Targeting androgen receptor phase separation to overcome antiandrogen resistance.

Patients with castration-resistant prostate cancer inevitably acquire resistance to antiandrogen therapies in part because of androgen receptor (AR) mutations or splice variants enabling restored AR signaling. Here we show that ligand-activated AR can form transcriptionally active condensates. Both structured and unstructured regions of AR contribute to the effective phase separation of AR and disordered N-terminal domain plays a predominant role. AR liquid-liquid phase separation behaviors faithfully report transcriptional activity and antiandrogen efficacy. Antiandrogens can promote phase separation and transcriptional activity of AR-resistant mutants in a ligand-independent manner. We conducted a phase-separation-based phenotypic screen and identified ET516 that specifically disrupts AR condensates, effectively suppresses AR transcriptional activity and inhibits the proliferation and tumor growth of prostate cancer cells expressing AR-resistant mutants. Our results demonstrate liquid-liquid phase separation as an emerging mechanism underlying drug resistance and show that targeting phase separation may provide a feasible approach for drug discovery.

Genipin protects against acute liver injury by abrogating ferroptosis via modification of GPX4 and ALOX15-launched lipid peroxidation in mice.

It is essential to further characterize liver injury aimed at developing novel therapeutic approaches. This study investigated the mechanistic basis of genipin against carbon tetrachloride (CCl4)-triggered acute liver injury concerning ferroptosis, a novel discovered modality of regulated cell death. All experiments were performed using hepatotoxic models upon CCl4 exposure in mice and human hepatocytes in vitro. Immunohistochemistry, immunoblotting, molecular docking, RNA-sequencing and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were conducted. CCl4 intoxication was manifested with lipid peroxidation-dictated ferroptotic cell death, together with changes in a cascade of ferroptosis-associated events and several regulatory pathways. Both the administration of genipin and ferrostatin-1 (Fer-1) significantly prevented this hepatotoxicity in response to CCl4 intoxication via upregulating GPX4 and xCT (i.e., critical regulators of ferroptosis). RNA-sequencing unraveled that arachidonic acid metabolism was considerably influenced upon genipin treatment. Accordingly, genipin treatment attenuated arachidonate 15-lipoxygenase (ALOX15)-launched lipid peroxidation in terms of UHPLC-MS/MS analysis and inflammation. In vitro, genipin supplementation rescued erastin-induced hepatocellular inviability and lipid ROS accumulation. The siRNA knockdown of GPX4 partially abrogated the protective effects of genipin on erastin-induced cytotoxicity, whereas the cytotoxicity was less severe in the presence of diminished ALOX15 expression in L-O2 cells. In conclusion, our findings uncovered that genipin treatment protects against CCl4-triggered acute liver injury by abrogating hepatocyte ferroptosis, wherein the pharmacological modification of dysregulated GPX4 and ALOX15-launched lipid peroxidation was responsible for underlying medicinal effects as molecular basis.

Preliminary MRI Study of Extracellular Volume Fraction for Identification of Lymphovascular Space Invasion of Cervical Cancer.

BACKGROUND: Lymphovascular space invasion (LVSI) is a risk factor for poor prognosis of cervical cancer. Preoperative identification of LVSI is very difficult. PURPOSE: To evaluate the potential of extracellular volume (ECV) fraction based on T1 mapping in preoperative identification of LVSI in cervical cancer compared with dynamic contrast-enhanced MRI (DCE-MRI). STUDY TYPE: Retrospective. SUBJECTS: A total of 79 patients (median age 54 years) with cervical cancer were classified into LVSI group (n = 29) and without LVSI group (n = 50) according to postoperative pathology. FIELD STRENGTH/SEQUENCE: A 3-T, noncontrast and contrast-enhanced T1 mapping performed with volume interpolated breath hold examination (VIBE) sequence, DCE-MRI applied with 3D T1-weighted VIBE sequence. ASSESSMENT: Regions of interest along the medial edge of the lesion were drawn on slices depicting the maximum cross-section of the tumor. The noncontrast and contrast-enhanced T1 value of the tumor and arteries in the same slice were measured, and ECV was calculated from T1 values. The parametric maps (Ktrans , kep , and ve ) derived from DCE-MRI standard Toft's model were evaluated. STATISTICAL TESTS: ECV, Ktrans , kep , and ve between groups with and without LVSI were compared using Student's t-test. The receiver operating characteristic (ROC) curve and DeLong test were used to evaluate and compare the diagnostic performance of ECV, Ktrans , kep , and ve for differentiating LVSI. P < 0.05 was considered statistically significant. RESULTS: The ECV and Ktrans of the LVSI group were significantly higher than that of non-LVSI group (52.86% vs. 36.77%, 0.239 vs. 0.176, respectively), and no significant differences in Kep or ve values were observed (P = 0.071 and P = 0.168, respectively). The ECV fraction showed significantly higher area under ROC curve than Ktrans for differentiating LVSI (0.874 vs. 0.655, respectively). DATA CONCLUSION: ECV measurements based on T1 mapping might improve the discrimination between patients with and without LVSI in cervical cancer, showing better performance for this purpose than DCE-MRI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

The relationship between patient-reported health-related quality of life and malnutrition risk in cirrhosis: an observational cohort study.

Patients with cirrhosis experience worse health-related quality of life (HRQoL), and attempts are warranted further exploration of modifiable factors to improve HRQoL. Data on the impact of malnutrition risk on HRQoL among cirrhosis are limited; thus, we aimed to strengthen understanding by clarifying the relationship between nutritional status and low HRQoL in patients with decompensated cirrhosis. Consecutive inpatients with cirrhosis attending our department within a tertiary hospital were studied. Generic health profiles and malnutrition risk were evaluated by the EuroQol-5D (EQ-5D) and Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) score, respectively. Multiple linear regression analysis was used to determine association of malnutrition risk with low HRQoL. In this cohort of 364 patients with median age of 64 years and 49·5 % male, 55·5 % of the study population reported impairment pertinent to HRQoL in at least one dimension in terms of the EQ-5D. Moreover, malnutrition risk (RFH-NPT score: ß coefficient = -0·114, P = 0·038) was proved to be independently associated with poor HRQoL in multiple analysis, after adjustment for significant variables like age, BMI and markers of decompensation. Notably, we found that health dimensions representing physical function (i.e. mobility, self-care and usual activities) are substantially affected, while malnourished patients reported less frequencies of complaints in other domain such as anxiety/depression. In conclusion, the risk of malnutrition assessed by the RFH-NPT score is independently associated with low HRQoL. It is operational to improve HRQoL by identifying patients at high malnutrition risk and providing timely nutrition treatment.

Efficacy of endoscopic ultrasound and endoscopic resection for esophageal schwannoma.

BACKGROUND: Esophageal schwannoma (ES) is a rare submucosal tumor, and its complete and safe resection is a topic that deserves special attention. AIM: This study aimed to investigate the clinical value of endoscopic ultrasound (EUS) in the diagnosis of ES and the clinical efficacy of endoscopic resection for ES. METHODS: The clinical data, endoscopic characteristics, endoscopic treatment, postoperative complications, immunohistochemical results, and follow-up records of patients with ES admitted to the Tianjin Medical University General Hospital from January 2012 to January 2022 were retrospectively analyzed. RESULTS: Under white-light endoscopy, 81.8% (9/11) of lesions were submucosal elevations, covering the normal esophageal epithelium. Two of the lesions with redness and erosive surface. Eight lesions (72.7%) appear on EUS originating from the muscularis propria were homogeneous or inhomogeneous hypoechoic signals. Two lesions were inhomogeneous hyperechoic originating from the submucosa or muscularis propria, respectively. One lesion was homogeneous hypoechoic originating from the submucosa. All lesions had no blood flow signals, cystic changes, or calcification, and were completely removed by submucosal tunnel endoscopic resection (STER) or endoscopic submucosal dissection (ESD). All patients did not experience serious adverse events as well as recurrence, metastasis, or cicatricial esophageal stenosis during the follow-up period. CONCLUSION: ES is a rare submucosal lesion, which endoscopic characteristics are difficult to distinguish from other esophageal submucosal tumors. Endoscopic resection can provide a minimally invasive and alternative treatment for ES.

Coexistent GLIM-Defined Malnutrition and Sarcopenia Increase the Long-Term Mortality Risk in Hospitalized Patients with Decompensated Cirrhosis.

INTRODUCTION: The synergistic impact of coexistent malnutrition and sarcopenia on morality in hospitalized patients with decompensated cirrhosis remains elusive. This prospective cohort study aimed to delineate the prevalence concerning coexistence of malnutrition and sarcopenia and the prognosticating role on long-term mortality among cirrhosis. METHODS: Adult cirrhotic patients with decompensated episodes between 2019 and 2021 were consecutively enrolled. Malnutrition and sarcopenia were diagnosed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and the European Working Group on Sarcopenia in Older People (EWGSOP2) algorithm, respectively. The entire cohort was divided into three groups: non-malnutrition and non-sarcopenia (NN), malnutrition or sarcopenia, and coexistent malnutrition and sarcopenia (MS). Log-rank test and multivariate Cox regression model were utilized to evaluate survival status and independent risk factors for mortality, respectively. RESULTS: Our findings indicated that malnutrition manifested in 44.6% of inpatients with decompensated cirrhosis, while sarcopenia presented in 16.4% of the entire cohort, indicative of a prevalence of 14.7% regarding coexistent malnutrition and sarcopenia. The Kaplan-Meier graphic demonstrated a significant difference regarding survival curves among the three groups, referring to the MS group presented with the lowest survival rate (log-rank test: p < 0.001). Moreover, coexistent malnutrition and sarcopenia were associated with nearly 4 times higher mortality risk (model 1: hazard ratio [HR] = 3.31, 95% confidence interval [CI]: 1.20-9.13, p = 0.020; model 2: HR = 4.34, 95% CI: 1.52-12.4, p = 0.006) in comparison with patients without any condition (NN group). CONCLUSIONS: Malnutrition and sarcopenia had superimposed negative impacts on inpatients with decompensated cirrhosis. It is imperative to identify this vulnerable subset to provide prompt therapeutic intervention for better prognosis.

Reduced muscle strength is closely linked to computed tomography-defined myosteatosis among inpatients with cirrhosis.

BACKGROUND: Myosteatosis indicates pathological fat infiltration in muscles and is regarded as a distinct disease from sarcopenia. This muscular condition exhibits a link to muscle fiber disarrangement coinciding with disrupted muscle contractility and weakened mechanical action, mirrored as decreased muscle quality. However, the relationship between handgrip strength (HGS) and computed tomography-defined myosteatosis among cirrhosis is unclear. We aimed to investigate the association between HGS and myosteatosis and determine gender-specific cutoffs regarding HGS to identify myosteatotic subjects. METHODS: We prospectively recruited 221 cirrhotic patients. The presence of myosteatosis was determined according to intramuscular adipose tissue content. The relationship between HGS and myosteatosis was evaluated according to Spearman correlation coefficient, area under the ROC curve, and multivariate logistic regression analysis. Moreover, a model based on the classification and regression tree method was generated. RESULTS: Our results showed that HGS exhibits modestly negative correlation with intramuscular adipose tissue content in the entire cohort (rs = -0.269, P < .001) and across diverse subgroups precluding extremely deteriorating conditions. After controlling for multiple clinical features and biochemical parameters, HGS (odds ratio = 0.921, P = .010) was independently associated with myosteatosis in addition to age and body mass index. On applying the Japan Society of Hepatology-recommended cutoffs, an area under the ROC curve of HGS was 0.627 with a sensitivity of 77.4% and a specificity of 47.9%. The decision tree including body mass index and low HGS correctly classified ~85% of the cases in development and validation sets. CONCLUSIONS: HGS was in close relation to myosteatosis among inpatients with cirrhosis.

The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties.

Fibronectin type III domain-containing protein 5 (FNDC5) is a transmembrane protein and the precursor of irisin, which serves as a systemic exerkine/myokine with multiple origins. Since its discovery in 2012, this hormone-like polypeptide has rapidly evolved to a component significantly involved in a gamut of metabolic dysregulations and various liver diseases. After a decade of extensive investigation on FNDC5/irisin, we are still surrounded by lots of open questions regarding its diagnostic and therapeutic values. In this review, we first concentrated on the structure-function relationship of FNDC5/irisin. Next, we comprehensively summarised the current knowledge and research findings regarding pathogenic roles/therapeutic applications of FNDC5/irisin in the context of non-alcoholic fatty liver disease, fibrosis, liver injury due to multiple detrimental insults, hepatic malignancy and intrahepatic cholestasis of pregnancy. Moreover, the prominent molecules involved in the underlying mechanisms and signalling pathways were highlighted. As a result, emerging evidence reveals FNDC5/irisin may act as a proxy for diagnosing liver disease pathology, a sensitive biomarker for assessing damage severity, a predisposing factor for surveilling illness progression and a treatment option with protective/preventive impact, all of which are highly dependent on disease grading and contextually pathological features.

Analysis of virulence genes, drug resistance detection, and pathogenicity in Enterococcus from farm animals.

This study aimed to investigate the presence of eight virulence genes (ace, asa1, esp, efaA, gelE, cylA, agg, fsr) in Enterococcus from a variety of animals and to explore the drug resistance and pathogenicity. This could provide a theoretical basis for clinical treatment of Enterococcus infections. Anal swabs from pigs, chickens, cattle, and dogs in farms and pet hospitals were collected for Enterococcus isolation and identification. Eight virulence genes were detected (PCR method), and drug resistance was assessed (drug-sensitive paper method). The strains containing different virulence genes were then divided into EV1, EV2, and EV3 groups. The LD50 and pathogenicity was examined by intra-peritoneal injection to infect mice. Differences were found in the detection rates of virulence genes in Enterococcus from the different animals. The highest overall detection rate was for the esp gene (78.0%), and the lowest for the cylA gene (15.5%). Eight genes were detected most frequently in Enterococcus from dogs and least frequently from cattle. Among the Enterococcus strains from four variety of animals, drug resistance was highest against sulfamethoxazole (100%), cefotaxime (>97%), and cefotaxitin (>93%). Drug resistance was lowest against vancomycin (0%), levofloxacin (<12%) and ciprofloxacin (<13%). The LD50 for each of the three groups was EV1LD50=8.71×109CFU， EV2LD50=2.34×1010CFU，and EV3LD50=9.33×1010CFU. The Enterococcus12LD50 dose group caused significant clinical symptoms in mice, with pathological effects on the heart, liver, lungs, and kidneys, and particularly on the urinary system. The abundance of Enterococcus virulence genes, drug resistance, and pathogenicity vary among different animal origins, and the pathology caused by Enterococcus requires effective treatment protocols based on species and regional characteristics.

Role of endoscopic ultrasound and endoscopic resection in the diagnosis and treatment of esophageal granular cell tumors.

BACKGROUND AND AIM: Diagnosis and complete resection of esophageal granular cell tumors (GCTs) is an area of concern. However, articles on endoscopic ultrasound (EUS) and endoscopic resection of esophageal granular cell tumors are few. To evaluate the role of endoscopic ultrasound and endoscopic resection in the diagnosis and treatment of esophageal granular cell tumors. METHODS: A retrospective analysis of 15 patients with esophageal granular cell tumors who underwent endoscopic ultrasound examination and endoscopic resection in our hospital was conducted. The clinical data, endoscopic ultrasound images, endoscopic treatment, pathological characteristics, postoperative complications and follow-up status of all patients were evaluated. Ten board-certified endoscopists independently evaluated the white light endoscopic images of the 15 patients (Test 1) and the endoscopic ultrasound images together with white light endoscopic images of the same patient set (Test 2). RESULT: Female patients accounted for 53.4% of the participants. The average age at the time of diagnosis was 49.13 ± 9.31 years old. Ten lesions (66.67%) showed hypoechoic signal, four lesions (26.67%) showed hyperechoic signal and one lesion showed medium signal. The diagnostic accuracy was significantly higher with Test 2(65.3% vs. 92.0%, p < .001). Complete endoscopic resection was performed in all the patients. No complications occurred in any of the patients. No esophageal stenosis, recurrence, or metastases was found in all patients during the follow-up period. CONCLUSION: The endoscopic ultrasound images of esophageal granular cell tumors have certain characteristics that help diagnose esophageal granular cell tumors. Endoscopic resection of esophageal granular cell tumors is an effective, safe and feasible treatment method.

Anatomical correlation between left atrium pulmonary vein ablation targets of atrial fibrillation and adjacent bronchi and pulmonary arteries by MSCT.

BACKGROUND: The ablation targets of atrial fibrillation (AF) are adjacent to bronchi and pulmonary arteries (PAs). We used computed tomography (CT) to evaluate the anatomical correlation between left atrium (LA)-pulmonary vein (PV) and adjacent structures. METHODS: Data were collected from 126 consecutive patients using coronary artery CT angiography. The LA roof was divided into three layers and nine points. The minimal spatial distances from the nine points and four PV orifices to the adjacent bronchi and PAs were measured. The distances from the PV orifices to the nearest contact points of the PVs, bronchi, and PAs were measured. RESULTS: The anterior points of the LA roof were farther to the bronchi than the middle or posterior points. The distances from the nine points to the PAs were shorter than those to the bronchi (5.19 ± 3.33 mm vs 8.62 ± 3.07 mm; P < .001). The bilateral superior PV orifices, especially the right superior PV orifices were closer to the PAs than the inferior PV orifices (left superior PV: 7.59 ± 4.14 mm; right superior PV: 4.43 ± 2.51 mm; left inferior PV: 24.74 ± 5.26 mm; right inferior PV: 22.33 ± 4.75 mm) (P < .001). CONCLUSIONS: The right superior PV orifices were closer to the bronchi and PAs than other PV orifices. The ablation at the mid-posterior LA roof had a higher possibility to damage bronchi. CT is a feasible method to assess the anatomical adjacency in vivo, which might provide guidance for AF ablation.

Scoparone as a therapeutic drug in liver diseases: Pharmacology, pharmacokinetics and molecular mechanisms of action.

Scoparone is an active and efficious ingredient of herbal medicine Artemisia capillaris Thunb, which has been used clinically in traditional Chinese medicine formula (e.g. Yin-Chen-Hao decoction) for the treatment of hepatic dysfunction, cholestasis and jaundice for over thousand years. More recently, scoparone has received increasing attention due to its multiple properties. In this comprehensive review, we provide the first summary of the pharmacological effects and pharmacokinetic characteristics of scoparone, and discuss future research prospects. The results implicated that scoparone possesses a wide spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, anti-fibrotic and hypolipidemic properties. Pharmacokinetic studies have addressed that isoscopoletin and scopoletin are major primary metabolites of scoparone. Moreover, hepatic dysfunction might promote bioavailability of scoparone due to limited intrinsic clearance. On the other hand, the bioavailability of multi-component including scoparone in certain TCM formula can also be enhanced by applying this formula at a high dose on account of their interacted effects. In view of good pharmacological actions, scoparone is anticipated to be a potential drug candidate for various liver diseases, such as acute liver injury, fulminant hepatitis, alcohol-induced hepatotoxicity, non-alcoholic fatty liver disease and fibrosis. However, further studies are warranted to clarify its molecular mechanisms and targets, elucidate its toxicity, and identify its interplay with other active ingredients of classical TCM formula in clinical settings.

Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe.

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

Prognostic impact of neutrophil-to-lymphocyte ratio in cirrhosis: A propensity score matching analysis with a prespecified cut-point.

BACKGROUND & AIMS: An elevated neutrophil-to-lymphocyte ratio (NLR) has received attention as a prognostic surrogate across chronic liver diseases. However, an exact threshold has not been fully elucidated. METHODS: A total number of 589 patients with cirrhosis (LC) were included. The value of NLR was calculated and its optimal cut-off was initially determined by X-tile program. Independent predictors of 90-day mortality were identified with Cox regression model. The Kaplan-Meier method was used to generate survival curves. To reduce influences of selection bias and possible confounders, a 1:2 propensity score matching (PSM) was performed. RESULTS: The X-tile indicated that the difference in survival was most significant for NLR more than 8.9. Serum NLR > 8.9 was an independent indicator in the entire cohort and PSM subset (HR 4.268, 95% CI 2.211-8.238, P < .001; HR 4.209, 95% CI 1.448-12.238, P = .008 respectively). Subgroup analysis showed that NLR > 8.9 was an independent risk factor of 90-day mortality regardless of age, gender, CTP or MELD score. CONCLUSIONS: The value of NLR more than 8.9 is a feasible cut-off across clinical settings among applicable population. The adding of NLR to other conventional predictive systems has the potential to provide incremental value without extra economic cost.

Peroral endoscopic myotomy versus pneumatic dilation - result from a retrospective study with 1-year follow-up.

BACKGROUND AND AIMS: On the basis of lesser rates of major adverse events and a short-term efficacy as Heller's myotomy, there is a growing enthusiasm in favor of peroral endoscopic myotomy (POEM), whereas study comparing POEM and pneumatic dilatation (PD) is quite rare. The aim of this study was to evaluate the efficacy of POEM and PD in Chinese achalasia patients in a retrospectively designed study. METHODS: Patients with achalasia, who underwent either PD (n = 26) or POEM (n = 40) were retrospectively recruited from September 2010 through March 2016 at a single tertiary center. During the 1-year follow-up, clinical outcome and functional data of lower esophageal sphincter (LES) were recruited. Clinical symptoms were assessed by use of the Eckardt score. The primary outcome was therapeutic success (Eckardt score ≤ 3). Functional data of LES (4-second integrated relaxation pressure [4s-IRP], LES relax rate, and LESP) at baseline and 1 month after treatment were also evaluated. Data was analyzed by SPSS 13.0 version using a significance level of p < 0.05. RESULTS: The success rates were 24/26 (92.31 %), 25/26 (96.15 %), and 24/26 (92.31 %), respectively, with POEM, as compared with 35/40 (87.50 %), 29/40 (72.50 %), and 23/40 (57.50 %), respectively, with PD, 1 month, 3 months, and 1 year after treatment. Statistically significant difference was observed between the 2 therapies (at 3 months, Fisher's exact test, p = 0.01; at 1 year, Fisher's exact test, p < 0.0001). Compared with PD, the Eckardt score was lower with POEM 1 month, 3 months, and 1 year after treatment. More patients in POEM group reported gastroesophageal reflux symptoms (after 3 months 7/26 (26.92 %) vs. 2/40 (5.00 %), Fisher's exact test, p = 0.01; after 1 year 6/26 (19.23 %) vs. 1/35 (2.86 %), Fisher's exact test, p = 0.02). The postoperative 4s-IRP and LESP were both lower with POEM than with PD, respectively. Type I achalasia had a better response with POEM than with PD. CONCLUSION: In this retrospective analysis with 1-year follow-up, POEM presents with a higher success rate and more reflux symptoms compared with PD. Change on LES function after treatment may explain the outcome in part. Type I achalasia may respond better to therapies compared with type II.

[Analysis of anti-fatigue mechanism and potential targets of ginseng].

Ginseng has effects in reinforcing vital energy,invigorating health effectively and relieving fatigue symptoms,and ginsenoside( GS) is the main component of its anti-fatigue effect. Totally 17 active components and 92 drug targets of ginseng compounds were screened from Traditional Chinese Medicine Systems Pharmacology; and 78 intersecting genes of diseases and drug targets were obtained based on R Language Technology. The protein-protein interaction( PPI) network was constructed by STRING 11. 0 software,and Matthews Correlation Coefficient( MCC) algorithm was used to screen core target genes. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were used to analyze the major genes and their roles in regulatory networks. The results indicated that ginseng could regulate the core target genes,including AKT serine/threonine kinase( AKT1),interleukin-1ß,Toll-like receptor binding molecule 1( ICAM1),mitogen-activated protein kinase 8( MAPK8),AP-1 transcription factor subunit( JUN),transducer and activator of transcription 1( STAT1) and prostaglandin peroxidase synthase 2( PTGS2). It could participate in the functions of cytokine receptor binding,cell adhesion molecule binding and tumor necrosis factor receptor superfamily binding,and also regulate the signal pathways of tumor necrosis factor,interleukin 17 and c-type lectin receptor,so as to exert an anti-fatigue effect. Based on the results of network analysis,32 four-week-old male SPFACR mice were randomly divided into control group,low-dose ginsenoside group,middle-dose ginsenoside group and high-dose ginsenoside group. The corresponding drugs were administrated for 3 weeks. The results showed that GS could significantly up-regulate the expressions of STAT1 and AKT1( P<0. 01,P<0. 05),and downregulate the expressions of PTGS2 and JUN( P<0. 01). However,there was no significant effect on MAPK8,IL-1ß and ICAM1. Ginseng's anti-fatigue regulation network was constructed through network pharmacology,and the results were verified by experiments,in order to reveal the anti-fatigue mechanism of ginseng and provide scientific basis for its clinical application.

Multiplex detection of microRNAs by combining molecular beacon probes with T7 exonuclease-assisted cyclic amplification reaction.

A simple, highly sensitive, and specific assay was developed for the homogeneous and multiplex detection of microRNAs (miRNAs) by combining molecular beacon (MB) probes and T7 exonuclease-assisted cyclic amplification. An MB probe with five base pairs in the stem region without special modification can effectively prevent the digestion by T7 exonuclease. Only in the presence of target miRNA is the MB probe hybridized with the target miRNA, and then digested by T7 exonuclease in the 5' to 3' direction. At the same time, the target miRNA is released and subsequently initiates the nuclease-assisted cyclic digestion process, generating enhanced fluorescence signal significantly. The results show that the combination of T7 exonuclease-assisted cyclic amplification reaction and MB probe possesses higher sensitivity for miRNA detection. Moreover, multiplex detection of miRNAs was successfully achieved by designing two MB probes labeled with FAM and Cy3, respectively. As a result, the method opens a new pathway for the sensitive and multiplex detection of miRNAs as well as clinical diagnosis. Graphical Abstract A simple, highly sensitive, and specific assay was developed for the detection of microRNAs by combining molecular beacon probes with T7 exonuclease-assisted cyclic amplification reaction.

Three robust Cd(II) coordination polymers as bifunctional luminescent probes for efficient detection of pefloxacin and Cr2O72- in water.

The accurate and rapid detection of antibiotics and heavy-metal-based toxic oxo-anions in water media employing coordination polymers (CPs) as luminescent probes has attracted a lot of attention. Three new Cd(II)-based ternary CPs derived from first-presented L ligands, including [Cd(DCTP)(L)(OH)]n (1), [Cd(TBTA)(L)(OH)]n (2), and [Cd(NPHT)(L)(H2O)]n (3) (L = 2-((1H-imidazol-1-yl)methyl)-5,6-dimethyl-1H-benzo[d]imidazole, H2DCTP = 2,5-dichloroterephthalic acid, H2TBTA = tetrabromoterephthalic acid and H2NPHT = 3-nitrophthalic acid), were successfully assembled and characterized. 1 and 2 show 2D hcb layers, which can be further extended into a 3D supramolecular framework via classic hydrogen bonding interactions. 3 features a 1D double chain that ultimately spreads into a 2D network through weak hydrogen bonding interactions. With the advantages of high stability and excellent luminescent properties, the three CPs display high sensitivity, selectivity, and good anti-interference for the sensing of pefloxacin (PEF) and Cr2O72- ions (LOD values toward PEF: 3.82 × 10-7 mol L-1 for 1, 4.06 × 10-7 mol L-1 for 2, and 1.36 × 10-8 mol L-1 for 3, and toward Cr2O72- ions: 5.97 × 10-7 mol L-1 for 1, 5.87 × 10-7 mol L-1 for 2, and 8.21 × 10-8 mol L-1 for 3). These CPs are the first examples of bifunctional luminescent sensors to detect PEF and Cr2O72- in aqueous solutions. The luminescence quenching mechanisms are explored in detail.

Health-related quality of life and frailty in liver cirrhosis.

BACKGROUND AND OBJECTIVES: There is limited evidence concerning the predictive value of health-related quality of life (HRQoL) on the presence of frailty in the context of cirrhosis. We aimed to elucidate the relationship between HRQoL and multidimensional frailty and to determine which HRQoL dimension independently impacted frail phenotype in our established cohort. METHODS: This was a prospective observational study by consecutively enrolling 355 patients with cirrhotic with decompensated signs in China. The HRQoL and frail phenotype were evaluated by the EuroQol-5D (EQ-5D) Questionnaire and Frailty Index, respectively. The relationship between EQ-5D utility index, as well as respective EQ-5D dimension, and Frailty Index was analysed according to the multiple linear regression analyses. RESULTS: More than half of the patients (56.3%) reported problems in any dimension of the EQ-5D, suggestive of impaired HRQoL. Moreover, the proportion of patients experiencing some/extreme problems significantly increased across all five dimensions (all p<0.001) in correspondence to transition from the robust to frail phenotype. Multiple linear regression analyses demonstrated that age, ascites and hepatic encephalopathy were positively associated with Frailty Index, while EQ-5D utility index (standardised ß coefficient= -0.442, p<0.001) negatively associated with Frailty Index. Notably, usual activities, self-care and mobility were the most influencing predictors associated with frailty. CONCLUSIONS: Our results support a rapid HRQoL assessment via EQ-5D may assist in predicting multidimensional frailty, and usual activities, self-care and mobility tend to be remediable targets while taking their effect on frail phenotype into consideration among patients with cirrhosis.

Association Between Quality of Life Defined by EuroQol Group 5 Dimension and Composite Inferior Outcome Among Inpatients with Cirrhosis.

Purpose: The utility of the EuroQol Group 5 Dimension (EQ-5D) measuring health-related quality of life (HRQoL) has been verified; however, knowledge gaps remain concerning predictive performance in cirrhosis. We aimed to identify the optimal threshold for risk stratification and the pronounced domain in the EQ-5D linked to inferior outcomes. Patients and Methods: The X-tile project was used to obtain a threshold, considering the composite outcome of 1-year all-cause mortality or readmission. A restricted cubic spline (RCS) was performed to test the non-linear relationship between the EQ-5D utility value and the primary outcome. Six multivariate Cox regression models incorporating EQ-5D utility value and each of the five domains were constructed. Setting/Participants: Totally, 420 patients with cirrhosis were recruited. Results: The median utility value of the study population was 0.77 and 59.8% reported impairment in minimal one EQ-5D domain. RCS indicated a linear relationship between the utility value and composite inferior outcome. X-tile pinpointed a utility value of 0.59 stratifying populations into high- and low-risk groups based on the outcome. Inpatients with cirrhosis and deteriorated HRQoL (utility value ≤0.59) were at higher risk of death or readmission (adjusted HR: 2.18, P < 0.001). Furthermore, mobility and usual activities were the most pronounced domains associated with composite inferior outcome. Conclusion: A utility value ≤0.59 can identify cirrhotic inpatients exhibiting compromised HRQoL and mortality/readmission risk. It is tempting to reverse the decreased HRQoL by applying longitudinal measurements and keeping surveillance on utility value, while interventions appear to mainly focus on improving mobility and usual activities.