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Gong Feng,1 Wu-Bin Shu,2 A-Bing Li2 1School of Medicine, Ningbo University, Ningbo, Zhejiang, 315211, People’s Republic of China; 2Department of Orthopedics, Ningbo Yinzhou Second Hospital, Ningbo, 315100, Zhejiang, People’s Republic of ChinaCorrespondence: A-Bing LiDepartment of Orthopedics, Ningbo Yinzhou Second Hospital, Ningbo, Zhejiang, 315100, People’s Republic of ChinaTel +86-15088557621Email bing19890807@hotmail.comBackground: The aim of the study was to develop a nomogram to predict the overall survival (OS) of patients with solitary plasmacytoma of bone (SBP).Materials and Methods: Patients diagnosed with SBP between 1993 and 2012 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. All eligible patients were randomly allocated to the training sets and the validation sets. The nomogram was developed with the training set and validated with the validation set using the concordance index (C-index), calibration plots, and decision curve analyses (DCA).Results: Age, marital status, tumor grade, treatment were independent prognostic indicators for OS (P< 0.05) and were integrated to construct the nomogram. C-indexes for OS prediction in the training and validation sets were 0.78 and 0.73, respectively. The calibration plots demonstrated good consistency between the predicted and actual survival. DCA demonstrated that the new model has great benefits. In the total cohort, the median OS of patients in the low- and high-risk groups were 12.17 (95% CI 11.92– 12.42) and 3.92 (95% CI 2.83– 5.01) years, respectively.Conclusion: The nomogram showed excellent applicability and accuracy, which could be a reliable tool for predicting OS in SBP patients.Keywords: solitary bone plasmacytoma, cancer risk factors, SEER, nomogram

Background Bone tissue engineering (BTE) is considered a promising technology for repairing bone defects. Mg2+ promotes osteogenesis, which makes Mg-based scaffolds popular for research on orthopedic implant materials. Angiogenesis plays an important role in the process of bone tissue repair and regeneration, and it is one of the important problems in BTE urgently needs to be solved. Methods Mg was firstly coated with Ca-deficient hydroxyapatite (CDHA) via hydrothermal treatment, and polydopamine (DOPA) was then used as the connecting medium to immobilize vascular endothelial growth factor (VEGF) on the CDHA coating. The physicochemical properties of the coatings were characterized by SEM, EDS, XPS, FTIR and immersion experiment in SBF. The ahesion, proliferation, and angiogenesis potential of the coatings were determined in vitro. Results The composite coating significantly improved the corrosion resistance of Mg and prohibited excessively high local alkalinity. VEGF could be firmly immobilized on Mg via polydopamine. The CCK-8, live/dead staining and adhesion test results showed that the VEGF-DOPA-CDHA coating exhibited excellent biocompatibility and could significantly improve the adhesion and proliferation of MC3T3-E1 cells on Mg. Microtubule formation, immunofluorescence and Quantitative Real-Time PCR (qRT-PCR) experiments showed that VEGF immobilized on Mg still possessed bioactivity in promoting the differentiation of rat mesenchymal stem cells into endothelial cells. Conclusion In this study, we enabled the angiogenic biological activity of Mg by immobilizing VEGF on Mg. Mg was successfully coated with a functional VEGF-DOPA-CDHA composite coating. The CDHA coating significantly increased the corrosion resistance of Mg and prohibited the negative effect of excessively high local alkalinity on the biological activity of VEGF. As an intermediate layer, the DOPA coating protects Mg, and DOPA provides a binding site for VEGF so that VEGF can be firmly immobilized on Mg and give Mg angiogenic bioactivity during the initial period of implantation. The translational potential of this article The treatment of large bone defect is still one of the orthopedic trauma diseases that are difficult to be completely treated in clinic. The development of tissue engineering technology provides a new option for the treatment of large bone defects. The regeneration of blood vessels is of great significance for the repair of bone defects. In this study, VEGF was connected on the surface of degradable magnesium by covalent bonding. Vascular biofunctionalized magnesium scaffolds are expected to regenerate bone tissue with blood transport and be used in the clinical treatment of large bone defects.

The hepatitis B virus X protein (HBx) is involved in the process of hepatocellular carcinoma via the activation of various oncogenes. Our previous study indicated that ARBB1 (arrestin beta 1) promotes hepatocellular carcinogenesis (HCC). However, the role of ARRB1 in HBx-related HCC remains unclear. Herein, we identified that ARRB1 was upregulated by HBx in vivo and in vitro. Arrb1 deficiency suppressed HBx-induced hepatocellular carcinogenesis in several mouse models. Furthermore, knockdown of ARRB1 blocked HBx-induced macroautophagic/autophagic flux and disrupted the formation of autophagosomes. ARRB1 interacted with HBx, and the autophagic core protein MAP1LC3/LC3, a scaffolding protein, was essential for complete autophagy. Inhibition of autophagy by 3-methyladenine or interference of ATG5 or ATG7 attenuated HBx-induced cell cycle acceleration and the subsequent proliferative response via the induction of G1/S arrest. The absence of autophagy abolished the phosphorylation of CDK2 and the activity of the CDK2-CCNE1 complex. Our results demonstrate that ARRB1 plays a critical role in HBV-related HCC via modulating autophagy and the CDKN1B-CDK2-CCNE1-E2F1 axis and indicate that ARRB1 may be a potential therapeutic target for HCC.

Background Only a small proportion of patients with compensated advanced chronic liver disease (cACLD) had varices needing treatment (VNT) after recommended esophagogastroduodenoscopy (EGD) screening. We aimed to create a non-invasive nomogram based on routine tests to detect VNT in cACLD patients. Methods The training cohort included 162 cACLD patients undergoing EGD in a university hospital, between January 2014 and September 2019. A nomogram was developed based on the independent predictors of VNT, selected using a multivariate logistic regression analysis. Thirty-three patients from eight university hospitals were prospectively enrolled as validation cohort between December 2018 and December 2019. Results The prevalence of VNT was 32.7% (53/162) and 39.4% (13/33) in training and validation cohorts, respectively. The univariate analysis identified six risk factors for VNT. On the multivariate analysis, four of them, i.e., gallbladder wall thickness (odds ratio [OR]: 1.23; 95% confidence interval [CI]: 0.98-1.56), spleen diameter (OR: 1.02; 95% CI: 1.00-1.04), platelet count (OR: 0.98; 95% CI: 0.97-0.99), and international normalized ratio (OR: 0.58; 95% CI: 0.06-5.84) were independently associated with VNT. Thus, a nomogram based on the four above - mentioned variables was developed, and showed a favorable performance for detecting VNT, with an area under receiver operating characteristic curve of 0.848 (95% CI: 0.769-0.927) in training cohort. By applying a cut-off value of 105 in validation cohort, 31.0% of EGD were safely spared with 3.4% of missed VNT. Conclusion A nomogram based on routine clinical parameters was developed for detecting VNT and avoiding unnecessary EGD in cACLD patients.

Hepatic ischemia-reperfusion injury (IRI) remains a common complication during liver transplantation (LT), partial hepatectomy and hemorrhagic shock in patients. As a member of the G protein-coupled receptors adaptors, ARRB2 has been reported to be involved in a variety of physiological and pathological processes. However, whether β-arrestin-2 affects the pathogenesis of hepatic IRI remains unknown. The goal of the present study was to determine whether ARRB2 protects against hepatic IR injury and elucidate the underlying mechanisms. To this end, 70% hepatic IR models were established in ARRB2 knockdown mice and wild-type littermates, with blood and liver samples collected at 1, 6 and 12 h after reperfusion to evaluate liver injury. The effect of ARBB2 on PI3K/Akt signaling during IR injury was evaluated in vivo, and PI3K/Akt pathway regulation by ARRB2 was further assessed in vitro. Our results showed that ARRB2 knockdown aggravates hepatic IR injury by promoting the apoptosis of hepatocytes and inhibiting their proliferation. In addition, ARRB2 deficiency inhibited PI3K/Akt pathway activation, while the administration of the PI3K/Akt inhibitor PX866 resulted in severe IR injury in mice. Furthermore, the liver-protecting effect of ARRB2 was shown to depend on PI3K/Akt pathway activation. In summary, our results suggest that β-Arrestin-2 protects against hepatic IRI by activating PI3K/Akt signaling, which may provide a novel therapeutic strategy for treating liver ischemia-reperfusion injury.

BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is a malignant disease worldwide. It is implicated in high cancer-related mortality rates in humans. β-Arrestin1 (ARRB1) has been demonstrated to be related to the development of several cancers, while the relationship between ARRB1 and metastasis in HCC is unknown. METHODS A tissue microarray of 68 tissues from HCC patients with or without metastasis was collected. Wild-type and ARRB1 knockout mice were used to examine the role of ARRB1 in metastasis in vivo. The level of ARRB1 in HCC tissues, mouse liver tissues, and cell lines was determined by quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry. Migration, invasion, and motility capacities of HCC cells were determined by transwell assay and wound healing assay. Vein injection of nude mice model was used to reveal the metastatic abilities of HCC cell lines. For the mechanism study, we investigated the effects of ARRB1 on the phosphorylation of ERK1/2 and the expression of epithelial-mesenchymal transition (EMT) markers in HCC. RESULTS We reveal that ARRB1 accelerates metastasis in HCC and that ARRB1 deficiency inhibits hepatocarcinogenesis and reverses EMT in mice. ARRB1 regulates HCC cell migration and invasion and suppresses HCC metastasis in vivo. Furthermore, we show that ARRB1 promotes EMT through the phosphorylation of ERK1/2. CONCLUSIONS Our data suggest that ARRB1 promotes HCC invasion and metastasis through p-ERK1/2-mediated EMT and that suppression of ARRB1 or p-ERK1/2 may offer potential therapeutic targets for HCC therapy.

Background and purpose Liver fibrosis is a serious cause of morbidity and mortality worldwide and has no adequate treatment. Accumulating evidence suggests that cannabinoid CB1 receptors regulate a variety of physiological and pathological processes in the liver, and blockage of CB1 receptor signalling shows promise as a new therapy for several liver diseases. The aim of this study was to investigate the potential therapeutic effects of CB1 receptors and a peripheral CB1 receptor antagonist JD5037 in liver fibrogenesis. Experimental approach Liver samples from both humans and mouse models were investigated. The peripheral CB1 receptor antagonist JD5037, β-arr1 wild type (β-arr1-WT) and β-arr1 knockout (β-arr1-KO) littermate models, and primary hepatic stellate cells (HSCs) were also used. The mechanisms underlying CB1 receptor-regulated HSCs activation in fibrosis and the therapeutic potential of JD5037 were further analysed. Key results CB1 receptors were induced in samples from patients with liver fibrosis and from mouse models. These receptors promoted activation of HSCs in liver fibrosis via recruiting β-arrestin1 and Akt signalling, while blockage of CB1 receptors with JD5037 attenuated CB1 receptor-regulated HSCs activation and liver fibrosis by suppressing β-arrestin1/Akt signalling. Conclusions and implications CB1 receptors promote the activation of HSCs and liver fibrosis via the β-arrestin1/Akt signalling pathway. The peripheral CB1 receptor antagonist JD5037 blocked this pathway, the activation of HSCs and liver fibrosis. This compound and the associated pathway may be a novel approach to the treatment of liver fibrosis.

Ferroptosis has recently emerged as an iron-dependent form of nonapoptotic cell death, which is also a regulated necrosis process and a response to tumor suppression. However, whether ferroptosis is involved in ulcerative colitis (UC) is unknown. The aims of this study were to investigate whether the ferroptosis is involved in UC, particularly intestinal epithelial cell (IEC) death, and to analyze the effect of the nuclear factor kappa Bp65 subunit (NF-κBp65) on ferroptosis. The gene expression of ferroptosis-related proteins was assessed in intestinal mucosal samples from human UC. The experimental model of UC was induced with dextran sulfate sodium (DSS). Ferroptosis of IECs was evaluated, the effect of NF-κBp65 on ferroptosis was analyzed by using IEC-specific NF-κBp65-deleted mice (p65IEC-KO), and the ferroptosis signaling pathway was investigated in vitro and in vivo. The results showed that ferroptosis was significantly induced in the IECs from UC patients and mice with colitis, and the ferroptosis was mediated by endoplasmic reticulum (ER) stress signaling. The specific deletion of IEC NF-κBp65 clearly upregulated ferroptosis and exacerbated colitis, and the result showed that phosphorylated-NF-κBp65 significantly inhibited ER stress signaling by directly binding eukaryotic initiation factor 2α. These data indicate that ferroptosis contributes to UC via ER stress-mediated IEC cell death, and that NF-κBp65 phosphorylation suppresses ER stress-mediated IEC ferroptosis to alleviate UC. The results suggest that ferroptosis involves in IEC death in UC, NF-κBp65 play a critical role in the ferroptotic inhibition, and ferroptosis is a potential therapeutic target for UC.

Background Prescribing errors may, influenced by some risk factors, cause adverse drug events. Most studies in this field focus on errors in prescriptions for hospital inpatients, with only a few on those for outpatients. Our study aimed to explore the incidence of prescribing errors in electronic prescriptions and illustrate the trend of prescribing workload and error rate over time. Methods The cross-section study was performed between September, 2015 and November, 2015. Prescribing errors were intercepted by pharmacists using a prescription reviewing system under which prescriptions with errors were transferred to a specific computer and recorded by another pharmacist and the incidence of total prescribing errors and severe errors was then calculated. A subgroup analysis was conducted in accordance to the number of drug orders, the age group of patients, the seniority of physicians, the specialty of physicians, the working day when prescriptions were issued, and the prescribing workload of physicians. A time-series analysis was employed to analyze the trend of prescribing workload and error rate, and the correlation between them. Results Totally, 65,407 patients were included in this study and 150,611 prescriptions with 294,564 drug orders (including 584 different drugs) were reviewed for identification of errors. A total of 534 prescribing errors (an error rate of 0.34%) were identified. Severe errors accounted for 13.62% of total errors. The subgroup analysis showed prescriptions of multiple drug orders, for pediatric patients aged 29 days to 12 years, from physicians specializing in ophthalmology and otorhinolaryngology, or prescribing on weekdays were more susceptible to errors. A time-series analysis demonstrated no correlation between prescribing workload and error rate which increased at the end of each working shift while prescribing workload decreased. Conclusion Less than 1% of the studied prescriptions came with errors among which one in seven were severe ones. But prescribing errors were in no relation to workloads. What’s more, further studies are needed to investigate pharmacist-led intervention to reduce prescribing errors.

Poly (butylene furandicarboxylate) based poly (ether ester), with poly (ethylene glycol) (PEG) molecular weight from 600 to 20 K g mol−1 and mass fraction of hard segments fixed at 50%, are synthesized through transesterification and melt polycondensation. When Mn (PEG) is less than 1500 g mol−1, the copolymers tend to be homogeneous. The tendency of microphase separation is facilitated by the increasing Mn (PEG). The mechanical properties and water swelling are influenced by Mn (PEG), equilibrium water-uptake and PEG crystals. Elastic modulus of samples with no PEG crystals vary from 34 to 64 MPa, with elongation at break exceeding 1000%. The hydrolytic degradation is strongly affected by Mn (PEG), degradation medium and alkalinity. The degradation of copolymers with short PEG (

Background: Mucosal epithelial apoptosis with non-specific inflammation is an essential pathological characteristic in portal hypertensive gastropathy (PHG). However, whether a coordinated crosstalk between myeloid cells and epithelial cells involved in PHG remains unclear. Methods: Gastric injury and mucosal apoptosis were examined in patients with PHG and the PHG model of p65ΔM/ΔM (myeloid cells specific NF-κBp65 deletion) and p65f/f (floxed p65) mice, PUMA-WT (PUMA wild-type) and PUMA-KO (PUMA knockout) mice. The interaction of IL-6, Fas, FasL, NF-κBp65 and PUMA expression was investigated, and the mechanisms underlying IL-6-regulated gastric epithelial apoptosis were analysed. Findings: IL-6, which is induced in the mucosa of PHG patients and mice, promotes FasL production via enhancing NF-κBp65 activation in myeloid cells, while blockage of IL-6 signaling by Tocilizumab or deletion of NF-κBp65 in myeloid cells attenuates the inflammatory response and Fas/FasL-mediated epithelial apoptosis in PHG. IL-6-driven FasL from myeloid cells combines with epithelial Fas receptor to encourage NF-κBp65/PUMA-mediated epithelial apoptosis in PHG, and inhibition of NF-κBp65 or knockout of PUMA dramatically alleviates Fas/FasL network-mediated epithelial apoptosis in PHG. Interpretation: These results indicate that IL-6 drives FasL generation via NF-κBp65 in myeloid cells to promote Fas/NF-κBp65/PUMA-mediated epithelial apoptosis in PHG. Funding: This work was supported by grants from the National Natural Science Foundation of China (U1501224, 81700536), the Natural Science Foundation Team Project of Guangdong Province (2018B03031200), the Science and Technology Developmental Special Foundation of Guangdong Province (2017B020226003), the Basic Research Programme of Young Teachers' Training Project of Sun Yat-sen University (17ykpy51), the Science and Technology Planning Projects of Guangzhou City (201604020118, 201604020002). Declaration of Interest: The authors declare that there are no conflicts of interest. Ethical Approval: The study protocol and the acquisition of the tissue samples were approved by the Institutional Review Board of The Third Affiliated Hospital of Sun Yat-Sen University.

BACKGROUND Clear cell sarcoma (CCS) of soft tissue, or malignant melanoma of soft parts, is a rare disease. We aimed to identify prognostic factors linked to patient survival in CCS by analyzing demographic and clinical features using the Surveillance, Epidemiology, and End Results (SEER) database. This study aimed to identify prognostic factors associated with CCS that would be of clinical value. MATERIAL AND METHODS We collected data from patients diagnosed with CCS between 1973 and 2009 from the SEER database. The Kaplan-Meier method and Cox regression analysis were performed to identify prognostic factors for patient survival. RESULTS A total of 175 patients with CCS were identified from the SEER database. The 5-year survival rate was 62.9%, and the 10-year survival rate was 51.3%. Patients with CCS with local stage, and with tumor size ≤3 cm were more likely to have good survival rates. CONCLUSIONS The findings from this study showed that the identifiable prognostic factors in patients with CCS were stage and tumor size. Local stage and tumor size ≤3 cm were favorable prognostic factors for patient survival in CCS.

Hepatocellular carcinoma (HCC) is a malignant disease caused by a variety of factors. However, the genomic and molecular aberrations in HCC are largely unknown. Herein, pituitary tumor transforming gene 1 (PTTG1) was discovered as a potential inflammation‐related oncogene in HCC, and its functions and molecular mechanisms were investigated. mRNA expression microarray, real‐time polymerase chain reaction (PCR), immunohistochemistry, and western blotting analyses revealed that PTTG1 is upregulated in HCC. Further in vitro and in vivo studies indicated that the proinflammatory cytokine tumor necrosis factor‐α (TNF‐α) induces PTTG1 expression, and PTTG1 was found to upregulate c‐myc, a well‐known oncogene. Downregulation of PTTG1 reduced c‐myc and proliferating cell nuclear antigen (PCNA) expression and inhibited cell proliferation. Interestingly, inhibition of c‐myc by 10058‐F4 did not affect PTTG1, which suggests that PTTG1 regulates c‐myc expression. Furthermore, PTTG1 expression levels are inversely correlated with HCC patient survival, indicating an independent prognostic biomarker for patients with HCC. Our data demonstrate that PTTG1 is involved in TNF‐α‐related HCC via c‐myc induction and that PTTG1 may be a potential therapeutic target for HCC., Our data suggest that pituitary tumor transforming gene 1 (PTTG1) plays a vital role in inflammation‐related hepatocellular carcinoma (HCC) via c‐myc induction and that PTTG1 may be a potential therapeutic target for HCC.

Background and study aims Gastrointestinal ulcers are responsible for a wide spectrum of diseases. Infection, drug-induced enteritis, malignancy, vasculitis and Inflammatory bowel disease are the most common causes; their clinical expression often varies according to the site and severity of intestinal involvement. We report on a 68-year-old male presenting with dyspepsia and melena and multiple gastrointestinal ulcers on endoscopy. We could not establish diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) despite multiple biopsies taken on several endoscopic sessions, and cytomegalovirus (CMV) infection was documented by presence of inclusion bodies on pathology. The immunohistochemical study showed a mixture of B lymphocytes and predominantly T lymphocytes, negative for cluster of differentiation (CD)7. Southern blot gene rearrangement was positive for T-cell receptor beta. Our patient eventually expired from a massive gastrointestinal hemorrhage following four cycles of chemotherapy. We wish to emphasize that a CMV infection, as a comorbidity, can potentially mask and delay diagnosis of PTCL-NOS, especially in cases with aberrant immunophenotype presentation.

Due to the initial flushing effect, many pollutants are carried in runoff in the early stage of rainfall, which is an important source of water quality degradation in urban receiving water bodies. ...

The PAX3 (paired box 3) gene plays an important role in embryonic development, diseases, and cancer formation. Our preliminary studies have shown that PAX3 gene is upregulated in glioma cells, which is associated with a worse prognosis. Moreover, PAX3, by facilitating cell proliferation and invasion and inhibiting cell apoptosis, plays an oncogenic role in glioma. However, the specific molecular mechanism of PAX3 acting as an oncogene in glioma remains unclarified. In the present study, we have found that PAX3 overexpression was observed in high grade glioma and predicted a worse prognosis. PAX3 overexpression did not correlate significantly to IDH1 mutation and MGMT methylation. Moreover, the expression of PAX3 was positively correlated with that of β-catenin. In U87 glioma cells, PAX3 interacted with β-catenin, as was confirmed by CO-IP. Besides, PAX3 overexpression promoted cell proliferation and cell cycle progression, while it inhibited cell apoptosis by altering the expressions of important molecules associated with the Wnt signaling pathway, including β-catenin, Myc, VEGF, cyclinD1, MMP7, and Wnt1. In the meantime, it was also proved that PAX3 correlated to β-catenin through a negative regulatory mechanism with respect to the promotion of U87 glioma cell proliferation and cell cycle progression and inhibition of the cell apoptosis. Our experiment demonstrated the role of PAX3 in promoting glioma growth and development, possibly by interacting directly with β-catenin and regulating the Wnt signaling pathway.

Background: Failure to activate autonomic neural and hormonal reflex mechanisms could result in orthostatic hypotension. Patients with orthostatic hypotension often experience symptoms of cerebral hypoperfusion, including syncope. The purpose of this study was to investigate the haemodynamic characteristics of patients with orthostatic hypotension and the factors affecting blood pressure regulation.Methods: This retrospective study enrolled 45 patients who were diagnosed with typical orthostatic hypotension by the head-up tilt test at Beijing Tiantan Hospital, Capital Medical University from June 2019 to December 2020. Changes in haemodynamic parameters in these patients were compared in the supine and tilted upright positions.Results: For all patients, haemodynamic parameters in the supine and tilted upright positions were compared, and systolic blood pressure, diastolic blood pressure, mean blood pressure, cardiac output and stroke volume were all significantly decreased per minute. Heart rate significantly increased per minute, but systemic vascular resistance did not significantly change. The absolute value, percentage and rate of increases in heart rate and the absolute value, percentage and rate of decreases in stroke volume from the supine to the titled upright position were significantly lower in patients 60 years and older than in patients under 60 years old. Linear regression analyses found that the changes in heart rate, stroke volume and systemic vascular resistance were related to changes in systolic blood pressure, while the changes in stroke volume and systemic vascular resistance had more important effects on systolic blood pressure.Conclusions: In patients with orthostatic hypotension, we observed no significant increase in systemic vascular resistance from the supine position to the tilted upright position. Nevertheless, an increase in systemic vascular resistance had a significant impact on the maintenance of systolic blood pressure. In addition, in orthostatic hypotension patients younger than 60 years of age, heart rate increased while stroke volume decreased significantly after tilting upright compared with orthostatic hypotension patients older than 60 years of age and older.

The non-orthogonal shafting total station (N-total station) is designed for large-scale measurement field, and composed of two rotation axes and a sight axis. Each axis is defined by a direction vector and a fixed point. The dynamic pose of the sight axis is the key parameter to solve the space point coordinate. A correction method for the sight axis of the N-total station after calibration is proposed. There are six offset terms to be set as coefficients when the sight axis shifts. Based on the kinematic measurement model, a new sight axis can be reshaped with the solution of the coefficient obtained by the optimization method. The experimental results well verify that the calibration method is suitable for the N-total station.

BACKGROUND & AIM: Coexisting alcoholic liver disease and virus-induced liver cirrhosis (ALD+HBV and ALD+HCV) has not been thoroughly studied. This cross-sectional study aims to showcase the influence of alcohol on the laboratory values and on the clinical outcomes of patients with hepatitis B and C virus-induced liver cirrhosis.METHOD: Patients diagnosed with liver cirrhosis (n=22287) from January 2010 to December 2019 were collected from our hospital electronic database, and divided into five groups according to the etiology: ALD (1652 cases, 7.4%), HBV (18079 cases, 81.1%), HCV (682 cases, 3.1%), ALD+HBV (1594 cases, 7.2%) and ALD+HCV (280 cases, 1.3%). Laboratory results and proportion of different liver cirrhosis complications were contrasted between groups.RESULTS: ALD+HBV and ALD+HCV presented with higher proportions of poor prognosis patients and cirrhosis complications compared to HBV and HCV respectively. Multivariate logistic regression revealed that the risk of HCC and that of EGVB in the ALD+HBV group was respectively 2.14-fold and 1.47-fold that in the HBV group (HCC: OR=2.14, 95%CI: [1.71-2.69]; EGVB: OR=1.47, 95%CI: [1.17-1.84]) after adjusting for potential confounders. Furthermore, a decrease in the risk of HCC and EGVB with the duration of alcohol abstinence was observed. Similar pattern was noticed while comparing ALD+HCV group to HCV group.CONCLUSION: Alcohol significantly increased the severity of liver function impairment and the prevalence of liver cirrhosis complications such as HCC and EGVB in hepatitis virus-induced liver cirrhosis patients. Remarkably, long period of alcohol abstinence significantly decreased the prevalence of HCC and EGVB in these populations.

BACKGROUND: Endoscopic therapy has been widely applied to prevent variceal rebleeding, but data addressing the effect of endoscopic variceal eradication (VE) are lacking. We aimed to clarify the clinical impact of VE and reveal the long-term incidence and mortality of gastrointestinal rebleeding. METHODS: This prospective study included 228 cirrhotic patients who underwent secondary prophylaxis for variceal bleeding and achieved VE through a systematic procedure we proposed as endoscopic sequential therapy (EST). Rebleeding rates before and after VE were compared and cumulative incidence of rebleeding and mortality were calculated using the Kaplan-Meier method. A logistic regression model and P for trend were used to investigate the optimal time limit for VE. RESULTS: During a median (interquartile range) follow-up duration of 33.0 (23.0–48.75) months, rebleeding was identified in 28 patients (12.3%) after VE and in 27 patients (11.8%) during endoscopic sessions. The cumulative incidence of rebleeding before and after VE was 8.4% and 1.8% at 6 months, and 14.9% and 4.0% at 1 year respectively (P12 months (P for trend

To assess measurement properties of the two youth versions of EQ-5D (i.e., 5-level EQ-5D-Y [Y-5L] and 3-level EQ-5D-Y [Y-3L]) and KIDSCREEN-10 in China. Children and adolescents attending schools in Shanghai, China were recruited to self-complete the Y-5L, KIDSCREEN-10, and Y-3L questionnaires. Their feasibility was assessed according to missing responses. Convergent validity of the EQ-5D-Y dimensions, a summated dimension score [SDS], and Visual Analogue Scale (VAS) were assessed by examining their correlations with the KIDSCREEN-10 index score and dimensions. Known-groups validity of SDS, VAS, and KIDSCREEN-10 index score were tested by comparing the scores of pupils with and without two conditions (i.e., overweight and shortsightedness), and the relative efficiency (RE) between them was also evaluated. A total of 262 pupils (girl: 58.4%; mean age: 12.7 years) were enrolled. Missing responses were low for both the Y-5L (0.3%) and Y-3L (2.4%), and KIDSCREEN-10 (0.3%). The overall ceiling effects were 40.3% for the Y-5L, 44.1% for the Y-3L and 1.1% for the KIDSCREEN-10. The SDSY-5L, SDSY-3L and VAS were moderately correlated with the KIDSCREEN-10 index score (|r|= 0.425 for SDSY-5L, 0.323 for SDSY-3L, and 0.435 for VAS; p 0.3). Both the SDSY-5L and SDSY-3L had lower values, and VAS and KIDSCREEN-10 index score had higher values for pupils without shortsightedness compared with those for their counterparts. The difference was statistical significance for the SDSY-5L and VAS (P

Background High-risk esophagogastric varices (EGV) are prone to bleeding and are recommended to be eradicated through endoscopic therapy by practice guideline. However, a considerable number of patients may fail the endoscopic variceal eradication (VE) when second-line non-endoscopic treatments, including radio-interventional and surgical therapy are required. To date, predictive factors for the multidisciplinary therapy switch are unclear. We aimed to investigate factors that determine the therapy switch and the length of endoscopic therapy to VE. Methods We carried out this retrospective study based on an established cohort of cirrhosis recruiting patients from 2011 to 2018. Relevant medical and endoscopic data were collected and comprehensively assessed. Multivariate analyses were performed to identify factors associated with the therapy switch in all included patients, and the length of time to VE in endoscopic VE-achieved patients. Results A total of 330 patients were included for analysis, of which 289 cases (87.6%) achieved VE through sequential endoscopic therapies. The median (Interquartile range, IQR) time to VE was 5 (2–10.5) months and the median (IQR) number of endoscopic sessions required was 3 (2–5). Meanwhile, thirty-two cases (9.7%) failed endoscopic VE and transferred to multidisciplinary therapy during endoscopic intervals (25 cases for surgical therapy and 7 cases for radio-interventional therapy). Multivariate analysis showed that splenomegaly (hazard ratio, HR 1.21, 95%CI 1.09–1.34), portal vein thrombosis (HR 2.88, 95%CI 1.20–6.88) and thrombocytopenia (HR 0.99, 95%CI 0.97–1.00) were associated with the therapy switch. Among endoscopic VE-achieved patients, male sex (HR 1.49, 95%CI 1.12–1.99), large varices (HR 4.01, 95%CI 2.22–7.23), long-segment varices (HR 1.70, 95%CI 1.04–2.78), and intercurrent bleeding (HR 2.24, 95%CI 1.53–3.30) were associated with prolonged time required for VE. Conclusions Patients with an enlarged spleen, portal vein thrombosis and low platelet count are at high risk of undergoing multidisciplinary therapy to eradicate EGV. Severe varices, male sex and interval bleeding event impair endoscopic efficacy significantly. Our findings may help improve patient risk stratification and medical resources allocation.

Background The combination of non-selective beta-blockers (NSBBs) and endoscopic band ligation has been recommended as the first-line therapy for preventing variceal rebleeding. However, little is known about the routine clinical use of this medication. We aimed to investigate the current situation of NSBBs use in respect of prevalence, tolerance and compliance in this study, and compare with that of endoscopic therapy. Methods We prospectively recruited cirrhotic patients undergoing secondary prophylaxis in our department from May 2019 to Jan 2020. Relevant medical and endoscopic data were collected. Bedside interviews were carried out using the specifically designed questionnaire. Therapy compliance was also assessed during the 6-month follow-up after initial therapy. Univariate and multivariate logistic regression were performed to explore the factors associated with therapy compliance. Results A total of 269 consecutive patients were screened, and 259 of them were included. Main etiologies of cirrhosis were hepatitis B/C (72.2%) and alcohol consumption (10.0%). Fifty-two (20.1%) patients were on the treatment of NSBBs and 53 (20.5%) patients were treated with NSBBs before, whereas 23 patients (8.9%) were with contraindications. Thirteen patients (25.0%) achieved hemodynamic response and the target dose was 32.1 mg/d for propranolol and 12.5 mg/d for carvedilol respectively. Overall adverse effects (AEs) were substantially more prevalent in endoscopic therapy than in NSBBs therapy (61.4% vs 25.7%, P Conclusions Clinical use of NSBBs for cirrhotic patients is far from optimal considering the low prevalence and high proportion of ineffective low-dose. NSBBs medication bears a higher rate of severe AEs compared with endoscopic therapy. Therapy compliance of both NSBBs and endoscopy are unsatisfactory, and optimized follow-up management is greatly needed.

Background Regnase-1 (MCPIP) has been identified as an anti-inflammatory agent, but little is known about its influence on liver ischemia/reperfusion (I/R) injury. Macrophages can evolve biphasic responses and differentiate into remarkable polarizations, contributing greatly to the uncontrolled inflammatory cascades during liver I/R injury. Therefore, the aim of this study was to explore whether regnase-1 participated in liver I/R via manipulating macrophage polarization. Materials and methods C57BL/6 mice were randomly divided into five groups: Sham, I/R, Clodronate, Clo + BMDM, and Clo + LV MCPIP BMDM. A liver I/R model was established, and histopathological and immunostaining examinations were performed for the liver specimens; double immunofluorescence staining was used to localize MCPIP in the liver. Primary hepatocytes were isolated to simulate a hypoxia and reoxygenation (H/R) model in vitro. Bone marrow-derived macrophages (BMDM) were extracted and subjected to lentiviral transduction to knockdown MCPIP expression. BMDM with or without MCPIP deletion were exposed to H/R supernatants, and the polarized states were measured by flow cytometry. RT-PCR analysis and Western blot were also conducted. Results Compared to those in the Sham group, liver functions and Suzuki's scores were deteriorated in the I/R group, which were reversed in the Clodronate group. The increased expression of regnase-1 in the I/R group diminished with pretreatment of clodronate liposomes. Subsequent double immunofluorescence staining established the localization of regnase-1 in macrophages in the liver. The insulted lesions in the Clodronate group became progressively aggravated with adoptive transfer of BMDM in the Clo + BMDM group, and they were further exacerbated with the transfusion of BMDM with MCPIP knockdown in the Clo + LV MCPIP BMDM group. Gene expressions of M1 and M2 markers were detected by RT-PCR, suggesting that MCPIP knockdown tended to favor the M1 transformation. Subsequently, ex vivo flow cytometrical detection showed that, upon stimulation by H/R supernatants, LV-MCPIP BMDM posed a higher ratio of M1/M2 than BMDM. Finally, we found that MCPIP participated in macrophage M1/M2 polarization through the NF-κB, C/EBPβ, and PPARγ signaling pathways during liver I/R. Conclusion Our study confirms that regnase-1 plays a critical role in liver I/R via regulation of macrophage polarization and, thus, might offer a potential therapeutic target.

Background Polymyxin B once had to exit the market due to its toxicity. As antibacterial is widely used, the problem of drug-resistance, especially the gram-negative bacteria, has become a major threat to global health. Polymyxin B has reappeared as a last resort for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria. With its return, the use of polymyxin B greatly increased over time in China. The aim of our study was to overview the actual clinical application of polymyxin B in patients with MDR and XDR Gram-negative bacteria in Peking Union Medical College Hospital (PUMCH), Moreover its usage characteristics were summarized in detail.Methods: All the patients hospitalized in Perking Union Medical College of Hospital (PUMCH) from August 2018 (available in PUMCH) to December 2019 who received polymyxin B were enrolled in the study. Patients’ basic information, previous medical history, antimicrobial susceptibility, the use of antimicrobials throughout the hospital stay, adverse reactions, and clinical outcomes were extracted and recorded for descriptive analysis.Results: A total of 84 hospitalized patients received polymyxin B intravenous injection. Most of the patients had underlying conditions such as hypertension, diabetes or in the states of immunosuppression, who had already received other antibiotic therapy, particularly carbapenems, β-lactam/β-lactamase inhibitor and tigecycline, prior to receiving polymyxin B. About 73.81% of the patients had mixed infections, with pneumonia being the most common. The leading pathogens were Acinetobacter baumannii (73.81%) followed by Pseudomonas aeruginosa (28.57%) and Klebsiella pneumonia (20.23). The microbiological clearance of the targeted bacteria after therapy was 17.88%. Clinical amelioration at the last day of polymyxin B therapy was observed in 52.38% of cases, while mortality was observed in 32.14%. Nephrotoxicity and neurotoxicity were observed in 5 and 1 cases respectively.Conclusion: Polymyxin B was used to fight against MDR and XDR Gram-negative bacterial infections under the conditions of previous treatment failure, changes of antimicrobial susceptibility, and drug intolerance in PUMCH. However, owing to lack of experience and widely recognized application criteria, the use of polymyxin B demanded more research to help achieve uniform standards and rules to guide the clinical application of polymyxin B, thus leading to better clinical outcomes.

Bladder cancer is a common urological malignancies world-wide. Recently, a growing number of evidence have highlighted the importance of long noncoding RNAs (lncRNAs) in multiple cancers development and progression. However, the expression pattern of lncRNAs in bladder cancer and their underlying function remain poorly understood. To identify lncRNAs profile alterations and uncover valuable lncRNA candidates for bladder cancer diagnostic, we conducted a comprehensively lncRNAs profiling analyses and explored their clinical relevance using The Cancer Genome Atlas (TCGA) data and three independent microarray profiling data from the Gene Expression Omnibus (GEO). After annotation and analyses of these data, we found that lots of lncRNAs were dysregulated in bladder specimen when compared with normal control specimen. In addition, we found that differential expression of these lncRNAs is accompanied by genomic variations, including genome loci copy number deletion or amplification. Importantly, a part of these lncRNAs are related to bladder cancer patients outcome, such as SNHG10, SNHG12 and LINC00115. Finally, we validated two of these lncRNAs' (DUXAP8 and SNHG12) function in bladder cancer cells by down-regulating their expression with siRNAs, and found that down-regulation of DUXAP8 and SNHG12 could inhibit bladder cancer cells proliferation in vitro. In summary, this study demonstrated that a lot of lncRNAs are dysregulated in bladder cancer, and might provide useful lncRNAs resource for potential prognostic or diagnostic markers for this disease.

Purpose The optimal internal fixation device for unstable intertrochanteric fracture remains a matter of controversy. By performing network meta-analysis, we developed a ranking of the following four surgical methods: proximal femoral nail antirotation, InterTan nail, gamma nail (GN) and sliding hip screws. We compare the complication rates in patients with unstable intertrochanteric fractures. Materials and methods After an exhaustive search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for relevant studies, randomized controlled trials meeting selection criteria were entered into our network meta-analysis. Statistical analyses were conducted using Stata software, version 13.0 (Stata Corporation, College Station, Texas, USA). Results We included 12 randomized controlled trials. Compared to Sliding hip screw, there were no substantial differences in rates of complications in unstable intertrochanteric fractures patient undergoing various treatments (all p > 0.05). Nevertheless, the surface under the cumulative ranking curve (SUCRA) for GN (80.6%) was significantly higher than those of the other three methods. Conclusion GN had the highest probability of reducing the total incidence of complications among the four interventions for treating unstable intertrochanteric fractures.

Summary About 10% of gastric carcinomas are associated with Epstein–Barr virus (EBV), which are defined as EBV-associated gastric carcinomas (EBVaGCs). EBVaGCs are usually accompanied by massive lymphocytes infiltration, among which CD8+ T cells are predominant. To date, the apoptosis of the infiltrating CD8+ T cells in EBVaGC has not been investigated. In the present study, we assessed the immunophenotype and apoptosis of tumour infiltrating lymphocytes (TILs) in both EBVaGC and EBV-negative gastric carcinoma (EBVnGC). We found that CD8+CCR7+ T lymphocytes were increased in EBVaGC compared to EBVnGC [60.53 ± 28.41/high power fields (HPF) vs 19.63 ± 15.97/HPF; p

Background and aim β-Arrestins (β-arrs) are regulators and mediators of G protein-coupled receptor signaling that are functionally involved in inflammation. Nuclear factor-κB p65 (NF-κBp65) activation has been observed early in the onset of pancreatitis. However, the effect of β-arrs in acute pancreatitis (AP) is unclear. The aim of this study is to investigate whether β-arrs are involved in AP through activation of NF-κBp65. Methods Acute pancreatitis was induced by either caerulein injection or choline-deficient supplemented with ethionine diet (CDE). β-arr1 wild-type and β-arr1 knockout mice were used in the experiment. The survival rate was calculated in the CDE model mice. Histological and western blot analyses were performed in the caerulein model. Inflammatory mediators were detected by real-time polymerase chain reaction in the caerulein-induced AP mice. Furthermore, AR42J and PANC-1 cell lines were used to further study the effects of β-arr1 in caerulein-induced pancreatic cells. Results β-Arr1 but not β-arr2 is significantly downregulated in caerulein-induced AP in mice. Targeted deletion of β-arr1 notably upregulated expression of the pancreatic inflammatory mediators including tumor necrosis factor α and interleukin 1β as well as interleukin 6 and aggravated AP in caerulein-induced mice. β-Arr1 deficiency increased mortality in mice with CDE-induced AP. Further, β-arr1 deficiency enhanced caerulein-induced phosphorylation of NF-κBp65 both in vivo and in vitro. Conclusion β-Arr1 alleviates AP via repression of NF-κBp65 activation, and it is a potentially therapeutic target for AP.

Detection of different classes of atherosclerotic plaques is important for early intervention of coronary artery diseases. However, previous methods focused either on the detection of a specific class of coronary plaques or on the distinction between plaques and normal arteries, neglecting the classification of different classes of plaques. Therefore, we proposed an automatic multi-class coronary atherosclerosis plaque detection and classification framework. Firstly, we retrieved the transverse cross sections along centerlines from the computed tomography angiography. Secondly, we extracted the region of interests based on coarse segmentation. Thirdly, we extracted a random radius symmetry (RRS) feature vector, which incorporates multiple descriptions into a random strategy and greatly augments the training data. Finally, we fed the RRS feature vector into the multi-class coronary plaque classifier. In experiments, we compared our proposed framework with other methods on the cross sections of Rotterdam Coronary Datasets, including 729 non-calcified plaques, 511 calcified plaques, and 546 mixed plaques. Our RRS with support vector machine outperforms the intensity feature vector and the random forest classifier, with the average precision of 92.6 ± 1.9% and average recall of 94.3 ± 2.1%. The proposed framework provides a computer-aided diagnostic method for multi-class plaque detection and classification. Graphical abstract Diagram of the proposed automatic multi-class coronary atherosclerosis plaque detection and classification framework. ᅟ.

Background Long non-coding RNAs (lncRNAs) show great potential as diagnostic tools in many diseases. We aimed to develop sensitive and noninvasive biomarkers in saliva for detecting early hepatocellular carcinoma (HCC). Methods Candidate lncRNA biomarkers identified by Agilent microarray were subjected to validation using qPCR for the quantification of their expression levels in independent tissue, plasma and saliva sample sets, including healthy controls, HBsAg carriers, patients with chronic Hepatitis B, liver cirrhosis, early HCC, and advanced HCC. Levels of candidate biomarkers were also measured in totally 108 saliva samples from patients with any one of other nine leading causes of cancer death in men and women. Findings Lnc-PCDH9-13:1 was significantly elevated in HCC tissues, plasma and saliva of HCC patients compared with healthy controls and groups of several benign liver diseases and other leading cancers. Its level was significantly reduced after curative hepatectomy but significantly elevated again if HCC recurrence occurred. Salivary lnc-PCDH9-13:1 showed reasonable specificities and sensitivities for detecting HCC compared with several control groups. Furthermore, the overexpression of lnc-PCDH9-13:1 promotes cell proliferation and migration in vitro. Interpretation Salivary lnc-PCDH9-13:1 is a desirable biomarker for early HCC. It may help warrant prospective validation with larger sample sizes in multi-centers., Highlights • This study highlight the potential of salivary lncRNAs for detecting early HCC and HCC recurrence, which might provide patients with chances of curative operation and longer survival. Long non-coding RNAs (lncRNAs) show great potential as diagnostic tools in many diseases. Lnc-PCDH9-13:1 was significantly elevated in cancer tissues, plasma and saliva of patients with liver cancer compared with healthy controls and groups of several benign liver diseases and other leading cancers. Its level was significantly reduced after the curative operation but significantly elevated again if liver cancer recurrence occurred. Salivary lnc-PCDH9-13:1 showed reasonable specificities and sensitivities for detecting liver cancer. Conclusively, salivary lnc-PCDH9-13:1 is indicative of the early diagnosis and recurrence of liver after the operation with reasonable sensitivities and specificities.

In this network meta-analysis, we determined the optimal surgical method for treating unstable femoral intertrochanteric fractures. We searched the EMBASE, Cochrane Library and Medline databases for studies evaluating sliding hip screws (SHS), gamma nail (GN) or proximal femoral nail antirotation (PFNA) methods, and included nine randomized controlled trials that met the inclusion criteria. Our analysis showed no differences in the rates of complications between SHS and PFNA relative to GN (p > 0.05). However, the surface under the cumulative ranking curve (SUCRA) score for PFNA (77.6%) was higher than the SUCRA scores for GN (65%) and SHS (7.5%). This suggests PFNA is the better surgical method than GN or SHS for unstable femoral intertrochanteric fractures.

The threat of antibiotic resistant bacteria has called for alternative antimicrobial strategies that would mitigate the increase of classical resistance mechanism. Many bacteria employ quorum sensing (QS) to govern the production of virulence factors and formation of drug-resistant biofilms. Targeting the mechanism of QS has proven to be a functional alternative to conventional antibiotic control of infections. However, the presence of multiple QS systems in individual bacterial species poses a challenge to this approach. Quorum sensing inhibitors (QSI) and quorum quenching enzymes (QQE) have been both investigated for their QS interfering capabilities. Here, we first simulated the combination effect of QQE and QSI in blocking bacterial QS. The effect was next validated by experiments using AiiA as QQE and G1 as QSI on Pseudomonas aeruginosa LasR/I and RhlR/I QS circuits. Combination of QQE and QSI almost completely blocked the P. aeruginosa las and rhl QS systems. Our findings provide a potential chemical biology application strategy for bacterial QS disruption.

Yong-Fa Chen, Wu-Bin Tang, Xin-Xi Pan, Chu-Rong Wu, Yang Cao, Wen Yang Department of Oncology, People’s Hospital of Nanhai District, Southern Medical University, Foshan, People’s Republic of China Objective: To evaluate efficacy and safety of nimotuzumab combined with chemotherapy and radiotherapy in women with locally advanced cervical cancer.Materials and methods: Women with locally advanced cervical cancer (stage IIB, III, or IVA) who experienced relapse after first-line chemoradiotherapy and one or more lines of palliative chemotherapy were enrolled. All patients received nimotuzumab weekly at 200 mg/m2 as single agent for 4 weeks (induction phase), then concurrent with 6 cycles (21-day per cycle) of gemcitabine (800 mg/m2) or cisplatin (50 mg/m2) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Overall response rate (ORR) was assessed after 4 weeks of induction therapy and then every 3 months according to response evaluation criteria in solid tumors version 1.1 (primary end point). Secondary end points include progression-free survival (PFS), overall survival (OS), and drug toxicity. Descriptive statistics was used for ORR, and Kaplan–Meier curves were generated for OS and PFS.Results: A total of 80 women with locally advanced cervical cancer were enrolled and evaluated for safety and efficacy. Our results demonstrated that none of the patients had a complete response (0%), 11 patients had a partial response (14%), and 10 patients had progressive disease (13%), giving a tumor response rate of 14%. A total of 59 patients had stable disease (74%), giving a disease control rate of 88% (70/80). Median PFS was 8.21 months (95% confidence interval [CI]: 5.09–12.45). Median OS was 11.96 months (95% CI: 8.11–23.95). The most common adverse events were mucositis, myelosuppression, and gastrointestinal disturbance.Conclusion: Our study results suggested that nimotuzumab in combination with chemotherapy and radiotherapy is well tolerated, and could be a better treatment alternative in patients with locally advanced cervical cancer. Keywords: nimotuzumab, metastatic cervical cancer, Chinese patients, radiotherapy, chemoradiotherapy

Multi-agent chemotherapy is recognized as the most common and effective treatment for Burkitt lymphoma, and intestinal mucosal injury is a common gastrointestinal complication following intensive chemotherapy. The aim of the present study was to describe a case of non-Hodgkin lymphoma with intestinal obstruction after chemotherapy in a young adult. The patient presented with aggravated vomiting during the second session of chemotherapy, which was initially attributed to superior mesenteric artery syndrome. However, following surgical intervention, the symptom was proven to be due to extreme intestinal stenosis in the ascending part of the duodenum. The patient underwent duodenojejunectomy and end-to-side anastomosis, and he recovered well from the operation. Although intestinal perforation and hemorrhage induced by chemotherapy have been previously reported sporadically, to the best of our knowledge, this is the first case report of distal duodenal obstruction due to intestinal atresia induced by polychemotherapy for lymphoma. We herein analyze the possible underlying reasons for the intestinal atresia and review the clinical and pathological characteristics of previously published relevant studies. The present findings may be helpful for increasing clinical awareness of this type of complication, as well as improving the management of patients treated with cytotoxic chemotherapeutic agents.

COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC). β-arrestin1 (β-arr1), which acts as a scaffold protein, is involved in PGE2-mediated signaling pathways. However, the interaction between PGE2 and β-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE2 were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. PGE2 treatment was found to alleviate mucosal injury and induce EP4 expression during dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) mice. Following DSS-induced injury, β-arr1 deficient mice showed increased signs of colitis compared to β-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in β-arr1 deficient mice. In parallel, HCT116 cells transfected with β-arr1 siRNA were examined in the presence or absence of PGE2in vitro. PGE2 treatment in the β-arr1 WT/KO DSS model and β-arr1 siRNA transfection of HCT116 cells confirmed that PGE2 upregulated β-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE2/EP4 upregulates the β-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis. Thus, these findings provide support for the future development and clinical application of COX-1/PGE2 in UC.

Supplemental Digital Content is available in the text, There have been no studies on implementing effective screening models for esophageal adenocarcinoma and squamous cell carcinoma survivors. We used a proportional subdistribution hazards model to estimate second primary malignancy risks among patients with esophageal adenocarcinoma and squamous cell carcinoma. We validated models using a bootstrap cross-validation method and performed decision curve analysis to evaluate their clinical utility. Age group and SEER historic stage were significantly associated with second primary malignancy risk after diagnosis of esophageal adenocarcinoma and squamous cell carcinoma. Saving positive lymph nodes and distant metastasis were significant factors in the adenocarcinoma group, and marital status, tumor location, and chemotherapy were significant factors in the squamous cell carcinoma group. Calibration plots show good concordance between predicted and actual outcomes except in high-probability areas for the risk of a second primary malignancy in patients with esophageal squamous cell carcinoma. Discrimination performances of the Fine–Gray models were evaluated using c-indices, which were 0.691 and 0.662 for second primary malignancies in patients with esophageal adenocarcinoma and squamous cell carcinoma, respectively. Decision curve analysis yielded a range of threshold probabilities (0.020–0.177 and 0.021–0.133 for patients with esophageal adenocarcinoma and squamous cell carcinoma, respectively) at which the clinical net benefit of the risk model was larger than those of hypothetical all-screening and no-screening scenarios. Our nomograms enable selection of patient populations at high risk for a second primary malignancy and thus will facilitate the design of prevention trials for affected populations.

Background Esophagogastric varices (EGV) is a major consequence of portal hypertension highly associated with dreadful variceal hemorrhage, and complete variceal eradication may greatly improve recurrence and prognosis. Little is known about the endoscopic resources invested for EGV eradication in China. This observational study aimed to clarify the practice of variceal eradication by modern combination endoscopic strategies and investigate factors associated with treatment sessions. Methods Clinical data were extracted from the endoscopic recording database and medical charts. Cirrhotic patients underwent the initial endoscopic treatment in our department and followed up for more than 2 months were included between Oct 2011 to Jun 2018. Endoscopic sequential therapy (EST) is an integrated protocol comprising endoscopic cyanoacrylate injection (ECI) sequenced by repeated sessions of endoscopic band ligation (EBL) and/or endoscopic injection sclerotherapy (EIS), and this protocol was performed for every patient. Patients were intensively followed up until complete EGV eradication. Results Among the 337 patients recruited to follow up, 291 (86.4%) who successfully reached variceal eradication were included for analysis. A total of 1029 episodes of endoscopic treatments were performed for the patients. Among them, 132 (45.4%) patients had Child-Pugh class B or C liver disease, and 46 (15.8%) had MELD score equal or over 15. EBL was the most prevalent method used in 283 (97%) patients, followed by ECI for 121 patients (41.6%) and EIS for 53 patients (18.2%). A mean 3.5 sessions of endoscopic therapy was needed to reach complete variceal eradication during an average of 9.6 months (range, 24 days-75 months). The median endoscopic interval between sessions for each patient was 2.0 months (IQR 1.3–3.0). There was a significant positive association between portal vein diameter and both the number of endoscopic sessions (P Conclusions Most cirrhotic patients with EGV undergoing EST would achieve variceal eradication. EVL is the mainstay of the endoscopic method. Portal vein diameter is related to endoscopic resources invested for variceal eradication. Interval between sessions is far from optimal in China and physicians should pay more attention to patient compliance in clinical practice.

Background Esophagogastric variceal bleeding (EGVB) is a severe complication of liver cirrhosis and variceal eradication by modern endoscopic strategies may improve the recurrence and prognosis. Scant data is available about long-term observation after EGV eradication. We reported the incidence of rebleeding, variceal recurrence and mortality by endoscopic sequential therapy (EST), and investigated risk factors associated with prognosis. Methods We carried out a retrospective cohort study recruiting consecutive cirrhotic patients with EGV who were regularly followed up in our endoscopy centre from Oct 2011 to June 2018. EST was defined as a combination strategy of band ligation, histoacryl injection and sclerotherapy. All patients had undergone EST until complete variceal eradication. Relevant medical and endoscopic data were collected. Rebleeding, variceal recurrence and all-cause mortality were considered as major outcomes. We calculated cumulative incidences of the outcomes and used Cox proportional hazard model to estimate hazard ratio (HR) and to identify risk factors. Results We identified 468 patients for screening and 291 of them were finally included for analysis. The mean follows up duration was 32.4 months. After eradication of EGV, rebleeding was identified in 29 patients, and the cumulative incidence of rebleeding at 1 year, 2 year and 5 year was 3.4%, 6.5% and 9.6% respectively. Variceal recurrence was observed in 49 patients while the cumulative incidence at 1 year, 2 year and 5 year was 5.5%, 11.6% and 15.5% respectively. Ten patients died and the cumulative mortality at 1 year, 2 year and 5 year was 0.3%, 1.7% and 3.4% respectively. Patients of viral and alcoholic mixed etiology and patients with higher baseline MELD score (≥20) had a higher rebleeding risk (HR, 6.69 and 5.75, respectively), and patients underwent more sessions of endoscopic treatment had lower variceal recurrence risk (HR 0.81). Baseline presence of portal vein thrombosis and MELD score was highly associated with mortality (HR 8.1 and 8.4 respectively). Conclusions Recurrent bleeding and mortality have been greatly improved after variceal eradication through EST in cirrhotic patients with EGV. A mixed cirrhotic etiology increased the risk of rebleeding, and portal vein thrombosis and high MELD score increased the risk of mortality.