Cholangiocarcinoma combined with biliary obstruction: an exosomal circRNA signature for diagnosis and early recurrence monitoring.

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with currently suboptimal diagnostic and prognostic approaches. We present a novel system to monitor CCA using exosomal circular RNA (circRNA) via serum and biliary liquid biopsies. A pilot cohort consisting of patients with CCA-induced biliary obstruction (CCA-BO, n = 5) and benign biliary obstruction (BBO, n = 5) was used to identify CCA-derived exosomal circRNAs through microarray analysis. This was followed by a discovery cohort (n = 20) to further reveal a CCA-specific circRNA complex (hsa-circ-0000367, hsa-circ-0021647, and hsa-circ-0000288) in both bile and serum exosomes. In vitro and in vivo studies revealed the three circRNAs as promoters of CCA invasiveness. Diagnostic and prognostic models were established and verified by two independent cohorts (training cohort, n = 184; validation cohort, n = 105). An interpreter-free diagnostic model disclosed the diagnostic power of biliary exosomal circRNA signature (Bile-DS, AUROC = 0.947, RR = 6.05) and serum exosomal circRNA signature (Serum-DS, AUROC = 0.861, RR = 4.04) compared with conventional CA19-9 (AUROC = 0.759, RR = 2.08). A prognostic model of CCA undergoing curative-intent surgery was established by calculating early recurrence score, verified with bile samples (Bile-ERS, C-index=0.783) and serum samples (Serum-ERS, C-index = 0.782). These models, combined with other prognostic factors revealed by COX-PH model, enabled the establishment of nomograms for recurrence monitoring of CCA. Our study demonstrates that the exosomal triple-circRNA panel identified in both bile and serum samples serves as a novel diagnostic and prognostic tool for the clinical management of CCA.

Prognostic factors associated with early recurrence following liver resection for colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is the 3rd most common malignancy with the liver being the most common site of metastases. The recurrence rate of colorectal liver metastases (CRLM) after liver resection (LR) is notably high, with an estimated 40% of patients experiencing recurrence within 6 months. In this context, we conducted a meta-analysis to synthesize and evaluate the reliability of evidence pertaining to prognostic factors associated with early recurrence (ER) in CRLM following LR. METHODS: Systematic searches were conducted from the inception of databases to July 14, 2023, to identify studies reporting prognostic factors associated with ER. The Quality in Prognostic Factor Studies (QUIPS) tool was employed to assess risk-of-bias for included studies. Meta-analysis was then performed on these prognostic factors, summarized by forest plots. The grading of evidence was based on sample size, heterogeneity, and Egger's P value. RESULTS: The study included 24 investigations, comprising 12705 individuals, during an accrual period that extended from 2007 to 2023. In the evaluation of risk-of-bias, 22 studies were rated as low/moderate risk, while two studies were excluded because of high risk. Most of the studies used a postoperative interval of 6 months to define ER, with 30.2% (95% confidence interval [CI], 24.1-36.4%) of the patients experiencing ER following LR. 21 studies were pooled for meta-analysis. High-quality evidence showed that poor differentiation of CRC, larger and bilobar-distributed liver metastases, major hepatectomy, positive surgical margins, and postoperative complications were associated with an elevated risk of ER. Additionally, moderate-quality evidence suggested that elevated levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA199), lymph node metastases (LNM) of CRC, and a higher number of liver metastases were risk factors for ER. CONCLUSION: This review has the potential to enhance the efficacy of surveillance strategies, refine prognostic assessments, and guide judicious treatment decisions for CRLM patients with high risk of ER. Additionally, it is essential to undertake well-designed prospective investigations to examine additional prognostic factors and develop salvage therapeutic approaches for ER of CRLM.

Combining a glycolysis­related prognostic model based on scRNA­Seq with experimental verification identifies ZFP41 as a potential prognostic biomarker for HCC.

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis, and its heterogeneity affects the response to clinical treatments. Glycolysis is highly associated with HCC therapy and prognosis. The present study aimed to identify a novel biomarker for HCC by exploring the heterogeneity of glycolysis in HCC. The intersection of both marker genes of glycolysis­related cell clusters from single­cell RNA sequencing analysis and mRNA data of liver HCC from The Cancer Genome Atlas were used to construct a prognostic model through Cox proportional hazard regression and the least absolute shrinkage and selection operator Cox regression. Data from the International Cancer Genome Consortium were used to validate the results of the analysis. Immune status analysis was then conducted. A significant gene in the prognostic model was identified as a potential biomarker and was verified through in vitro experiments. The results revealed that the glycolysis­related prognostic model divided patients with HCC into high­ and low­risk groups. A nomogram combining the model and clinical features exhibited accurate predictive ability, with an area under the curve of 0.763 at 3 years. The high­risk group exhibited a higher expression of checkpoint genes and lower tumor immune dysfunction and exclusion scores, suggesting that this group may be more likely to benefit from immunotherapy. The tumor tissues had a higher zinc finger protein (ZFP)41 mRNA and protein expression compared with the adjacent tissues. In vitro analyses revealed that ZFP41 played a crucial role in cell viability, proliferation, migration, invasion and glycolysis. On the whole, the present study demonstrates that the glycolysis­related prognostic gene, ZFP41, is a potential prognostic biomarker and therapeutic target, and may play a crucial role in glycolysis and malignancy in HCC.

METTL3-mediated m6A modification of lncRNA TSPAN12 promotes metastasis of hepatocellular carcinoma through SENP1-depentent deSUMOylation of EIF3I.

In a previous study, we discovered that the level of lnc-TSPAN12 was significantly elevated in hepatocellular carcinoma (HCC) and correlated with a low survival rate. However, the function and mechanism of lnc-TSPAN12 in modulating epithelial-mesenchymal transition (EMT) and metastasis in HCC remains poorly understood. This study demonstrates that lnc-TSPAN12 positively influences migration, invasion, and EMT of HCC cells in vitro and promotes hepatic metastasis in vivo. The modification of N6-methyladenosine, driven by METTL3, is essential for the stability of lnc-TSPAN12, which may partially contribute to the upregulation of lnc-TSPAN12. Mechanistically, lnc-TSPAN12 exhibits direct interactions with EIF3I and SENP1, acting as a scaffold to enhance the SENP1-EIF3I interaction. As a result, the SUMOylation of EIF3I is inhibited, preventing its ubiquitin-mediated degradation. Ultimately, this activates the Wnt/ß-catenin signaling pathway, stimulating EMT and metastasis in HCC. Our findings shed light on the regulatory mechanism of lnc-TSPAN12 in HCC metastasis and identify the lnc-TSPAN12-EIF3I/SENP1 axis as a novel therapeutic target for HCC.

Short-term and long-term clinical outcomes of combined major vessel resection for hilar cholangiocarcinoma: a propensity score analysis.

Purpose: In the treatment of hilar cholangiocarcinoma (HCCA), combined resection of important hepatic vessels remains controversial. The purpose of this study was to compare the postoperative complications and prognosis of combined and non-combined major vessel resections in patients undergoing radical resection for HCCA. Methods: In this study, patients with HCCA who underwent curative resection between January 2007 and December 2018 were retrospectively enrolled. Postoperative complications and prognosis between the groups were compared using propensity score-matching (PSM) analysis. Results: There were 310 patients included in this study. The portal vein resection (PVR) and hepatic artery resection (HAR) groups had a higher incidence of postoperative complications than the control group. Patients in the HAR group had an increased risk of abdominal and pleural effusion after surgery. Patients who underwent combined PVR had better overall survival (OS; P = 0.020) and disease-free survival (DFS; P = 0.020). After curative-intent resection, patients in the HAR group had improved OS (P = 0.027) and DFS (P = 0.023). The postoperative complications of combined vascular resection (VR) did not worsen long-term survival for patients. Conclusion: In patients with HCCA, combined VR improved prognosis. The postoperative complications of combined VR do not worsen patient survival. Therefore, radical surgical resection is recommended.

Epidemiology, risk factors, diagnosis, and treatment of intra-abdominal traumatic neuromas - a narrative review.

Traumatic neuroma (TN) is a disorganized proliferation of injured nerves arising from the axons and Schwann cells. Although TN rarely occurs in the abdominal cavity, the incidence of TN may be underestimated because of the large number of asymptomatic patients. TN can cause persistent pain, which seriously affects quality of life. TN of the biliary system can cause bile duct obstruction, leading to acute cholangitis. It is difficult to differentiate TN from malignancies or recurrence of malignancy, which results in a number of patients receiving aggressive treatment. We collected cases reports of intra-abdominal TN over the past 30 years form PubMed and cases diagnosed in our medical center over the past 20 years, which is the largest case series of intra-abdominal TN to the best of our knowledge. In this review, we discuss the epidemiology, pathophysiology, risk factors, classification, diagnosis, and management of intra-abdominal TN.

Biliary drainage in malignant biliary obstruction: an umbrella review of randomized controlled trials.

Background: There are still many controversies about biliary drainage in MBO, and we aimed to summarize and evaluate the evidence associated with biliary drainage. Methods: We conducted an umbrella review of SRoMAs based on RCTs. Through July 28, 2022, Embase, PubMed, WOS, and Cochrane Database were searched. Two reviewers independently screened the studies, extracted the data, and appraised the methodological quality of the included studies. GRADE was used to evaluate the quality of the evidence. Results: 36 SRoMAs were identified. After excluding 24 overlapping studies, 12 SRoMAs, including 76 RCTs, and 124 clinical outcomes for biliary drainage in MBO were included. Of the 124 pieces of evidence evaluated, 13 were rated "High" quality, 38 were rated "Moderate", and the rest were rated "Low" or "Very low". For patients with MBO, 125I seeds+stent can reduce the risk of stent occlusion, RFA+stent can improve the prognosis; compared with PC, SEMS can increase the risk of tumor ingrowth and reduce the occurrence of sludge formation, and the incidence of tumor ingrowth in C-SEMS/PC-SEMS was significantly lower than that in U-SEMS. There was no difference in the success rate of drainage between EUS-BD and ERCP-BD, but the use of EUS-BD can reduce the incidence of stent dysfunction. For patients with obstructive jaundice, PBD does not affect postoperative mortality compared to direct surgery. The use of MS in patients with periampullary cancer during PBD can reduce the risk of re-intervention and stent occlusion compared to PC. In addition, we included four RCTs that showed that when performing EUS-BD on MBO, hepaticogastrostomy has higher technical success rates than choledochoduodenostomy. Patients who received Bilateral-ENBD had a lower additional drainage rate than those who received Unilateral-ENBD. Conclusions: Our study summarizes a large amount of evidence related to biliary drainage, which helps to reduce the uncertainty in the selection of biliary drainage strategies for MBO patients under different circumstances.

Timing of surgery in patients with synchronous colorectal cancer liver metastases undergoing neoadjuvant chemotherapy: a propensity score analysis.

BACKGROUND: The optimal timing of surgery after neoadjuvant chemotherapy (NAC) in patients with synchronous colorectal cancer liver metastases (SLM) remains controversial. We plan to analyze whether the choice of different surgical timings will have different effects on the perioperative and oncologic outcomes of patients. METHOD: We retrospectively collected all patients who met the inclusion and exclusion criteria from 2010 to 2020 in West China Hospital. Patients were grouped according to time interval (TI) after NAC to surgery. The perioperative and oncologic outcomes of the two groups were compared after propensity score matching. Univariate and multivariate analyzes were used to screen factors associated with prognosis. RESULT: Among 255 enrolled patients, 188 were matched with comparable baseline (94 each group). Patients in the 6≦TI≦8 group had longer operation time, less intraoperative blood loss, and less postoperative complications than those in the 4≦TI < 6 group. However, the overall survival (OS) (p = 0.012) and disease-free survival (DFS) (p = 0.013) of the patients in the 4≦TI < 6 group were better than those in the 6≦TI≦8 group. Subgroup analysis found that the above conclusions still apply in age ≥ 60, non-anemic patients, and patients who underwent R0 resection. OS was inversely correlated with TI in patients without preoperative jaundice. DFS was negatively correlated with TI in patients with preoperative jaundice. Multivariate analysis showed that the prolongation of TI after NAC to surgery was an independent prognostic risk factor for OS and DFS. CONCLUSIONS: Patients with SLM may be a better choice for surgery within 4-6 weeks after receiving NAC. Although patients with SLM undergoing surgery 4-6 weeks after NAC has a higher rate of postoperative complications, radical surgery is still recommended for a better survival benefit.

A meta-analysis of prognostic factors for early recurrence in perihilar cholangiocarcinoma after curative-intent resection.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) is a type of cancer that has a high rate of recurrence after curative-intent surgery, with about half of all recurrences occurring within the first year. The primary aim of this study was to identify prognostic factors (PFs) for early recurrence (ER, within 12 months) after surgery. METHODS: Systematic searching was conducted from database inception to September 28th, 2022, with duplicate independent review and data extraction. Data on eight predefined PFs were collected, and meta-analysis was performed on PFs for ER, summarized using forest plots. RESULTS: The study enrolled 11 studies comprising 2877 patients. In the risk-of-bias assessment, seven studies were rated as low risk and four as moderate risk. More than 34.3% (95% confidence interval [CI], 26.1-42.5%) of the patients experienced ER after curative-intent pCCA resection. Of the PFs, vascular invasion (HR, 2.41; 95% CI, 1.47-3.95; OR, 1.60; 95% CI, 1.17-2.18), lymph node metastases (HR, 2.54; 95% CI, 1.92-3.37; OR, 4.26; 95% CI, 2.40-7.57), and R1 resection (HR, 3.27; 95% CI, 1.81-5.92; OR, 2.40; 95% CI, 1.36-4.22) were associated with an increased hazard for ER. The combined OR values also showed that tumor size, poor tumor differentiation, and perineural invasion were linked to an elevated risk of ER, but all of them had apparent heterogeneity. CONCLUSION: These findings from the review could be used to plan surveillance of ER and guide post-operative individualized management in pCCA. Furthermore, prospective studies are needed to explore more prognostic factors for ER of pCCA.

Chemotherapy and targeted therapy for advanced biliary tract cancers: an umbrella review.

BACKGROUND: Malignant tumors of the biliary system are characterized by a high degree of malignancy and strong invasiveness, and they are usually diagnosed at late stages with poor prognosis. For patients with advanced biliary tract cancer, chemotherapy and targeted therapy are two of the options available to improve prognosis and delay tumor progression. This study aimed to comprehensively evaluate the safety and effectiveness of various chemotherapy schemes for the treatment of advanced biliary tract cancer in published systematic reviews and meta-analyses (SRoMAs). METHODS: An umbrella review method was adopted, which aims to summarize the existing evidence from multiple studies around a research topic. SRoMAs up to April 9, 2022, were identified using PubMed, Web of Science, the Cochrane database, and manual screening. Eligible studies were screened according to inclusion and exclusion criteria. This study had been registered at PROSPERO (CRD42022324548). For each eligible study, we extracted the data of general characteristics and the main findings. The methodological quality of the included studies were assessed by the AMSTAR2 scale, and the quality of evidence was evaluated by the GRADE tools. RESULTS: A total of 1833 articles were searched; 14 unique articles with 94 outcomes were identified by eligibility criteria. The incidence of skin rash (RR = 18.11, 95% CI 5.13-63.91, GRADE: Moderate) and diarrhea (RR = 2.48, 95% CI 1.2-5.10, GRADE: Moderate) was higher in patients receiving gemcitabine-based chemotherapy plus targeted therapy than in patients receiving gemcitabine monotherapy. The number of patients receiving gemcitabine-based chemotherapy who developed leukopenia (OR = 7.17, 95% CI 1.43-36.08, GRADE: Moderate), anemia (OR = 7.04, 95% CI 2.59-19.12, GRADE: High), thrombocytopenia (RR = 2.45, 95% CI 1.39-4.32, GRADE: Moderate), and neutropenia (RR = 3.30, 95% CI 1.04-10.50, GRADE: Moderate) was significantly higher than that of patients who received gemcitabine-free regimens. In addition, patients receiving S-1 monotherapy had significantly better ORR (RR = 2.46, 95% CI 1.27-4.57, GRADE: Moderate) than patients receiving S-1 + gemcitabine. Patients receiving fluoropyrimidine-based chemotherapy had longer OS (HR = 0.83, 95% CI 0.7-0.99, GRADE: Moderate), higher DCR (0R = 5.18, 95% CI 3.3-10.23, GRADE: Moderate), and higher ORR (0R = 3.24, 95% CI 1.18-8.92, GRADE: Moderate) compared with patients who received 5-FU/LV monotherapy or supportive therapy. Surprisingly, we found evidence that gemcitabine-based chemotherapy did not improve postoperative patients' OS (HR = 0.91, 95% CI 0.74-1.12, GRADE: Moderate) when compared with best supportive care. CONCLUSIONS: This study comprehensively evaluated the safety and efficacy of chemotherapy or targeted therapy regimens for advanced biliary tract cancer and found 11 outcomes with "Moderate" or "High" levels; however, most of the outcomes were still at "low" or "very low" levels. More randomized controlled studies are needed in the future to further summarize high levels of evidence.

Cuproptosis-related genes score: A predictor for hepatocellular carcinoma prognosis, immunotherapy efficacy, and metabolic reprogramming.

Background: Cuproptosis is a newly identified type of programmed cell death, characterized by aggregation of mitochondrial lipoylated proteins and the destabilization of Fe-S cluster proteins triggered by copper. However, its role in hepatocellular carcinoma (HCC) remains unclear. Methods: We analyzed the expression and prognostic significance of cuproptosis-related genes using the data obtained from TCGA and ICGC datasets. A cuproptosis-related genes (CRG) score was constructed and validated via least absolute shrinkage and selection operator (LASSO) Cox regression, multivariate Cox regression and nomogram model. The metabolic features, immune profile and therapy guidance of CRG-classified HCC patients were processed via R packages. The role of kidney-type glutaminase (GLS) in cuproptosis and sorafenib treatment has been confirmed via GLS knockdown. Results: The CRG score and its nomogram model performed well in predicting prognosis of HCC patients based on the TCGA cohort (training set), ICGC cohort and GEO cohort (validation set). The risk score was proved as an independent predictor for overall survival (OS) of HCC. The area under the curves (AUCs) of the model in the training and validation cohorts were all around 0.83 (TCGA, 1- year), 0.73 (TCGA, 3- year), 0.92 (ICGC, 1- year), 0.75 (ICGC, 3- year), 0.77 (GEO, 1- year), 0.76(GEO, 3- year). Expression levels of metabolic genes and subtypes of immune cells, and sorafenib sensitiveness varied significantly between the high-CRG group and low-CRG group. One of the model-included gene, GLS, might be involved in the process of cuproptosis and sorafenib treatment in HCC cell line. Conclusion: The five cuproptosis-related genes model contributed to prognostic prediction and provided a new sight for cuproptosis-related therapy in HCC.

Prognostic Implications of Novel Gene Signatures in Gastric Cancer Microenvironment.

BACKGROUND Increasing studies have shown the important clinical role of immune and stromal cells in gastric cancer microenvironment. Based on information of immune and stromal cells in The Cancer Genome Atlas, this study aimed to construct a prognostic risk assessment model for gastric cancer. MATERIAL AND METHODS Based on the immune/structural scores, differentially expressed genes (DEGs) were filtered and analyzed. Afterwards, DEGs associated with prognosis were screened and the risk assessment model was constructed in the training set. Moreover, the validity of the model was verified both in the testing set and the overall sample. RESULTS In this study, patients were divided into high-score and low-score groups based on immune/stromal score, and 919 DEGs were identified. By applying least absolute shrinkage and selection operator (LASSO) and Cox analysis, 10 mRNAs were selected to form a prognostic risk assessment model, risk score=(0.294*SLC17A9) + (-0.477*FERMT3) + (0.866*NRP1) + (0.350*MMRN1) + (0.381*RNASE1) + (0.189*TRIB3) + (0.230*PGAP3) + (0.087*MAGEA3) + (0.182*TACR2) + (0.368*CYP51A1). In the training set, the low-risk group divided by the model was found to have better overall survival, and the prediction efficiency of the model was demonstrated to be good. Multivariate Cox analysis indicated that the model could work as a prognostic factor independently. Similar results were shown in the testing group and overall patients cohort group. Finally, the risk assessment model and other clinical variables were integrated to construct a nomogram. CONCLUSIONS In general, this study constructs a prognostic risk assessment model for gastric cancer, which could improve the prognosis stratification of patients combined with other clinical indicators.

Identification and validation of an individualized autophagy-clinical prognostic index in gastric cancer patients.

BACKGROUND: The purpose of this study is to perform bioinformatics analysis of autophagy-related genes in gastric cancer, and to construct a multi-gene joint signature for predicting the prognosis of gastric cancer. METHODS: GO and KEGG analysis were applied for differentially expressed autophagy-related genes in gastric cancer, and PPI network was constructed in Cytoscape software. In order to optimize the prognosis evaluation system of gastric cancer, we established a prognosis model integrating autophagy-related genes. We used single factor Cox proportional risk regression analysis to screen genes related to prognosis from 204 autophagy-related genes in The Atlas Cancer Genome (TCGA) gastric cancer cohort. Then, the generated genes were applied to the Least Absolute Shrinkage and Selection Operator (LASSO). Finally, the selected genes were further included in the multivariate Cox proportional hazard regression analysis to establish the prognosis model. According to the median risk score, patients were divided into high-risk group and low-risk group, and survival analysis was conducted to evaluate the prognostic value of risk score. Finally, by combining clinic-pathological features and prognostic gene signatures, a nomogram was established to predict individual survival probability. RESULTS: GO analysis showed that the 28 differently expressed autophagy-related genes was enriched in cell growth, neuron death, and regulation of cell growth. KEGG analysis showed that the 28 differently expressed autophagy-related genes were related to platinum drug resistance, apoptosis and p53 signaling pathway. The risk score was constructed based on 4 genes (GRID2, ATG4D,GABARAPL2, CXCR4), and gastric cancer patients were significantly divided into high-risk and low-risk groups according to overall survival. In multivariate Cox regression analysis, risk score was still an independent prognostic factor (HR = 1.922, 95% CI = 1.573-2.349, P < 0.001). Cumulative curve showed that the survival time of patients with low-risk score was significantly longer than that of patients with high-risk score (P < 0.001). The external data GSE62254 proved that nomograph had a great ability to evaluate the prognosis of individual gastric cancer patients. CONCLUSIONS: This study provides a potential prognostic marker for predicting the prognosis of GC patients and the molecular biology of GC autophagy.

Identification of Hub Genes and Pathways in Gastric Adenocarcinoma Based on Bioinformatics Analysis.

BACKGROUND Gastric adenocarcinoma accounts for 95% of all gastric malignant tumors. The purpose of this research was to identify differentially expressed genes (DEGs) of gastric adenocarcinoma by use of bioinformatics methods. MATERIAL AND METHODS The gene microarray datasets of GSE103236, GSE79973, and GSE29998 were imported from the GEO database, containing 70 gastric adenocarcinoma samples and 68 matched normal samples. Gene ontology (GO) and KEGG analysis were applied to screened DEGs; Cytoscape software was used for constructing protein-protein interaction (PPI) networks and to perform module analysis of the DEGs. UALCAN was used for prognostic analysis. RESULTS We identified 2909 upregulated DEGs (uDEGs) and 7106 downregulated DEGs (dDEGs) of gastric adenocarcinoma. The GO analysis showed uDEGs were enriched in skeletal system development, cell adhesion, and biological adhesion. KEGG pathway analysis showed uDEGs were enriched in ECM-receptor interaction, focal adhesion, and Cytokine-cytokine receptor interaction. The top 10 hub genes - COL1A1, COL3A1, COL1A2, BGN, COL5A2, THBS2, TIMP1, SPP1, PDGFRB, and COL4A1 - were distinguished from the PPI network. These 10 hub genes were shown to be significantly upregulated in gastric adenocarcinoma tissues in GEPIA. Prognostic analysis of the 10 hub genes via UALCAN showed that the upregulated expression of COL3A1, COL1A2, BGN, and THBS2 significantly reduced the survival time of gastric adenocarcinoma patients. Module analysis revealed that gastric adenocarcinoma was related to 2 pathways: including focal adhesion signaling and ECM-receptor interaction. CONCLUSIONS This research distinguished hub genes and relevant signal pathways, which contributes to our understanding of the molecular mechanisms, and could be used as diagnostic indicators and therapeutic biomarkers for gastric adenocarcinoma.

Ameliorative effects of a fusion protein dual targeting interleukin 17A and tumor necrosis factor α on imiquimod-induced psoriasis in mice.

In recent decades, biological agents such as tumor necrosis factor-α (TNF-α) inhibitors, have revolutionized the treatment of psoriasis. However, inhibition of a single cytokine may not achieve satisfactory therapeutic results. It is against this background that this research was undertaken to investigate the anti-psoriatic effect of a novel fusion protein (DTF) dual targeting TNF-α and interleukin-17 A (IL-17 A). Imiquimod (IMQ) was topically applied to the skin of mice to develop psoriasis-like skin and treated with etanercept or different doses of DTF. Results showed that DTF treatment (1 mg/kg, 3 mg/kg, 5 mg/kg) significantly attenuated IMQ-induced typical psoriasis-like inflammation, severity score, and epidermis thickening in a dose-dependent manner, and was again more efficient than etanercept (3 mg/kg) in alleviating all these parameters at the same dose. Furthermore, DTF was more potent than etanercept in suppressing the expression of inflammatory factors (IL-17 A, IL-6, IL-1ß, IL-23, IL-22 and IL-12) in the serum, spleen and psoriasis-like skin compared with etanercept at the same dose. In addition, DTF was more efficient than etanercept in reducing the expression of keratins, decreasing the mRNA expression of Ly-6 G and Ly-6C, and enhancing the expression of filaggrin and caspase 14 in IMQ-induced psoriasis-like skin. We conclude that DTF alleviates IMQ-induced psoriasis by attenuating inflammatory cascades, reducing keratinocytes proliferation and improving epidermal barrier function through suppressing TNF-α and IL-17 A signal pathways. These data suggest that DTF has potential to be a novel therapeutic candidate for psoriasis.