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Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.

Uterine artery pseudoaneurysm (UAP) is rare but can cause life-threatening postpartum hemorrhage (PPH). To evaluate a novel sandwich embolization technique as a treatment for PPH caused by UAP. This retrospective study included 10 patients with PPH caused by UAP who were treated using a modified sandwich embolization technique at the Radiology Department, Third Affiliated Hospital of Guangzhou Medical University between April 2009 and September 2018. Baseline clinical characteristics, intraoperative data (including treatment effectiveness) and postoperative data (including re-bleeding events and complications) were extracted from the medical records. Uterine arterial angiography showed cystic shadowing of the vascular wall during the arterial phase in all patients. Spraying of contrast agent into the pseudoaneurysm was observed for large UAPs, and the pseudoaneurysm disappeared in the venous phase. The pseudoaneurysm blood supply was from the uterine artery in 9 patients (90%) and the uterine, superior vesical, internal pudendal and nameless little arteries in 1 patient (10%). Bleeding symptoms were completely relieved in all patients after sandwich embolization. Eight patients experienced painful contractions in the perioperative period, but there were no other postoperative complications. During the 1-year postoperative follow-up, 9 patients (90%) had no re-bleeding symptoms/signs. One patient (10%), who had a pseudoaneurysm supplied by the uterine, superior vesical, internal pudendal and nameless little arteries, experienced re-bleeding 20 days after surgery and was treated by hysterectomy. Modified sandwich embolization is an effective treatment for PPH caused by UAP.

Background & Aims There is limited evidence on the efficacy and safety of nucleos(t) ide analogues (NAs) in the treatment of HBV-ACLF. Our objective was to evaluate the outcomes among TAF, TDF and ETV, three first-line antivirals against chronic hepatitis B, in patients with HBV-ACLF. Methods Patients with HBV-related ACLF were recruited and received daily TAF (25 mg/d), TDF (300 mg/d) and ETV (0.5 mg/d). They were prospectively followed-up. The primary endpoint was overall survival at week 12 and week 48, the secondary endpoints were virological response and biochemical response. Results Forty gender and age matched eligible subjects were recruited and divided into three groups: TAF group, TDF group and ETV group. By week 48, 8 (80%) patients in TAF group, 6 (60%) patients in TDF group and 17 (85%) patients in ETV group survived without liver transplantation (P = 0.251). After 4 weeks of NAs treatment, all three groups showed paralleling reduction of HBV DNA levels. All three groups presented similar biochemical responses at week 4, patients treated with TAF showed a priority in total bilirubin reduction, albumin and cholesterol maintenance. Additionally, although there was no significant difference in changes of serum urea, serum creatinine, serum cystatin C and estimated GFR among the three groups by treatment week 4, TDF showed unfavorable renal safety even in short -term treatment. The treatment using NAs was well-tolerated and there was no serious drug-related adverse event reported. Conclusions TAF, TDF and ETV are of similar efficacy and safety in short-term and long-term treatment of HBV-ACLF. Trial registration This study is ongoing and is registered with ClinicalTrials.gov, NCT03640728 (05/02/2019).

Clinical development of Hu5c8, a monoclonal antibody against CD40L intended for treatment of autoimmune disorders, was terminated due to unexpected thrombotic complications. These life-threatening side effects were not discovered during preclinical testing due to the lack of predictive models. In the present study, we describe the development of a microengineered system lined by human endothelium perfused with human whole blood, a "Vessel-Chip." The Vessel-Chip allowed us to evaluate key parameters in thrombosis, such as endothelial activation, platelet adhesion, platelet aggregation, fibrin clot formation, and thrombin anti-thrombin complexes in the Chip-effluent in response to Hu5c8 in the presence of soluble CD40L. Importantly, the observed prothrombotic effects were not observed with Hu5c8-IgG2σ designed with an Fc domain that does not bind the FcγRIIa receptor, suggesting that this approach may have a low potential risk for thrombosis. Our results demonstrate the translational potential of Organs-on-Chips, as advanced microengineered systems to better predict human response.

BackgroundThere is lack of clinical evidence supporting the value of the Kyoto classification of gastritis for the diagnosis of Helicobacter pylori (H. pylori) infection in Chinese patients, and there aren’t enough specific features for the endoscopic diagnosis of past infections, which is of special significance for the prevention of early gastric cancer (GC).MethodsThis was a prospective and multicenter study with 650 Chinese patients. The H. pylori status and gastric mucosal features, including 17 characteristics based on the Kyoto classification and two newly-defined features unclear atrophy boundary (UAB) and RAC reappearance in atrophic mucosa (RAC reappearance) were recorded in a blind fashion. The clinical characteristics of the subjects were analyzed, and the diagnostic odds ratio (DOR), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the receiver operating characteristics curve (ROC/AUC), and 95% confidence intervals were calculated for the different features, individually, and in combination.ResultsFor past infection, the DOR of UAB was 7.69 (95%CI:3.11−19.1), second only to map-like redness (7.78 (95%CI: 3.43−17.7)). RAC reappearance showed the highest ROC/AUC (0.583). In cases in which at least one of these three specific features of past infection was considered positive, the ROC/AUC reached 0.643. For current infection, nodularity showed the highest DOR (11.7 (95%CI: 2.65−51.2)), followed by diffuse redness (10.5 (95%CI: 4.87−22.6)). Mucosal swelling showed the highest ROC/AUC (0.726). Regular arrangement of collecting venules (RAC) was specific for no infection.ConclusionsThis study provides evidence of the clinical accuracy and robustness of the Kyoto classification of gastritis for the diagnosis of H. pylori in Chinese patients, and confirms UAB and RAC reappearance partly supplement it for the diagnosis of past infections, which is of great benefit to the early prevention of GC.

Background A series of evidence revealed that body mass index was an important confounding factor in the research of uric acid and ischemic heart disease/hypertension. The objective of this study was to investigate whether obesity status can modify the association between serum uric acid and the severity of liver damage in NAFLD, and the possible interactive effect of hyperuricemia and obesity. Methods We conducted a cross-sectional study in a total of 557 ultrasound diagnosed-NAFLD. The hepatic steatosis and liver fibrosis were quantitatively evaluated by transient elastography. Hyperuricemia was defined as serum uric acid > 420 μmol/L in men, > 360 μmol/L in women and obesity was defined as body mass index ≥ 25 kg/m2. The adjusted OR values of hyperuricemia and obesity were analyzed by multivariate logistic regression analysis, and the additive model was used to investigate the possible interactive effect. Results Multivariate regression analysis showed that hyperuricemia was associated with serious hepatic steatosis (1.74[1.09–2.79]) and elevated ALT (2.17[1.38–3.41]), but not with advanced fibrosis (1.61[0.91–2.85]). The association was further investigated in different BMI group. Hyperuricemia was associated with higher odds of serious hepatic steatosis (2.02[1.14–3.57]) and elevated ALT (2.27[1.37–3.76]) only in obese NAFLD, not in non-obese subjects. Similarly, patients with hyperuricemia had higher odds of advanced fibrosis in obese subjects (2.17[1.13–4.18]), not in non-obese subjects (0.60[0.14–2.70]). Furthermore, there was an additive interaction between hyperuricemia and obesity on the odds of serious hepatic steatosis (AP: 0.39[0.01–0.77]) and advanced fibrosis. (AP: 0.60[0.26–0.95]). Conclusions Hyperuricemia and obesity had a significantly synergistic effect on the hepatic steatosis and fibrosis. Thus, management of uric acid may need to be targeted in obese NAFLD.

Lysobacter enzymogenesOH11 is a non-flagellated, ubiquitous soil bacterium with broad-spectrum antifungal activities. Although lacking flagella, it employs another type of motile behavior, known as twitching motility that is powered by type IV pilus (T4P) to move towards neighboring crop fungal pathogens to kill them as food. At present, little is known about how this non-flagellated bacterium controls twitching motility that is crucial for its predatory lifestyle. Herein, we present a report on how a non-canonical PilZ domain, PilZLe3639, controls such motility in the non-flagellatedL. enzymogenes; it failed to bind with c-di-GMP but seemed to be required for twitching motility. Using bacterial two-hybrid and pull-down approaches, we identified PilBLe0708, one of the PilZLe3639-binding proteins that are essential for the bacterial twitching motility, could serve as an ATPase to supply energy for T4P extension. Through site-mutagenesis approaches, we identified one essential residue of PilZLe3639that is required for its binding affinity with PilBLe0708and its regulatory function. Besides, two critical residues within the ATPase catalytic domains of PilBLe0708were detected to be essential for regulating twitching behavior but not involved in binding with PilZLe3639. Overall, we illustrated that the PilZ-PilB complex formation is indispensable for twitching motility in a non-flagellated bacterium.

Kruppel-like factor 10 (KLF10) has been identified as an important regulator in carcinogenesis and cancer progression. However, the role of KLF10 in multiply myeloma (MM) development and progression remains unknown. In present study, we found that KLF10 mRNA and protein were down-regulated in MM tissues and cell lines. Notably, KLF10 inhibited cell proliferation, cell cycle progression and promoted apoptosis in vitro and in vivo. Furthermore, we confirmed that KLF10 inhibited β-catenin nuclear translocation and inhibited PTTG1 transcription. PTTG1 knockdown could mimic the biological effects of KLF10. Moreover, we demonstrated that KLF10 expression was regulated by miR-106b-5p. In MM tissues, miR-106b-5p has an inverse correlation with KLF10 expression. Conclusively, our results demonstrated that KLF10 functions as a tumor suppressor in regulating tumor growth of MM under regulation of miR-106b-5p, supporting its potential therapeutic target for MM.

Lysobacter enzymogenes (L. enzymogenes) is an agriculturally important Gram-negative bacterium that employs T4P (type IV pili)-driven twitching motility to exhibit its antifungal function. Yet, it is still unclear how this bacterium regulates its twitching motility. Here, by using strain OH11 as the working model organism, we showed that a hybrid two-component system ChpA acts as a positive regulator in controlling twitching motility in L. enzymogenes. ChpA is a hybrid TCS (two-component transduction system) contains 7 domains including those for auto-phosphorylation and phosphate group transfer, as well as a phosphate receiver (REC) domain. Mutation of chpA completely abolished the wild-type twitching motility, as evidenced by the absence of mobile cells at the margin of the mutant colonies. Further studies of domain-deletion and phenotypic characterization reveal that domains responsible for phosphorylation and phosphotransfer, but not the REC domain, were indispensable for ChpA in regulating twitching motility. Transcriptome analyses of the chpA knockout strain indicated that ChpA was extensively involved in controlling expression of a wide variety of genes (totaling 243). The products of these differentially expressed genes were involved in multiple physiological and biological functions in L. enzymogenes. Thus, we have not only identified a new regulator controlling twitching motility in L. enzymogenes, but also provided the first report demonstrating the broad impact of the conserved ChpA in gene regulation in Gram-negative bacteria.

Background To systematically review and assess the in vivo effectiveness and safety of probiotics for prophylaxis and treating oral candidiasis. Methods A literature search for studies published in English until August 1, 2018 was conducted in the following databases: PubMed, EMBASE, Cochrane Library, and Web of Science. Randomized controlled clinical trials and experimental mouse animal model studies comparing probiotics (at any dosage and in any form) with control groups (placebo, blank control or other agents) and reporting outcomes of the prophylactic and therapeutic effects were considered for inclusion. A descriptive study and, potentially, a meta-analysis were planned. Results Six randomized controlled clinical trials and 5 controlled experiments of mouse animal models were included in the systematic review. Four randomized controlled clinical trials comparing a probiotics group with a placebo/blank control group in 480 elderly and denture wearers were included in the meta-analysis. The overall combined odds ratio of the (random effects) meta-analysis was 0.24 (95% CI =0.09–0.63, P

Objective To examine potential risk factors associated with the success rate following fallopian tube recanalization (FTR) in infertile women with obstruction of the proximal fallopian tube. Methods We retrospectively studied patients who underwent FTR for tubal obstructive infertility between January 2016 and December 2018 at the Third Affiliated Hospital of Guangzhou Medical University. FTR was performed using a catheter and guidewire system to clear tubal obstruction. Predictive factors potentially associated with the success rate were assessed by logistic regression. Results A total of 762 patients were included. Multivariable analysis showed that age (odds ratio [OR] = 2.38, 95% confidence interval [CI]: 1.24–4.58), infertility type (OR = 2.82, 95% CI: 1.36–6.21), history of ectopic pregnancy (OR = 7.87, 95% CI: 4.05–15.81), history of abdominal surgery (OR = 4.30, 95% CI: 2.22–8.60), history of artificial abortion curettage (OR = 4.08, 95% CI: 2.12–8.03), and duration of infertility (OR = 2.03, 95% CI: 1.06–3.85) were independently associated with postoperative tubal patency. Conclusions Our findings suggest that risk factors, such as age ≥35 years, secondary infertility, duration of infertility ≥5 years, and histories of ectopic pregnancy, abdominal surgery, and artificial abortion curettage, affect the success rate of FTR. These factors may also predict surgical success in treating tubal obstructive infertility.