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ObjectiveThere is some evidence for an association between gut microbiota and nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, but no studies have explored their causal relationship.MethodsInstrumental variables of the gut microbiota (N = 13266) and gut microbiota-derived metabolites (N = 7824) were acquired, and a Mendelian randomization study was performed to explore their influence on NAFLD (1483 European cases and 17,781 European controls), ALD (2513 European cases and 332,951 European controls), and viral hepatitis risk (1971 European cases and 340,528 European controls). The main method for examining causality is inverse variance weighting (IVW).ResultsIVW results confirmed that Anaerotruncus (p = 0.0249), Intestinimonas (p = 0.0237), Lachnoclostridium (p = 0.0245), Lachnospiraceae NC2004 group (p = 0.0083), Olsenella (p = 0.0163), and Peptococcus (p = 0.0472) were protective factors for NAFLD, and Ruminococcus 1 (p = 0.0120) was detrimental for NAFLD. The higher abundance of three genera, Lachnospira (p = 0.0388), Desulfovibrio (p = 0.0252), and Ruminococcus torques group (p = 0.0364), was correlated with a lower risk of ALD, while Ruminococcaceae UCG 002 level was associated with a higher risk of ALD (p = 0.0371). The Alistipes (p = 0.0069) and Ruminococcaceae NK4A214 group (p = 0.0195) were related to a higher risk of viral hepatitis. Besides, alanine (p = 0.0076) and phenyllactate (p = 0.0100) were found to be negatively correlated with NAFLD, while stachydrine (Op = 0.0244) was found to be positively associated with NAFLD. The phenylacetate (p = 0.0353) and ursodeoxycholate (p = 0.0144) had a protective effect on ALD, while the threonate (p = 0.0370) exerted a detrimental influence on ALD. The IVW estimates of alanine (p = 0.0408) and cholate (p = 0.0293) showed their suggestive harmful effects against viral hepatitis, while threonate (p = 0.0401) displayed its suggestive protective effect against viral hepatitis.ConclusionIn conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.

BackgroundMany reports have described that abnormal nectin-4 expression may be used as a prognostic marker in many tumors. However, these studies failed to reach a consensus. Here, we performed a meta-analysis to comprehensively evaluate the prognostic value of nectin-4 in cancers.MethodsRelevant studies were identified through a comprehensive search of PubMed, EMBASE and Web of science until August 31, 2022. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the relationship between nectin-4 expression and overall survival (OS) and disease-free survival/progression-free survival/relapse-free survival (DFS/PFS/RFS). Odds ratios (ORs) with 95% CIs were applied to assess the relationship between nectin-4 expression and clinicopathologic features. Subgroup analysis was performed to explore the sources of heterogeneity. Sensitivity analysis and funnel plot were used to test the reliability of the results. All data analyses were performed using STATA version 12.0 software.ResultsFifteen articles involving 2245 patients were included in the meta-analysis. The pooled analysis showed that high nectin-4 expression was significantly associated with poor OS (HR: 1.75, 95% CI: 1.35–2.28). There was no relationship between high nectin-4 expression and DFS/PFS/RFS (HR: 178, 95% CI: 0.78–4.08).Subgroup analyses revealed that that high nectin-4 expression mainly presented adverse OS in esophageal cancer (EC) (HR: 1.78, 95% CI: 1.30–2.44) and gastric cancer (GC) (HR: 1.92, 95% CI: 1.43–2.58). We also found that high nectin-4 expression was associated with tumor diameter (big vs small) (OR: 1.96, 95% CI: 1.02–3.75), tumor stage (III-IV vs I-II) (OR: 2.04, 95% CI: 1.01–4.12) and invasion depth (T3+T4 vs T2+T1) (OR: 3.95, 95% CI: 2.06–7.57).ConclusionsNectin-4 can be used as an effective prognostic indicator for specific cancers.

BackgroundNumerous studies showed that preoperative platelet-albumin-bilirubin (PALBI) grade was closely related to the prognostic outcome of patients with hepatocellular carcinoma (HCC). However, the conclusions were inconsistent. Therefore, we implemented the study to comprehensively evaluate the association between PALBI grade and prognosis in patients with HCC.MethodsRelevant articles were collected from the specified databases until February 10, 2022. We included all studies exploring the relationship between PALBI grade and prognosis in HCC patients. We used the hazard ratio (HR) and 95% confidence interval (CI) to calculate the comprehensive analysis. All data analyses were performed using STATA 12.0.ResultsThirteen retrospective articles containing 15534 patients were included in the meta-analysis. The pooled results displayed that the high PALBI grade was obviously correlated with poor overall survival (OS) (HR: 1.71, 95% CI: 1.46-2.02) and disease-free survival/relapse-free survival (DFS/RFS) (HR:1.31; 95% CI: 1.11–1.54). Subgroup analyses further confirmed the reliability of the comprehensive results.ConclusionsPALBI may be a valid prognostic indicator in HCC patients. More investigations were needed to test our findings.

Background: Although many genes related to epithelial-mesenchymal transition (EMT) have been explored in hepatocellular carcinoma (HCC), their prognostic significance still needs further analysis.Methods: Differentially expressed EMT-related genes were obtained through the integrated analysis of 4 Gene expression omnibus (GEO) datasets. The univariate Cox regression and Lasso Cox regression models are utilized to determine the EMT-related gene signature. Based on the results of multivariate Cox regression, a predictive nomogram is established. Time-dependent ROC curve and calibration curve are used to show the distinguishing ability and consistency of the nomogram. Finally, we explored the correlation between EMT risk score and immune immunity.Results: We identified a nine EMT-related gene signature to predict the survival outcome of HCC patients. Based on the EMT risk score’s median, HCC patients in each dataset were divided into high and low-risk groups. The survival outcomes of HCC patients in the high-risk group were significantly worse than those in the low-risk group. The prediction nomogram based on the EMT risk score has better distinguishing ability and consistency. High EMT risk score was related to immune infiltration.Conclusion: The nomogram based on the EMT risk score can reliably predict the survival outcome of HCC patients, thereby providing benefits for medical decisions.

BackgroundThe prognostic significance of tumor burden score (TBS) on patients who underwent curative-intent resection of intrahepatic cholangiocarcinoma (ICC) has not been evaluated. The present study aimed to investigate the impact of TBS and its synergistic effect with CA19-9 (combination of TBS and CA19-9, CTC grade) on long-term outcomes.MethodsPatients who underwent radical resection of ICC between 2009 and 2017 were retrospectively identified from a multi-center database. The overall survival (OS) and recurrence-free survival (RFS) were examined in relation to TBS, serum preoperative CA19-9, and CTC grade.ResultsA total of 650 patients were included in our study (509 in the derivation cohort and 141 in the validation cohort). Kaplan–Meier curves showed that both TBS and CA19-9 levels were strong predictors of survival outcomes. Patients with elevated TBS grade or elevated CA19-9 were associated with worse OS and RFS (both p < 0.001). As expected, CTC grade also performed well in predicting long-term outcomes. Patients with low TBS/low CA19-9 (CTC grade 1) were associated with the best OS as well as RFS, while high TBS/high CA19-9 (CTC grade 3) correlated to the worst outcomes. In the validation cohort, TBS grade, preoperative CA19-9, and CTC grade also stratified prognosis among patients (p < 0.001 for each).ConclusionsBoth tumor morphology (tumor burden) and tumor-specific biomarker (serum CA19-9) were important when evaluating prognosis of patients with resectable ICC. Serum CA19-9 and TBS showed a synergistic effect on prognostic evaluation. CTC grade was a promising tool in stratifying prognosis of ICC patients after curative resection.

PurposeTo unravel the oncogenic role of CDCA4 in different cancers from the perspective of tumor immunity.MethodsRaw data on CDCA4 expression in tumor samples and paracancerous samples were obtained from TCGA and GTEX databases. In addition, we investigated pathological stages and the survival analysis of CDCA4 in pan-cancer across Gene Expression Profiling Interactive Analysis (GEPIA) database. Cox Proportional Hazards Model shows that high CDCA4 levels are associated with several vital indicators in oncology. On the one hand, we explored the correlation between CADA4 expression and tumor immune infiltration by the TIMER tool; On the other hand, we utilized the methods of CIBERSORT and ESTIMATE computational to evaluate the proportion of tumor infiltrating immune cells (TIIC) and the amounts of stromal and immune components based on TCGA database. The use of antineoplastic drugs and the expression of CDCA4 also showed a high correlation via linear regression. Protein–Protein Interaction analysis was performed in the GeneMANIA database, and enrichment analysis was performed and predicted signaling pathways were identified by using Gene Ontology and Kyoto Encyclopedia of Genes. The correlation between CDCA4 expression with Copy number variations (CNV) and methylation is detailed, respectively. Molecular biology experiments including Western blotting, flow cytometry, EDU staining, Transwell and Wound Healing assay to validate the cancer promoting role of CDCA4 in hepatocellular carcinoma (HCC).ResultsMost tumors highly expressed CDCA4. Elevated CDCA4 expression was associated with poor OS and DFS. There was a significant correlation between CDCA4 expression and TITCs. Moreover, markers of TIICs exhibited distinct patterns of CDCA4 associated immune infiltration. In addition, we pay attention to the association between the expression of CDCA4 and the use of the anti-tumor drugs. CDCA4 is related to biological progress (BP), cellular component (CC) and molecular function (MF). Dopaminergic Synapse, AMPK, Sphingolipid, Chagas Disease, mRNA Surveillance were significantly enriched pathways in positive and negative correlation genes with CDCA4. CNV is thought to be a positive correlation with CDCA4 expression. Conversely, methylation is negative correlation with CDCA4 expression. Molecular biology experiments confirm a cancer promoting role for CDCA4 in HCCConclusionCDCA4 may serve as a biomarker for cancer immunologic infiltration and poor prognosis, providing a new way of thinking for cancer treatment.

Background: The potential role of Neurotrophic factor-3(NTF3) in liver cancer is unknown. Therefore, we aimed to explore the clinical value of NTF3 in hepatocellular carcinoma (HCC).Methods: We used a variety of databases to analyze the expression, relationship with prognosis and immune significance of NTF3 in liver cancer through bioinformatics.Results: NTF3 was low expressed in HCC and was an independent prognostic factor in patients with HCC. CIBERSORT analysis indicated that NTF3 expression was positively correlated with CD4+ cells, mast cells, NK cells, macrophages and B cells in the tumor microenvironment. Furthermore, we found that NTF3 expression was negatively correlated with the immune checkpoints PD-L1, TIGIT and TIM-3. Functional network analysis revealed that NTF3 regulates HCC progression through a variety of cancer-related kinases, transcription factors and signaling pathways.Conclusions: We demonstrate that NTF3 correlates with prognosis and immune infiltration in HCC.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its prognosis remains unsatisfactory. The identification of new and effective markers is helpful for better predicting the prognosis of patients with HCC and for conducting individualized management. The oncogene Aurora kinase A (AURKA) is involved in a variety of tumors; however, its role in liver cancer is poorly understood. The aim of this study was to establish AURKA-related gene signatures for predicting the prognosis of patients with HCC.Methods: We first analyzed the expression of AURKA in liver cancer and its prognostic significance in different data sets. Subsequently, we selected genes with prognostic value related to AURKA and constructed a gene signature based on them. The predictive ability of the gene signature was tested using the HCC cohort development and verification data sets. A nomogram was constructed by integrating the risk score and clinicopathological characteristics. Finally, the influence of the gene signature on the immune microenvironment in HCC was comprehensively analyzed.Results: We found that AURKA was highly expressed in HCC, and it exhibited prognostic value. We selected eight AURKA-related genes with prognostic value through the protein-protein interaction network and successfully constructed a gene signature. The nine-gene signature could effectively stratify the risk of patients with HCC and demonstrated a good ability in predicting survival. The nomogram showed good discrimination and consistency of risk scores. In addition, the high-risk group showed a higher percentage of immune cell infiltration (i.e., macrophages, myeloid dendritic cells, neutrophils, and CD4+T cells). Moreover, the immune checkpoints SIGLEC15, TIGIT, CD274, HAVCR2, and PDCD1LG2 were also higher in the high-risk group versus the low-risk group.Conclusions: This gene signature may be useful prognostic markers and therapeutic targets in patients with HCC.

BackgroundCachexia is defined as an involuntary decrease in body weight, which can increase the risk of death in cancer patients and reduce the quality of life. Cachexia-inducing factors (CIFs) have been reported in colorectal cancer and pancreatic adenocarcinoma, but their value in diffuse large B-cell lymphoma (DLBCL) requires further genetic research.MethodsWe used gene expression data from Gene Expression Omnibus to evaluate the expression landscape of 25 known CIFs in DLBCL patients and compared them with normal lymphoma tissues from two cohorts [GSE56315 (n = 88) and GSE12195 (n = 136)]. The mutational status of CIFs were also evaluated in The Cancer Genome Atlas database. Based on the expression profiles of 25 CIFs, a single exploratory dataset which was merged by the datasets of GSE10846 (n = 420) and GSE31312 (n = 498) were divided into two molecular subtypes by using the method of consensus clustering. Immune microenvironment between different subtypes were assessed via single-sample gene set enrichment analysis and the CIBERSORT algorithm. The treatment response of commonly used chemotherapeutic drugs was predicted and gene set variation analysis was utilized to reveal the divergence in activated pathways for distinct subtypes. A risk signature was derived by univariate Cox regression and LASSO regression in the merged dataset (n = 882), and two independent cohorts [GSE87371 (n = 221) and GSE32918 (n = 244)] were used for validation, respectively.ResultsClustering analysis with CIFs further divided the cases into two molecular subtypes (cluster A and cluster B) associated with distinct prognosis, immunological landscape, chemosensitivity, and biological process. A risk-prognostic signature based on CCL2, CSF2, IL15, IL17A, IL4, TGFA, and TNFSF10 for DLBCL was developed, and significant differences in overall survival analysis were found between the low- and high-risk groups in the training dataset and another two independent validation datasets. Multivariate regression showed that the risk signature was an independently prognostic factor in contrast to other clinical characteristics.ConclusionThis study demonstrated that CIFs further contribute to the observed heterogeneity of DLBCL, and molecular classification and a risk signature based on CIFs are both promising tools for prognostic stratification, which may provide important clues for precision medicine and tumor-targeted therapy.