around the world. METHODS: Between October 2020 and January 2021, an online questionnaire was sent to doctors from different regions in China via WeChat. Data on the practice patterns for endoscopic treatment with and without a multidisciplinary discussion team (MDT) clinic for GV were analyzed. RESULTS: Questionnaires were collected from 241 practitioners from 29 provinces in China. Before endoscopic treatment, 100 (41.5%) of the practitioners arranged computed tomography angiography (CTA) examination. In endoscopic tissue adhesive (ETA) treatment, 183 (75.9%) of the practitioners chose ETA combined with lauromacrogol. Approximately one-fourth of all practitioners did not prescribe drugs to reduce portal pressure. Only 75 (31.1%) of physicians preferred using early transjugular intrahepatic portosystemic shunt (TIPS) for patients at a high risk of treatment failure for GV. Compared to those without MDT clinics, practitioners with MDT clinics more often chose early TIPS for high-risk patients (39.0% vs 18.9%, P = 0.001). CONCLUSIONS: Treatment for GV differ across China. Practitioners with MDT clinics can better use assistant strategies such as CTA to evaluate the risk and efficacy. Further clinical studies are needed, and more guidelines and consensuses are warranted to standardize clinical practice for GV.

Ubiquitylation of cyclin C by HACE1 regulates cisplatin-associated sensitivity in gastric cancer.

BACKGROUND: Cyclin C (CCNC) was reported to take part in regulating mitochondria-derived oxidative stress under cisplatin stimulation. However, its effect in gastric cancer is unknown. This study aimed to investigate the role of cyclin C and its ubiquitylation in regulating cisplatin resistance in gastric cancer. METHODS: The interaction between HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase 1 (HACE1) and cyclin C was investigated by GST pull-down assay, co-immunoprecipitation and ubiquitylation assay. Mitochondria-derived oxidative stress was studied by MitoSOX Red assay, seahorse assay and mitochondrial membrane potential measurement. Cyclin C-associated cisplatin resistance was studied in vivo via xenograft. RESULTS: HACE1 catalysed the ubiquitylation of cyclin C by adding Lys11-linked ubiquitin chains when cyclin C translocates to cytoplasm induced by cisplatin treatment. The ubiquitin-modified cyclin C then anchor at mitochondira, which induced mitochondrial fission and ROS synthesis. Depleting CCNC or mutation on the ubiquitylation sites decreased mitochondrial ROS production and reduced cell apoptosis under cisplatin treatment. Xenograft study showed that disrupting cyclin C ubiquitylation by HACE1 conferred impairing cell apoptosis response upon cisplatin administration. CONCLUSIONS: Cyclin C is a newly identified substrate of HACE1 E3 ligase. HACE1-mediated ubiquitylation of cyclin C sheds light on a better understanding of cisplatin-associated resistance in gastric cancer patients. Ubiquitylation of cyclin C by HACE1 regulates cisplatin-associated sensitivity in gastric cancer. With cisplatin-induced nuclear-mitochondrial translocation of cyclin C, its ubiquitylation by HACE1 increased mitochondrial fission and mitochondrial-derived oxidative stress, leading to cell apoptosis.

Value of quantitative ultrasound and bioelectrical impedance analysis in detecting low bone mineral density in hemodialysis.

INTRODUCTION: Patients on maintenance hemodialysis (MHD) are highly predisposed to low bone mineral density (BMD). This study aims to assess the value of quantitative ultrasound (QUS), bioelectrical impedance analysis (BIA), and their combination in detecting high-risk patients for low BMD in MHD. METHODS: Patients' BMD of the total hip, femoral neck, and lumbar spine were measured using dual-energy X-ray absorptiometry (DXA). Bone mineral content (BMC) was assessed using BIA. Calcaneal BMD was measured using QUS. Patients with a T-score of ≤-2.5 were recorded as 'low BMD.' RESULTS: Overall, 93 subjects (62.37% female; mean age, 60.8 ± 16.2 years) were included in this cross-sectional study; approximately 36.56% met the 'low BMD' criteria. QUS-T score predicted low BMD with an area under the curve (AUC) value of 0.738, sensitivity of 70.59%, and specificity of 76.27%. The AUC for low BMD diagnosis using the BMC index (BMCI) measured through BIA was 0.679 (sensitivity, 91.18%; specificity, 38.98%). On the other hand, the combination of QUS-T score and BMCI yielded a higher AUC value of 0.762 with an improved specificity of 88.14%. Compared with the QUS and BIA alone, the net reclassification improvement (NRI) of the combination model increased by 47.16% (p = 0.022) and 78.36% (p < 0.0001), respectively. Integrated discrimination improvement (IDI) increased by 5.25% (p = 0.043) and 9.99% (p = 0.003), respectively. QUS-T score and BMCI were related to BMD independently assessed by DXA. CONCLUSION: The combination of QUS and BIA is effective in screening for low BMD among MHD patients.

The pharmacodynamic effect of terlipressin versus high-dose octreotide in reducing hepatic venous pressure gradient: a randomized controlled trial.

BACKGROUND: Vasoactive drugs can reduce portal venous pressure and control variceal bleeding. However, few studies have explored the hemodynamic effects of terlipressin and high-dose octreotide in such patients. Our purpose was to evaluate the hemodynamic changes and safety of using terlipressin and high-dose octreotide in patients with decompensated liver cirrhosis. METHODS: A multi-center randomized controlled trial was conducted. Cirrhotic patients with a history of variceal bleeding were included. Terlipressin or high-dose octreotide was administered during the procedure of measuring hepatic venous pressure gradient (HVPG). Hemodynamic parameters and symptoms were recorded. RESULTS: A total of 88 patients were included. HVPG was significantly reduced at 10, 20, and 30 min after drug administration in the terlipressin group (16.3±6.4 vs. 14.7±5.9, 14.0±6.1, and 13.8±6.1, respectively, P<0.001) and the high-dose octreotide group (17.4±6.6 vs. 15.1±5.8, 15.3±6.2, and 16.1±6.0, respectively P<0.01). Decreased heart rate and increased mean arterial pressure were more often observed in the terlipressin group. The overall response rates were not significantly different between the groups (52.8% vs. 44.8%, P=0.524). The terlipressin group had significantly higher response rates at 30 min compared to the high-dose octreotide group in those with alcoholic liver cirrhosis [6/6 (100%) vs. 0/4 (0%), P=0.005]. The incidence of adverse drug events was rare and similar in the two groups. CONCLUSIONS: Both terlipressin and high-dose octreotide were effective and safe for reducing HVPG. The pharmacodynamic effect of terlipressin persisted longer. The terlipressin group had higher response rates in those with alcoholic cirrhosis (trial number: NCT02119884).

Phosphocreatine attenuates Gynura segetum-induced hepatocyte apoptosis via a SIRT3-SOD2-mitochondrial reactive oxygen species pathway.

Purpose: To investigate the mitochondria-related mechanism of Gynura segetum (GS)-induced apoptosis and the protective effect of phosphocreatine (PCr), a mitochondrial respiration regulator. Methods: First, the mechanism was explored in human hepatocyte cell line. The mitochondrial oxidative stress was determined by fluorescence assay. The level of sirtuin 3 (SIRT3), acetylated superoxide dismutase 2 (Ac-SOD2), SOD2, and apoptosis were detected by Western blotting. Mito-TEMPO and cell lines of viral vector-mediated overexpression of SIRT3 and SIRT3H248Y were used to further verify the mechanism of GS-induced apoptosis. GS-induced liver injury mice models were built by GS through intragastric administration and interfered by PCr through intraperitoneal injection. A total of 30 C57BL/6J mice were assigned to 5 groups and treated with either saline, PCr (100 mg/kg), GS (30 g/kg), or PCr (50 or 100 mg/kg)+GS (30 g/kg). Liver hematoxylin and eosin (HE) staining, immunohistochemical analysis, and blood biochemical evaluation were performed. Results: GS induced hepatocyte apoptosis and elevated levels of mitochondrial ROS in L-02 cells. The expression of SIRT3 was decreased. Downregulation of SIRT3 was associated with increased levels of Ac-SOD2, which is the inactivated enzymatic form of SOD2. Conversely, when overexpressing SIRT3 in GS-treated cells, SOD2 activity was restored, and mitochondrial ROS levels and hepatocyte apoptosis declined. Upon administration of PCr to GS-treated cells, they exhibited a significant upregulation of SIRT3 and were protected against apoptosis. In animal experiments, serum ALT level and mitochondrial ROS of the mice treated with GS and 50 mg/kg PCr were significantly attenuated compared with only GS treated. The changes in SIRT3 expression were also consistent with the in vitro results. In addition, immunohistochemical analysis of the mouse liver showed that Ac-SOD2 was decreased in the PCr and GS co-treated group compared with GS treated group. Conclusion: GS caused liver injury by dysregulating mitochondrial ROS generation via a SIRT3-SOD2 pathway. PCr is a potential agent to treat GS-induced liver injury by mitochondrial protection.

Sevoflurane promotes migration, invasion, and colony-forming ability of human glioblastoma cells possibly via increasing the expression of cell surface protein 44.

Surgical resection of primary solid tumor under anesthesia remains a common practice. It has been concerned whether general anesthetics, especially volatile anesthetics, may promote the growth, migration, and invasion of cancer cells. In this study, we examined the effects of sevoflurane on human glioblastoma cells and determined the role of cluster of differentiation (CD) 44, a cell surface protein involved in cell growth, migration, and invasion, in sevoflurane's effects. We showed that exposure to 1%-4% sevoflurane did not change the cell proliferation, but concentration-dependently increased the invasion of human glioblastoma U251 cells. Furthermore, 4% sevoflurane significantly increased the migration and colony-forming ability of U251 cells. Similar results were observed in human glioblastoma A172 cells. Exposure to sevoflurane concentration-dependently increased the activity of calpains, a group of cysteine proteinases, and CD44 protein in U251 and A172 cells. Knockdown of CD44 with siRNA abolished sevoflurane-induced increases in calpain activity, migration, invasion, and colony-forming ability of U251 cells. Inhalation of 4% sevoflurane significantly increased the tumor volume and invasion/migration distance of U87 cells from the tumor mass in the nude mice bearing human glioblastoma U87 xenograft in the brain. The aggravation by sevoflurane was attenuated by CD44 silencing. In conclusion, sevoflurane increases the migration, invasion, and colony-forming ability of human glioblastoma cells in vitro, and their tumor volume and invasion/migration in vivo. Sevoflurane enhances these cancer cell biology features via increasing the expression of CD44.

Erratum: Label-free quantitative proteomic analysis identifies CTNNB1 as a direct target of FOXP3 in gastric cancer cells.

[This corrects the article DOI: 10.3892/ol.2018.8277.].

Label-free quantitative proteomic analysis identifies CTNNB1 as a direct target of FOXP3 in gastric cancer cells.

Forkhead box protein 3 (FOXP3) is expressed in numerous types of tumor cell and is associated with tumor progression and prognosis. A previous study reported that FOXP3 inhibited cellular proliferation and induced apoptosis of gastric cancer (GC) cells by activating the apoptosis signaling pathway. In the present study, label-free quantitative proteomic analysis and chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) was performed to investigate the mechanism by which the anticancer role of FOXP3 was mediated and the proteins that with which it may interact. Label-free quantitative proteomic analysis was used to screen for proteins differentially expressed between FOXP3-overexpressing GC (AF) and vector (ANC) cells. Catenin ß1 (CTNNB1) was one of the proteins that exhibited the greatest difference between AF and ANC among 3,313 proteins identified by liquid chromatography with tandem mass spectrometry analysis. The expression of CTNNB1 was evaluated by reverse transcription-quantitative PCR and western blotting. The association between FOXP3 and CTNNB1 was confirmed by ChIP-PCR in AGS cells. The changes in expression of epithelial-mesenchymal transition-associated proteins were analyzed by western blotting. The level of FOXP3 expression was positively associated with CTNNB1 and E-cadherin expression, but not with vimentin and N-cadherin expression. FOXP3 positively regulates CTNNB1 and binds to it directly. Along with the upregulation of glycogen synthase kinase 3ß (GSK3ß), which was also a protein whose expression was found to change significantly in proteomic analysis and has a key role in the Wnt pathway. This association is an attractive and novel hypothesis for the mechanism by which FOXP3 inhibits the invasion and metastasis of GC cells.

Insight into Central Asian flora from the Cenozoic Tianshan montane origin and radiation of Lagochilus (Lamiaceae).

The Tianshan Mountains play a significant role in the Central Asian flora and vegetation. Lagochilus has a distribution concentration in Tianshan Mountains and Central Asia. To investigate generic spatiotemporal evolution, we sampled most Lagochilus species and sequenced six cpDNA locations (rps16, psbA-trnH, matK, trnL-trnF, psbB-psbH, psbK-psbI). We employed BEAST Bayesian inference for dating, and S-DIVA, DEC, and BBM for ancestral area/biome reconstruction. Our results clearly show that the Tianshan Mountains, especially the western Ili-Kirghizia Tianshan, as well as Sunggar and Kaschgar, was the ancestral area. Ancestral biome was mainly in the montane steppe zone of valley and slope at altitudes of 1700-2700 m, and the montane desert zone of foothill and front-hill at 1000-1700 m. Here two sections Inermes and Lagochilus of the genus displayed "uphill" and "downhill" speciation process during middle and later Miocene. The origin and diversification of the genus were explained as coupled with the rapid uplift of the Tianshan Mountains starting in late Oligocene and early Miocene ca. 23.66~19.33 Ma, as well as with uplift of the Qinghai-Tibetan Plateau (QTP) and Central Asian aridification.

Methylation modification in gastric cancer and approaches to targeted epigenetic therapy (Review).

Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer-related mortality. Increasing discoveries have highlighted aberrant epigetic modifications actively contribute to the pathogenesis of this fatal disease. Among these epigenetic events, dysregulated methylation is particularly associated with GC progression. Importantly, these aberrant methylation modifications caused by the misregulation of methyltranferases are frequently reversible, which provides opportunities for targeted treatment using specific molecular inhibitors. In the present review, we provide an overview of the current literature on the changes of DNA and histone methylations that alter gene expressions in GC and describe the emerging targeted epigenetic therapy in GC.

Autophagy-related protein MoAtg14 is involved in differentiation, development and pathogenicity in the rice blast fungus Magnaporthe oryzae.

Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the vacuole/lysosome in eukaryotic cells. MoAtg14 in M. oryzae, a hitherto uncharacterized protein, is the highly divergent homolog of the yeast Atg14 and the mammal BARKOR. The MoATG14 deletion mutant exhibited collapse in the center of the colonies, poor conidiation and a complete loss of virulence. Significantly, the ΔMoatg14 mutant showed delayed breakdown of glycogen, less lipid bodies, reduced turgor pressure in the appressorium and impaired conidial autophagic cell death. The autophagic process was blocked in the ΔMoatg14 mutant, and the autophagic degradation of the marker protein GFP-MoAtg8 was interrupted. GFP-MoAtg14 co-localized with mCherry-MoAtg8 in the aerial hypha. In addition, a conserved coiled-coil domain was predicted in the N-terminal region of the MoAtg14 protein, a domain which could mediate the interaction between MoAtg14 and MoAtg6. The coiled-coil domain of the MoAtg14 protein is essential for its function in autophagy and pathogenicity.

Endoscopic cyanoacrylate injection with or without lauromacrogol for gastric varices: A randomized pilot study.

BACKGROUND AND AIM: Current guidelines recommend injection of cyanoacrylate as first-line therapy to prevent gastric variceal rebleeding. The method still poses a risk of ectopic embolism, which possibly correlates with the volume of cyanoacrylate used. In this trial, we evaluated the short-term efficacy and safety of tissue adhesive injection combined with lauromacrogol for treating gastric varices. METHODS: Patients admitted to our hospital for variceal hemorrhage were enrolled and blindly randomized into two treatment groups: lauromacrogol group (lauromacrogol-cyanoacrylate-lauromacrogol) and lipiodol group (lipiodol-cyanoacrylate-lipiodol). Patient follow-up was 6 months. Primary outcome was rebleeds, and secondary outcomes were mortality, gastric varices eradication, and treatment-related adverse events. RESULTS: Between March 6, 2013 and October 16, 2013, 96 patients met the criteria. Two cases were lost to follow-up, and all treated cases were successful. No procedural-related adverse events were observed in either group. Cyanoacrylate volumes used in the lauromacrogol group were significantly less than those of the lipiodol group (0.9 ± 0.5 vs 2.0 ± 1.2 mL, P = 0.000). Eleven patients developed upper gastrointestinal rebleeding, which did not show significant difference between groups. On multivaritate analysis, portal venous thrombosis and fever were potential risk factors of rebleeding. Treatment failure, complications, gastric varices obturation, and survival did not differ between the two groups. CONCLUSION: Tissue adhesives combined with lauromacrogol is a safe therapeutic option for gastric varices, with comparably less cyanoacrylate volume used. Because of the small number of study patients, it cannot be proven to have better efficacy than without lauromacrogol. Multicenter studies with larger patient groups are necessary.

Prognostic Value of Focal Adhesion Kinase (FAK) in Human Solid Carcinomas: A Meta-Analysis.

BACKGROUND: Recently, the number of reports on focal adhesion kinase (FAK) as a vital therapeutic target in solid carcinomas has increased; however, the prognostic role of FAK status remains poorly understood. This study aims to evaluate the prognostic effect of FAK by means of a meta-analysis. METHODS: We performed a systematic literature search in order to examine the correlation between expression of FAK and overall survival(OS). The hazard ratio (HR) of OS was used to measure survival. A random-effects model was used to pool study statistics. Sensitivity and publication bias analyses were also conducted. RESULTS: Thirty eligible studies involving 4702 patients were included. The median expression rate of FAK was 54%. Meta-analysis of the HRs demonstrated that high FAK expression was associated with worse OS (average HR = 2.073, 95%confidence interval[CI]:1.712-2.510, p = 0.000). Regarding cancer type, FAK was associated with worse OS in gastric cancer (HR = 2.646,95% CI:1.743-4.017, p = 0.000), hepatocellular carcinoma (HR = 1.788,95% CI:1.228-2.602, p = 0.002), ovarian cancer (HR = 1.815, 95% CI: 1.193-2.762, p = 0.005), endometrial cancer (HR = 4.149, 95% CI:2.832-6.079, p = 0.000), gliomas (HR = 2.650, 95% CI: 1.205-5.829, p = 0.015), and squamous cell carcinoma (HR = 1,696, 95% CI: 1.030-2.793, p = 0.038). No association was found between HR and disease staging according to our meta-regression analysis. CONCLUSIONS: Our study shows that high expression of FAK is associated with a worse OS in patients with carcinomas, but the association between FAK and prognosis varies according to cancer type. The value of FAK status in clinical prognosis in cancer needs further research.

Computed tomography in evaluating gastroesophageal varices in patients with portal hypertension: A meta-analysis.

AIMS: Gastroesophageal varices (GOV) is a common complication in patients with portal hypertension. We conducted a meta-analysis in attempt to evaluate the diagnostic accuracy of computed tomography (CT) as a noninvasive imaging tool for identifying GOV in reference to esophagogastroduodenoscopy (EGD). METHODS: A systemic literature search of multiple databases were conducted to identify articles that investigated the diagnostic performance of CT for GOV, while employing EGD as reference standard. A 2×2 table was conducted according to the available published data for both esophageal varices (EV) and gastric varices (GV) as individual subgroups. The following indices were calculated: pooled sensitivity and specificity, positive and negative likelihood ratio, diagnostic odds ratio, and area under receiver operating characteristics. All statistical analyses were conducted via STATA13.0 and RevMan5.3. RESULTS: A total of 11 studies were included in this meta-analysis, 10 articles evaluated the diagnostic accuracy of CT for EV (807 subjects) and 7 articles for GV (583 subjects). The pooled sensitivity and specificity for identifying EV were 0.896 (95% CI, 0.841-0.934) and 0.723 (95% CI, 0.644-0.791), respectively, with an AUROC of 0.86. The pooled sensitivity and specificity for identifying GV were 0.955 (95% CI, 0.903-0.980) and 0.658 (95% CI, 0.433-0.829), respectively, with an AUROC of 0.95. A subgroup analysis suggested varying CT technology could serve as a potential source of heterogeneity between included studies. A Deek's funnel plot indicated a low probability for publication bias. CONCLUSION: Computed tomography could potentially replace EGD as a primary screening tool for diagnosing GOV, however results should be interpreted with caution given its suboptimal specificity.

Long-term efficacy of endoscopic ligation plus cyanoacrylate injection with or without sclerotherapy for variceal bleeding.

OBJECTIVE: This study aimed to evaluate the long-term outcomes and efficacy of continued ligation plus cyanoacrylate injection compared with those of combined ligation and sclerotherapy plus cyanoacrylate injection for secondary prophylaxis of variceal bleeding in cirrhotic patients with concomitant esophageal and gastric varices. METHODS: Medical records of the patients who were admitted for variceal bleeding due to liver cirrhosis were retrospectively reviewed and their related data was collected. The patients were divided into two groups, including the continued ligation plus cyanoacrylate injection group [the sclerotherapy (-) group] and the combined ligation and sclerotherapy plus cyanoacrylate injection group [the sclerotherapy (+) group]. The Kaplan-Meier survival analysis was conducted and log-rank test was used to compare the differences between the two groups. RESULTS: Altogether 125 patients were enrolled between 1 April 2004 and 31 December 2012. After a median follow-up of 23.4 months, no significant difference was observed between the two groups in regard to variceal rebleeding (29.7% vs 47.5%, P = 0.097) and mortality (12.5% vs 14.8%, P = 0.879). Among patients with ascites the cumulative rebleeding rate was significantly lower in the sclerotherapy (-) group (26.3% vs 59.4%, P = 0.020). A relapse of bleeding after the initial endoscopic therapy was an independent prognostic factor of rebleeding (P = 0.004). Portal thrombosis was an independent prognostic factor for mortality (P = 0.044). CONCLUSION: No superiority of combined ligation and sclerotherapy compared with continued ligation and cyanoacrylate injection for secondary prophylaxis of variceal bleeding is observed.

Differences in regional homogeneity between patients with Crohn's disease with and without abdominal pain revealed by resting-state functional magnetic resonance imaging.

Abnormal pain processing in the central nervous system may be related to abdominal pain in patients with Crohn's disease (CD). The purpose of this study was to investigate changes in resting-state brain activity in patients with CD in remission and its relationship with the presence of abdominal pain. Twenty-five patients with CD and with abdominal pain, 25 patients with CD and without abdominal pain, and 32 healthy subjects were scanned using a 3.0-T functional magnetic resonance imaging scanner. Regional homogeneity (ReHo) was used to assess resting-state brain activity. Daily pain scores were collected 1 week before functional magnetic resonance imaging. We found that patients with abdominal pain exhibited lower ReHo values in the insula, middle cingulate cortex (MCC), and supplementary motor area and higher ReHo values in the temporal pole. In contrast, patients without abdominal pain exhibited lower ReHo values in the hippocampal/parahippocampal cortex and higher ReHo values in the dorsomedial prefrontal cortex (all P < 0.05, corrected). The ReHo values of the insula and MCC were significantly negatively correlated with daily pain scores for patients with abdominal pain (r = -0.53, P = 0.008 and r = -0.61, P = 0.002, respectively). These findings suggest that resting-state brain activities are different between remissive patients with CD with and without abdominal pain and that abnormal activities in insula and MCC are closely related to the severity of abdominal pain.

Randomized controlled trial comparing endoscopic ligation with or without sclerotherapy for secondary prophylaxis of variceal bleeding.

OBJECTIVES: A recently published network meta-analysis showed that ligation combined with sclerotherapy might be the most efficacious intervention for secondary prophylaxis of variceal bleeding. Most studies excluded patients with concomitant gastric varices; thus, the outcomes in such patients have not yet been reported. The present study aimed to investigate the efficacy of two endoscopic procedures for secondary prophylaxis in cirrhotic patients presenting with both esophageal and gastric varices. MATERIALS AND METHODS: A randomized controlled study was carried out in a tertiary care referral center. Patients were randomized into two groups: sclerotherapy- and sclerotherapy+ group. Continued endoscopic ligation was used to treat esophageal varices in the sclerotherapy- group, whereas combined ligation and sclerotherapy with lauromacrogol was performed in the sclerotherapy+ group. A cyanoacrylate injection was used for gastric varices in both groups. All participants were followed up for 6 months. RESULTS: Overall, 96 patients were included between 25 March 2012 and 25 June 2013. Three patients were lost during follow-up (one in the sclerotherapy- group and two in the sclerotherapy+ group). The cumulative recurrence rate of bleeding was significantly higher in the sclerotherapy+ group (14.6 vs. 35.4%, P=0.013). The cumulative mortality rate (2.1 vs. 6.3%, P=0.286) and the incidence rate of adverse events were similar between the two groups. CONCLUSION: Continued ligation+cyanoacrylate injection was superior to combined ligation and sclerotherapy+cyanoacrylate injection during the first 6 months in terms of rebleeding in cirrhotic patients presenting with both esophageal and gastric varices. Long-term results entail further investigation (http://www.clinicaltrials.gov, NCT01592578).

Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway.

Kruppel-like factor 2 (KLF2) is a crucial anti-angiogenic factor. However, its precise role in hepatic angiogenesis induced by liver sinusoidal endothelial cells (LSECs) remain unclear. This study was aimed to evaluate the effect of KLF2 on angiogenesis of LSECs and to explore the corresponding mechanism. Cultured human LSECs were infected with different lentiviruses to overexpress or suppress KLF2 expression. The CCK-8 assay, transwell migration assay and tube formation test, were used to investigate the roles of KLF2 in the proliferation, migration and vessel tube formation of LSECs, respectively. The expression and phosphorylation of ERK1/2 were detected by western blot. We discovered that the up-regulation of KLF2 expression dramatically inhibited proliferation, migration and tube formation in treated LSECs. Correspondingly, down-regulation of KLF2 expression significantly promoted proliferation, migration and tube formation in treated LSECs. Additionally, KLF2 inhibited the phosphorylation of ERK1/2 pathway, followed by the function of KLF2 in the angiogenesis of LSECs disrupted. In conclusion, KLF2 suppressed the angiogenesis of LSECs through inhibition of cell proliferation, migration, and vessel tube formation. These functions of KLF2 may be mediated through the ERK1/2 signaling pathway.

Crosstalk between SNF1 pathway and the peroxisome-mediated lipid metabolism in Magnaporthe oryzae.

The SNF1/AMPK pathway has a central role in response to nutrient stress in yeast and mammals. Previous studies on SNF1 function in phytopathogenic fungi mostly focused on the catalytic subunit Snf1 and its contribution to the derepression of cell wall degrading enzymes (CWDEs). However, the MoSnf1 in Magnaporthe oryzae was reported not to be involved in CWDEs regulation. The mechanism how MoSnf1 functions as a virulence determinant remains unclear. In this report, we demonstrate that MoSnf1 retains the ability to respond to nutrient-free environment via its participation in peroxisomal maintenance and lipid metabolism. Observation of GFP-tagged peroxisomal targeting signal-1 (PTS1) revealed that the peroxisomes of ΔMosnf1 were enlarged in mycelia and tended to be degraded before conidial germination, leading to the sharp decline of peroxisomal amount during appressorial development, which might impart the mutant great retard in lipid droplets mobilization and degradation. Consequently, ΔMosnf1 exhibited inability to maintain normal appressorial cell wall porosity and turgor pressure, which are key players in epidermal infection process. Exogenous glucose could partially restore the appressorial function and virulence of ΔMosnf1. Toward a further understanding of SNF1 pathway, the ß-subunit MoSip2, γ-subunit MoSnf4, and two putative Snf1-activating kinases, MoSak1 and MoTos3, were additionally identified and characterized. Here we show the null mutants ΔMosip2 and ΔMosnf4 performed multiple disorders as ΔMosnf1 did, suggesting the complex integrity is essential for M. oryzae SNF1 kinase function. And the upstream kinases, MoSak1 and MoTos3, play unequal roles in SNF1 activation with a clear preference to MoSak1 over MoTos3. Meanwhile, the mutant lacking both of them exhibited a severe phenotype comparable to ΔMosnf1, uncovering a cooperative relationship between MoSak1 and MoTos3. Taken together, our data indicate that the SNF1 pathway is required for fungal development and facilitates pathogenicity by its contribution to peroxisomal maintenance and lipid metabolism in M. oryzae.