IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis.

Introduction: Sorafenib is currently the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, sorafenib resistance remains a huge challenge in the clinic. Therefore, it is urgent to elucidate the mechanisms underlying sorafenib resistance for developing novel treatment strategies for advanced HCC. In this study, we aimed to investigate the role and mechanisms of interleukin-22 (IL-22) in sorafenib resistance in HCC. Methods: The in vitro experiments using HCC cell lines and in vivo studies with a nude mouse model were used. Calcium staining, chromatin immunoprecipitation, lactate dehydrogenase release and luciferase reporter assays were employed to explore the expression and roles of IL-22, STAT3 and CD155 in sorafenib resistance. Results: Our clinical results demonstrated a significant correlation between elevated IL-22 expression and poor prognosis in HCC. Analysis of transcriptomic data from the phase-3 STORM-trial (BIOSTORM) suggested that STAT3 signaling activation and natural killer (NK) cell infiltration may associate sorafenib responses. STAT3 signaling could be activated by IL-22 administration in HCC cells, and then enhanced sorafenib resistance in HCC cells by promoting cell proliferation and reducing apoptosis in vitro and in vivo. Further, we found IL-22/STAT3 axis can transcriptionally upregulate CD155 expression in HCC cells, which could significantly reduce NK cell-mediated HCC cell lysis in a co-culture system. Conclusions: Collectively, IL-22 could contribute to sorafenib resistance in HCC by activating STAT3/CD155 signaling axis to decrease the sensitivities of tumor cells to sorafenib-mediated direct cytotoxicity and NK cell-mediated lysis. These findings deepen the understanding of how sorafenib resistance develops in HCC in terms of IL-22/STAT3 signaling pathway, and provide potential targets to overcome sorafenib resistance in patients with advanced HCC.

A turn-on fluorescence probe for imaging tyrosinase at the wound site in broken tail of zebrafish.

Tyrosinase (TYR) is a copper-containing oxidase that affects the synthesis of melanin in the human body, which is regulate to the pigmentation of the skin. Nevertheless, abnormal expression of TYR can lead to albinism, vitiligo and other skin diseases. Excessive accumulation of TYR is a marker of melanoma cancer and an important factor leading to pigmentation during wound healing, freckles and browning of fruits and vegetables. Efficient tracking of TYR is of significance for studying its pathophysiological mechanism. Herein, we synthesized a benzindole-based fluorescent probe Pro-OH to detect TYR in living cells and zebrafish. The probe displayed a high selectivity and sensitivity in distinguishing TYR from other analytes with the low detection limit of 1.024 U/mL. Importantly, Pro-OH was successfully used to imagine TYR at the wound site of broken tail of zebrafish.

Immune signatures predict response to house dust mite subcutaneous immunotherapy in patients with allergic rhinitis.

BACKGROUND: Identifying predictive biomarkers for allergen immunotherapy response is crucial for enhancing clinical efficacy. This study aims to identify such biomarkers in patients with allergic rhinitis (AR) undergoing subcutaneous immunotherapy (SCIT) for house dust mite allergy. METHODS: The Tongji (discovery) cohort comprised 72 AR patients who completed 1-year SCIT follow-up. Circulating T and B cell subsets were characterized using multiplexed flow cytometry before SCIT. Serum immunoglobulin levels and combined symptom and medication score (CSMS) were assessed before and after 12-month SCIT. Responders, exhibiting ≥30% CSMS improvement, were identified. The random forest algorithm and logistic regression analysis were used to select biomarkers and establish predictive models for SCIT efficacy in the Tongji cohort, which was validated in another Wisco cohort with 43 AR patients. RESULTS: Positive SCIT response correlated with higher baseline CSMS, allergen-specific IgE (sIgE)/total IgE (tIgE) ratio, and frequencies of Type 2 helper T cells, Type 2 follicular helper T (TFH 2) cells, and CD23+ nonswitched memory B (BNSM ) and switched memory B (BSM ) cells, as well as lower follicular regulatory T (TFR ) cell frequency and TFR /TFH 2 cell ratio. The random forest algorithm identified sIgE/tIgE ratio, TFR /TFH 2 cell ratio, and BNSM frequency as the key biomarkers discriminating responders from nonresponders in the Tongji cohort. Logistic regression analysis confirmed the predictive value of a combination model, including sIgE/tIgE ratio, TFR /TFH 2 cell ratio, and CD23+ BSM frequency (AUC = 0.899 in Tongji; validated AUC = 0.893 in Wisco). CONCLUSIONS: A T- and B-cell signature combination efficiently identified SCIT responders before treatment, enabling personalized approaches for AR patients.

Effects of allergen immunotherapy on follicular regulatory T cells.

PURPOSE OF REVIEW: Emerging evidence indicating that the dysfunction of T follicular regulatory (T FR ) cells contributes to excessive immunoglobulin E (IgE) production and the development of allergic diseases. Conversely, allergen immunotherapy (AIT) modulates T FR cells abundance and function to promote immune tolerance. This review focus on the role of T FR cells in allergic diseases and AIT, with the objective of providing novel insights into the mechanisms underlying immune tolerance of AIT and proposing the potential targeting of T FR cells in the context of allergic diseases. RECENT FINDINGS: Numerous studies have consistently demonstrated that T FR cells play a pivotal role in the inhibition of class switch recombination to IgE in both humans and specific murine models. This suppression is attributed to the actions of neuritin and IL-10 secreted by T FR cells, which exert direct and indirect effects on B cells. In patients with allergic rhinitis, reduced frequencies of circulating or tonsillar T FR cells have been reported, along with impaired functionality in suppressing IgE production. AIT, whether administered subcutaneously or sublingually, reinstates the frequency and functionality of T FR cells in allergic rhinitis patients, accompanied by changes of the chromatin accessibility of T FR cells. The increase in T FR cell frequency following AIT is associated with the amelioration of clinical symptoms. SUMMARY: T FR cells exert an inhibitory effect on IgE production and demonstrate a correlation with the clinical efficacy of AIT in patients with allergic rhinitis, suggesting T FR cells hold promise as a therapeutic target for allergic diseases and potential biomarker for AIT.

Supramolecular Self-Healing Antifouling Coating for Dental Materials.

In orthodontic treatment, orthodontic appliances are prone to bacterial infections, which pose a risk to oral health. Surface modification of orthodontic appliances has been explored to improve their antifouling properties and impart antibacterial capabilities, inhibiting initial bacterial adhesion and biofilm formation. However, coatings are susceptible to damage in the complex oral environment, leading to a loss of functionality. Here, we have prepared an antifouling self-healing coating based on supramolecular bonding by employing a simple spin coating method. The presence of the hydrophilic zwitterionic trimethylamine N-oxide (TMAO) and the hydrophobic antimicrobial moieties triclosan acrylate (TCSA) imparts to the polymers an amphiphilic structure and enhances the interaction with bacteria, resulting in excellent antimicrobial activity and surface antifouling properties. The multiple hydrogen bonds of ureido-pyrimidinone methacrylate (UPyMA) and ionic interactions contained in the polymers not only increased the adhesion of the coating to the material substrate (approximately 3 times) but also endowed the coating with the intrinsic self-healing ability to restore the antibiofouling properties at oral temperature and humidity. Finally, the polymer coating is biologically safe both in vitro and in vivo, showing no cytotoxic effects on cells and tissues. This research offers a promising avenue for improving the performance of orthodontic appliances and contributes to the maintenance and treatment of oral health.

[Comparison of different laryngeal preservation strategies based on chemoradiotherapy in locally advanced hypopharyngeal carcinoma].

Objective:This study aimed to evaluate the clinical features and treatment outcomes of the value of response-adapted treatment following radiotherapy and induction chemotherapy follwing subsequent comprehensive therapy in patients with resectable locally advanced hypopharyngeal carcinoma. Methods:This cohort study was conducted from September 2010 to September 2020 in our hospital, 231 patients pathologically confirmed stage Ⅲ and ⅣB resectable locally advanced hypopharyngeal carcinoma included. For the IC-directed ART strategy, IC is used to select good candidates to receive radical RT or CCRT, and others undergo surgery. He response-adapted strategy was determined based on the primary tumor response, which was evaluated at a dose of 50 Gy. If the response reached complete response or partial response（more than 80% tumor regression）, patients received radical RT or CCRT; otherwise, they received surgery, if possible, at 4 to 6 weeks after RT. The end points of the study were OS（overall survival）, progression free survival（PFS）, locoregional recurrence-free survival（LRRFS） and LDFS. Results:In IC-directed group, 75.0%（57/76） patients reached PR after 2 cycles of induction chemotherapy. While in RT-directed group, 70.3%（109/155） patients reached large PR at dose of 50 Gy. The median interquartile range follow-up period of the whole cohort was 63.8 months. The 5-year OS, PFS, LRRFS and SFL of the whole cohort were 47.9%、39.6%、44.3% and 36.2%, respectively. In evaluations based on the different treatment strategies, the 5-year OS and SFL were 51.3% versus 37.0%（HR 0.67; 95%CI 0.43-1.05; P=0.07） and 27.8% versus 39.8%（HR 0.68; 95%CI 0.46-0.99; P=0.04） between IC-directed and RT-directed groups. In additional, surgery complications did not significantly differ between these two groups. Conclusion:In this cohort study, the response-adapted strategy based on an early RT response facilitated better treatment tailoring, and higher laryngeal preservation compared with IC-directed strategies. This approach could provide a feasible laryngeal preservation strategy in patients with resectable locally advanced hypopharyngeal carcinoma.

Sinonasal mucosal melanoma: Is there a need for elective neck irradiation?

BACKGROUND AND PURPOSE: Sinonasal mucosal melanoma (SNMM) is a rare malignant neoplasm. The regional failure pattern and effectiveness of elective neck irradiation (ENI) were not well defined. Here, we would assess the value of ENI for clinical node negative (cN0) SNMM patients. MATERIALS AND METHODS: A total of 107 SNMM patients treated at our institution over a period of 30 years was retrospectively analyzed. RESULTS: Five patients had lymph node metastases at diagnosis. Among the 102 cN0 patients analyzed, 37 patients had received ENI, and 65 patients had not. ENI significantly reduced the regional recurrence rate from 23.1% (15/65) to 2.7% (1/37). Ipsilateral levels Ib and II were the most common locations of regional relapse. Multivariate analysis also showed that ENI was the only independent favorable predictor for the achievement of regional control (HR: 9.120; 95% CI: 1.204-69.109; P = 0.032). CONCLUSION: This is the largest cohort of SNMM patients from a single institution analyzed for the assessment of the value of ENI on regional control and survival. ENI significantly reduced the regional relapse rate in our study. Ipsilateral levels Ib and II might be considerable when deliver elective neck irradiation, more evidence is needed in the future.

Improved Cancer-Specific Risk Stratification by the Lymph Node Ratio-Based Nomogram: A Potential Role in Guiding Postoperative Management Decisions for Oral Cavity Carcinoma.

PURPOSE: To develop and validate a nomogram integrating lymph node ratio (LNR) to predict cancer-specific survival (CSS) and assist decision making for postoperative management in nonmetastatic oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS: We retrospectively retrieved 6,760 patients with OCSCC primarily treated with surgery from surveillance, epidemiology, and end results database between 2010 and 2015. They were randomly divided into training and validation cohorts. Performance of the nomogram was evaluated by calibration curve, consistency index, area under the curve, and decision curve analysis and was compared with that of the LNR, positive lymph nodes (PLN) and tumor node metastasis (TNM) staging. According to the individualized nomogram score, patients were classified into three risk cohorts. The therapeutic efficacy of postoperative radiotherapy and chemotherapy was evaluated in each cohort. RESULTS: The nomogram incorporated six independent variables, including race, tumor site, grade, T stage, PLN, and LNR. Calibration plots demonstrated a good match between the predicted and observed CSS. C-indices for training and validation cohorts were 0.746 (95% CI, 0.740 to 0.752) and 0.726 (95% CI, 0.713 to 0.739), compared with 0.687, 0.695, and 0.669 for LNR, PLN, and TNM staging, respectively (P < .001). Decision curve analyses confirmed that nomogram showed the best performance in clinical utility. Postoperative radiotherapy presented survival benefit in medium-and high-risk groups but showed a negative effect in the low-risk group. Chemotherapy was only beneficial in the high-risk group. CONCLUSION: The LN status-incorporated nomogram demonstrated good discrimination and predictive accuracy of CSS for patients with OCSCC and could identify those most likely to benefit from adjuvant therapy.

Spatial architecture of regulatory T-cells correlates with disease progression in patients with nasopharyngeal cancer.

Purpose: This study aims to investigate the prognostic value of composition and spatial architecture of tumor-infiltrating lymphocytes (TILs) as well as PDL1 expression on TILs subpopulations in nasopharyngeal carcinoma (NPC). Methods: A total of 121 patients with NPC were included and divided into two groups: favorable (n = 68) and unfavorable (n = 53). The archived tumor tissues of the included patients were retrieved, and a tissue microarray was constructed. The density and spatial distribution of TILs infiltration were analyzed using the multiplex fluorescent immunohistochemistry staining for CD3, CD4, CD8, Foxp3, cytokeratin (CK), PDL1, and 4',6-diamidino-2-phenylindole (DAPI). The infiltration density of TILs subpopulations and PDL1 expression were compared between the two groups. The Gcross function was calculated to quantify the relative proximity of any two types of cells. The Cox proportional hazards regression model was used to identify factors associated with overall survival (OS) and disease-free survival (DFS). Results: The densities of regulatory T-cells (Tregs), effector T-cells (Teffs), PDL1+ Tregs, and PDL1+ Teffs were significantly higher in patients with unfavorable outcomes. PDL1 expression on tumor cells (TCs) or overall TILs was not associated with survival. Multivariate analysis revealed that higher PDL1+ Tregs infiltration density was independently associated with inferior OS and DFS, whereas Tregs infiltration density was only a prognostic marker for DFS. Spatial analysis revealed that unfavorable group had significantly stronger Tregs and PDL1+ Tregs engagement in the proximity of TCs and cytotoxic T lymphocyte (CTLs). Gcross analysis further revealed that Tregs and PDL1+ Tregs were more likely to colocalize with CTLs. Moreover, increased GTC : Treg (Tregs engagement surrounding TCs) and GCTL : PDL1+ Treg were identified as independent factors correlated with poor outcomes. Conclusion: TILs have a diverse infiltrating pattern and spatial distribution in NPC. Increased infiltration of Tregs, particularly PDL1+ Tregs, as well as their proximity to TCs and CTLs, correlates with unfavorable outcomes, implying the significance of intercellular immune regulation in mediating disease progression.

Healthcare for Patients with Hepatitis B Virus: Analysis of 367 381 Inpatient Cases in China.

OBJECTIVE: Hepatitis B virus (HBV) infection, which has been recognized as an international public health challenge, has caused significant morbidity for the entire world. This research focused on patients with HBV in China to examine health utilization and expenses. METHODS: Patients hospitalized with HBV from 2017 to 2019 in tertiary hospitals in Hubei, a province located in central China, were selected as the study population. Healthcare information was collected from the provincial inpatient electronic system database. Univariate and regression analyses were performed to describe the basic situation of healthcare services and determine the influencing indicators of inpatient service expenditure. RESULTS: A total of 367 381 cases of HBV infection were identified in the study area. Most of these cases were patients who were married (90.2%) and males (63%). With the great efforts by the universal coverage of the basic medical insurance (BMI) in China, the increasing rate of inpatient hospitalization for HBV was 3.5 times higher than that of the total inpatient health service cases in the study area. The average age of this group was 52.84±14.10 years and 11.1% of patients paid for their own medical expenditures without insurance. The average length of stay (LOS) was 11.10 days, and the average cost per patient was 15 712.05 RMB. Both values were higher than the average level in study area. Gender, marital status, career, payment type, and kind of hospitals significantly influenced healthcare utilization. Males and the elderly might incur higher healthcare costs than their counterparts. CONCLUSION: The BMI operated by government has played a role in the utilization release of health services for HBV carriers. However, researchers must pay more attention to the continuing increase in the medical expenses of this group.

Stage-dependent conditional survival and failure hazard of non-metastatic nasopharyngeal carcinoma after intensity-modulated radiation therapy: Clinical implications for treatment strategies and surveillance.

PURPOSE: Conditional survival (CS) and failure hazard estimations can provide important dynamic prognostic information for clinical decision-making and surveillance counseling. The current study aimed to investigate the CS and dynamic failure hazard in non-metastatic nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). METHODS: Conditional overall survival (COS) and progression-free survival (CPFS) estimates adjusted for age and gender against each AJCC 8th stage were calculated. Multivariable Cox regression (MCR) models were fitted in the entire population at baseline and subsequently separate MCR models were fitted in patients who have maintained event-free time of 1 to 10 years to generate respective hazard ratio (HR). Annual hazard rates of death and progression over 10 years for each stage were also estimated. RESULTS: A total of 1993 patients were eligible for analysis. The estimated 5-year OS and PFS for entire cohort were 79.0% and 70.7% at initial diagnosis. After 5 years of event-free follow-up, additional 5-year COS and CPFS increased to 85.9% and 85.5%, respectively. Stage I/II maintained dramatically favorable CS and low hazard (< 5%) of death and progression over time. Relative to stage I/II, stage III manifested non-significantly higher failure hazard for the first 3 years of survivorship and approached to similar level of stage I/II afterwards. Stage IVA presented most impressive improvement in terms of both COS (∆=9.8%) and CPFS (∆ = 16.8%) whereas still drastically inferior to that of stage I-III across all conditional time points. After 4 years of follow-up, progression hazard of stage IVA became relatively steady of approximate 6%. CONCLUSIONS: Survival prospect of non-metastatic NPC improves over years with distinct dynamic patterns across stages, providing important implications for personalized decision-making in terms of both clinical management and surveillance counseling. Stage-dependent and hazard-adapted clinical management and surveillance are warranted.

Integrated Bioinformatics Analysis Identifies ELAVL1 and APP as Candidate Crucial Genes for Crohn's Disease.

Immune imbalance and barrier destruction of intestinal mucosa are the central pathogenic factors of Crohn's disease (CD). In this study, three independent microarray studies of CD were integrated and 9912 differentially expressed genes (DEGs) were analysed by NetworkAnalyst to screen candidate crucial genes. NetworkAnalyst identified ELAV-like RNA binding protein 1 (ELAVL1) as the most crucial upregulated gene and amyloid-ß precursor protein (APP) as the most crucial downregulated gene in peripheral blood of CD patients. By computing significance with hypergeometric test based on the KEGG pathway database, upregulated DEGs highlight the pathways of T cell receptor signaling and the differentiation of T helpers. Downregulated DEGs were found enriched in pathways in multiple cancers, MAPK signaling, Rap1 signaling, and PI3K-AKT signaling. Further taking all DEGs together, Gene Set Enrichment Analysis (GSEA) brought out the NOD-like receptor (NLR) signaling pathway which could be regulated by ELAVL1. xCell found decreased naïve and differentiated T cell proportions in the peripheral blood of CD patients suggesting T cell migration to the intestinal tissue and/or exhaustion. Further, ELAVL1 expression correlating with multiple T cell proportions suggests that ELAVL1 may regulate T cell activation. These findings illustrated that ELAVL1 and APP were candidate crucial genes in the peripheral blood of CD patients. ELAVL1 possibly acts as a key regulator of T cell activation via the NLR signaling pathway. APP might be a downstream effector of infliximab treatment connecting with MAPK signaling.

Phytic acid functionalized ZIF-67 decorated graphene nanosheets with remarkably boosted electrochemical sensing performance.

Recently, metal-organic frameworks (MOFs) display great application potential in the field of electrochemical catalysis and sensing due to its extraordinary properties. Herein, Co-based MOFs (ZIF-67) decorated graphene nanosheets (GS) heterogeneous hybrids (ZIF-67@GS) with sandwich-like morphology is first prepared by a facile in situ synthesis method. The electrochemical activity of ZIF-67 polyhedrons is effectively enhanced for the introduction of the high conductivity of graphene nanosheets. Subsequently, phytic acid functionalized ZIF-67 with unique core-shell structure decorated GS (PA-ZIF-67@GS) is prepared through the chemical etching effect of phytic acid. Surprisingly, the exposure level of metal active sites, electrochemical active surface area, electron transfer kinetic of the chemically etched ZIF-67@GS are further significantly boosted. Benefiting from the greatly modified interface property, the as-obtained PA-ZIF-67@GS hybrids exhibit excellent electrocatalytic activity toward the oxidation of glucose, and an ultrasensitive nonenzymatic electrochemical sensing platform is then developed. It is believed that this work may provide effective guidance for optimizing the electrochemical catalytic and sensing performance of other series of MOFs.

The Role of Postoperative Radiotherapy and Prognostic Model in Primary Squamous Cell Carcinoma of Parotid Gland.

BACKGROUND: Primary squamous cell carcinoma of parotid gland (parotid SCC) is a high malignant histologic subtype of parotid cancers with aggressive clinical presentation. However, the clinical features and survival benefit of postoperative radiotherapy (PORT) for primary parotid SCC are not well known. METHODS: A retrospective population-based study was performed to identify the role of PORT in parotid SCC patients diagnosed between 1975 and 2016 from SEER database. A prognostic risk model was established based on patient clinical features, including age, tumor stage, and node involvement status. Patients were stratified into high, intermediate, and low risk according to this model. The survival benefit of radiotherapy was compared in the whole cohort and different risk groups. RESULTS: Nine hundred thirty-one parotid SCC patients were extracted from SEER database, 634 (68.1%) in the RT group and 286 (30.7%) in the non-RT group. Overall, 503 (54.0%) deaths occurred, with a median follow-up of 84 months, the 5-year OS was 43.6% in the whole cohort, 47.7 vs 35.9% in patients with/without PORT (P = 0.005), and 58.9 vs. 38.8 vs. 27.1% in low-, intermediate-, and high-risk group (P < 0.001). Compared with surgery alone, PORT significantly improved the OS of patients with medium risk (47.5 vs. 20.6, P < 0.001), whereas not in the low risk (61 vs. 54%, P = 0.710) and high (25.6 vs. 28.7%, P = 0.524). CONCLUSION: This prognostic model can separate the patients with parotid squamous cell carcinoma into different risk. PORT significantly improved the OS of patients with intermediate risk, whereas high-risk group may need more intensive treatment strategies.

Cathepsin B inhibition ameliorates the non-alcoholic steatohepatitis through suppressing caspase-1 activation

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease. NLRP3 inflammasome activation has been widely studied in the pathogenesis of NAFLD. Cathepsin B (CTSB) is a ubiquitous cysteine cathepsin, and the role of CTSB in the progression and development of NAFLD has received extensive concern. However, the exact roles of CTSB in the NAFLD development and NLRP3 inflammasome activation are yet to be evaluated. In the present study, we used methionine choline-deficient (MCD) diet to establish mice NASH model. CTSB inhibitor (CA-074) was used to suppress the expression of CSTB. Expressions of CTSB and caspase-1 were evaluated by immunohistochemical staining. Serum IL-1Beta and IL-18 levels were also determined. Palmitic acid was used to stimulate Kupffer cells (KCs), and protein expressions of CTSB, NLRP3, ASC (apoptosis-associated speck-like protein containing CARD), and caspase-1 in KCs were detected. The levels of IL-1Beta and IL-18 in the supernatant of KCs were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that CTSB inhibition improved the liver function and reduced hepatic inflammation and ballooning, and the levels of pro-inflammatory cytokines IL-1Beta and IL-18 were decreased. The expressions of CTSB and caspase-1 in liver tissues were increased in the NASH group. In in vitro experiments, PA stimulation could increase the expressions of CTSB and NLRP3 inflammasome in KCs, and CTSB inhibition downregulated the expression of NLRP3 inflammasome in KCs, when challenged by PA. Moreover, CTSB inhibition effectively suppressed the expression and activity of caspase-1 and subsequently secretions of IL-1Beta and IL-18. Collectively, these results suggest that CTSB inhibition limits NLRP3 inflammasome-dependent NASH formation through regulating the expression and activity of caspase-1, thus providing a novel anti-inflammatory signal pathway for the therapy of NAFLD

Predictive Value of BRAFV600E Mutation for Lymph Node Metastasis in Papillary Thyroid Cancer: A Meta-analysis.

BRAFV600E mutation has been thought to be a valuable molecular marker that may predict a worse prognosis for papillary thyroid cancer (PTC). But whether BRAFV600E mutation is associated with lymph node metastasis (LNM) remains controversial. Different surgical strategies may bring a bias in demonsstrating the association between them. In order to delineate a risk stratification to guide a tailored initial approach to tumors that express BRAFV600E mutation, we performed this meta-analysis by using the articles in which total or near-total thyroidectomy plus bilateral central lymph node dissection was routinely performed to avoid the bias from the surgical strategy. We searched the Medline, Embase and CNKI database for eligible studies from January 2003 to May 2018. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed-effects or randomeffects models. Fifteen clinical studies were included with a total of 4909 PTC patients. Our meta-analysis results reported that BRAFV600E mutation was associated with LNM (OR=1.34; 95% CI: 1.09-1.65; P=0.005), as well as central LNM (OR=1.59; 95% CI: 1.35-1.88; P<0.00001). Moreover, in patients with papillary thyroid microcarcinoma, we also confirmed the predictive value of BRAFV600E mutation for LNM (OR=3.49; 95% CI: 2.02-6.02; P<0.00001). This meta-analysis demonstrates that BRAFV600E mutation is closely related to LNM in PTC patients. The results suggest that BRAFV600E mutation can be considered as a risk factor for LNM in PTC. Moreover, combining BRAFV600E mutation with other risk factors to determine the initial surgical treatment may bring benefits for PTC patients.

Cathepsin B inhibition ameliorates the non-alcoholic steatohepatitis through suppressing caspase-1 activation.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease. NLRP3 inflammasome activation has been widely studied in the pathogenesis of NAFLD. Cathepsin B (CTSB) is a ubiquitous cysteine cathepsin, and the role of CTSB in the progression and development of NAFLD has received extensive concern. However, the exact roles of CTSB in the NAFLD development and NLRP3 inflammasome activation are yet to be evaluated. In the present study, we used methionine choline-deficient (MCD) diet to establish mice NASH model. CTSB inhibitor (CA-074) was used to suppress the expression of CSTB. Expressions of CTSB and caspase-1 were evaluated by immunohistochemical staining. Serum IL-1ß and IL-18 levels were also determined. Palmitic acid was used to stimulate Kupffer cells (KCs), and protein expressions of CTSB, NLRP3, ASC (apoptosis-associated speck-like protein containing CARD), and caspase-1 in KCs were detected. The levels of IL-1ß and IL-18 in the supernatant of KCs were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that CTSB inhibition improved the liver function and reduced hepatic inflammation and ballooning, and the levels of pro-inflammatory cytokines IL-1ß and IL-18 were decreased. The expressions of CTSB and caspase-1 in liver tissues were increased in the NASH group. In in vitro experiments, PA stimulation could increase the expressions of CTSB and NLRP3 inflammasome in KCs, and CTSB inhibition downregulated the expression of NLRP3 inflammasome in KCs, when challenged by PA. Moreover, CTSB inhibition effectively suppressed the expression and activity of caspase-1 and subsequently secretions of IL-1ß and IL-18. Collectively, these results suggest that CTSB inhibition limits NLRP3 inflammasome-dependent NASH formation through regulating the expression and activity of caspase-1, thus providing a novel anti-inflammatory signal pathway for the therapy of NAFLD.

M1-Polarized Macrophages Promote Self-Renewing Phenotype of Hepatic Progenitor Cells with Jagged1-Notch Signalling Involved: Relevance in Primary Sclerosing Cholangitis.

The immunologic interaction between parenchyma cells and encircling inflammatory cells is thought to be the most important mechanism of biliary damage and repair in primary sclerosing cholangitis (PSC). Monocytes/macrophages as master regulators of hepatic inflammation have been demonstrated to contribute to PSC pathogenesis. Macrophages coordinate with liver regeneration, and multiple phenotypes have been identified with diverse expressions of surface proteins and cytokine productions. We analyzed the expression of Notch ligand Jagged1 in polarized macrophages and investigated the relevance of Notch signalling activation in liver regeneration. M1 or M2 macrophages were generated from mouse bone marrow-derived macrophages (BMDMs) by classical or alternative activation, respectively. Then, the expression levels of Jagged1 (Jag1) of each phenotype were measured. The effects of polarized BMDMs on the expression of hepatic progenitor cell- (HPC-) specific markers and hairy and enhancer of split-1 (HES1) in HPCs in coculture were also analyzed. Monocyte-macrophage and Notch signalling-associated gene signatures were evaluated in the GEO database (access ID: GSE61260) by gene set enrichment analysis (GSEA). M1 macrophages were found associated with elevated Jag1 expression, which increased the fraction of HPC with self-renewing phenotypes (CD326+CD44+ or CD324+CD44+) and HES1 expression level in cocultured HPC. Blocking Jagged1 by siRNA or antibody in the coculture system attenuates HPC self-renewing phenotypes as well as HES1 expression in HPC. GSEA data show that macrophage activation and Notch signalling-associated gene signatures are enriched in PSC patients. These findings suggest that M1 macrophages promote an HPC self-renewing phenotype which is associated with Notch signalling activation within HPC. In the liver of PSC patients, the prevalence of activated macrophages, with M1 polarized accounting for the main part, is associated with increment of Notch signalling and enhancement of HPC self-renewal.

Long-term treatment outcomes and prognosis of mucosal melanoma of the head and neck: 161 cases from a single institution.

OBJECTIVES: This study aimed to evaluate the clinical features, treatment outcomes and prognostic factors of mucosal melanoma of the head and neck (MMHN) in patients who were treated at our institution. MATERIALS AND METHODS: Between Jan. 1981 and Oct. 2015, 161 patients with non-metastatic MMHN were treated at our institution. The patients' clinical characteristics, treatment modalities, outcomes, prognostic factors, and failure patterns were retrospectively analysed. RESULTS: With a median follow-up time of 74months, the 5-year overall survival rate (OS), local control rate (LC), distant metastasis-free survival (DMFS) were 44.4%, 59.4%, and 49.3%, respectively. Regarding the different treatment modalities, the 5-year OS was 50.0% in the surgery group and 43.1% in the surgery combined with radiotherapy group, while, the 5-year LC rate was 42.5% in the surgery group and 75.3% in the surgery combined with radiotherapy (p<0.001). According to the AJCC 7th edition staging system for MMHN, the 5-year OS for patients with stage III, stage IVA, and stage IVB MMHN were 65.2%, 33.1% and 14.3%, respectively (p<0.001). In the multivariate analysis, the T stage, neck lymph node involvement, and surgical margins were independent prognostic factors for OS; surgical margins and adjuvant radiotherapy were independent prognostic factors for LC. CONCLUSION: The addition of radiotherapy improves the local control rate of MMHN. T stage, neck lymph node status, and surgical margins are independent prognostic factors for the OS in patients with MMHN. The AJCC 7th edition staging system for MMHN appears to effectively stage this disease.

Diagnostic accuracy of ultrasonographic features for lymph node metastasis in papillary thyroid microcarcinoma: a single-center retrospective study.

BACKGROUND: Whether sonography is an appropriate imaging modality for cervical lymph nodes in patients with papillary thyroid microcarcinoma (PTMC) remains unclear. Hence, this study aimed to evaluate the diagnostic value of ultrasonography (US) features for lymph node metastasis in PTMC. METHODS: Seven hundred twelve patients with PTMC who underwent conventional ultrasonography examinations of the cervical lymph nodes were included. All included cases underwent total thyroidectomy plus prophylactic central lymph node dissection. The included lymph nodes were marked superficially, and the corresponding lymph nodes were completely removed and sent for pathological examination. The US features of lymph nodes with and without metastasis were compared, and the odds ratios of the suspicious US features were determined with univariate and multivariate analyses. RESULTS: Round shape, loss of an echogenic fatty hilum, cystic change, calcification, and abnormal vascularity were significantly more common in metastatic than nonmetastatic lymph nodes, whereas the boundary and echo did not significantly differ. Multivariate logistic regression analysis showed that round shape, loss of echogenic fatty hilum, cystic change, calcification, and abnormal vascularity were independent predictive factors for the assessment of metastatic lymph nodes. Round shape had the highest sensitivity of all variables, while loss of an echogenic fatty hilum had the highest specificity and accuracy. The area under the receiver operating characteristic curve, which was calculated to verify the relationship between the various US features and metastatic lymph nodes, was 0.793. CONCLUSIONS: Our study found that the US features of round shape, cystic change, calcification, loss of echogenic fatty hilum, and abnormal vascularity were useful sonographic criteria for differentiating between cervical lymph nodes with and without metastasis.