Adverse drug events associated with fluorouracil use in patients with metastatic colorectal cancer: a real-world pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND: Fluorouracil (5-FU) is widely used to treat metastatic colorectal cancer (mCRC), but real-world safety data is limited. Our study aimed to evaluate 5-FU's safety profile in a large mCRC population using the FAERS database. RESEARCH DESIGN AND METHODS: We conducted disproportionality analyses to identify adverse drug events associated with 5-FU use in mCRC patients from 2004 to 2023. Subgroup analyses, gender difference analyses, and logistic regression were also performed. RESULTS: We identified 1,458 reports with 5-FU as the primary suspected drug, with males accounting for 48.8% of reports. Gastrointestinal disorders were the most common adverse event (864 cases), while pregnancy-related conditions showed the strongest signal intensity (ROR = 2.97). We found 19 preferred terms with positive signals, including ischemic hepatitis (ROR = 59.32), blood iron increased (ROR = 59.32), and stress cardiomyopathy (ROR = 51.94). Males were more susceptible to weight loss and skin toxicity. Most adverse events occurred within the first month of 5-FU administration. CONCLUSION: Our study provides a comprehensive analysis of 5-FU's safety profile in mCRC patients, helping healthcare professionals mitigate risks in clinical practice.

Investigation of folate-modified EGCG-loaded thermosensitive nanospheres inducing immunogenic cell death and damage-associated molecular patterns in hepatocellular carcinoma.

BACKGROUND: The systemic treatment of advanced hepatocellular carcinoma is currently facing a bottleneck. EGCG, the primary active compound in green tea, exhibits anti-tumor effects through various pathways. However, there is a lack of study on EGCG-induced immunogenic cell death (ICD) in hepatocellular carcinoma. METHODS: In a previous study, we successfully synthesized folate-modified thermosensitive nano-materials, encapsulated EGCG within nanoparticles using a hydration method, and established the EGCG nano-drug delivery system. The viability of HepG2 cells post-EGCG treatment was assessed via the MTT and EdU assays. Cell migration and invasion were evaluated through wound healing experiments, Transwell assays, and Annexin V-FITC/PI assay for apoptosis detection. Additionally, the expression levels of damage-associated molecular patterns (DAMPs) were determined using immunofluorescence, ATP measurement, RT-qPCR, and Western Blot. RESULTS: The drug sensitivity test revealed an IC50 value of 96.94 µg/mL for EGCG in HepG2 cells after 48 h. EGCG at a low concentration (50 µg/mL) significantly impeded the migration and invasion of HepG2 cells, showing a clear dose-dependent response. Moreover, medium to high EGCG concentrations induced cell apoptosis in a dose-dependent manner and upregulated DAMPs expression. Immunofluorescence analysis demonstrated a notable increase in CRT expression following low-concentration EGCG treatment. As EGCG concentration increased, cell viability decreased, leading to CRT exposure on the cell membrane. EGCG also notably elevated ATP levels. RT-qPCR and Western Blot analyses indicated elevated expression levels of HGMB1, HSP70, and HSP90 following EGCG intervention. CONCLUSION: EGCG not only hinders the proliferation, migration, and invasion of hepatocellular carcinoma cells and induces apoptosis, but also holds significant clinical promise in the treatment of malignant tumors by promoting ICD and DAMPs secretion.

Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating epithelial-mesenchymal transition.

BACKGROUND: Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunotherapy. However, there is currently a lack of comprehensive investigation into how senescent and exhausted immune cells contribute to LM. METHODS: We gathered single-cell sequencing data from primary colorectal cancer (pCRC) and their corresponding matched LM tissues from 16 mCRC patients. In this study, we identified senescent and exhausted immune cells, performed enrichment analysis, cell communication, cell trajectory, and cell-based in vitro experiments to validate the results of single-cell multi-omics. This process allowed us to construct a regulatory network explaining the occurrence of LM. Finally, we utilized weighted gene co-expression network analysis (WGCNA) and 12 machine learning algorithms to create prognostic risk model. RESULTS: We identified senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) as the primary senescent and exhausted immune cells. Our findings indicate that SMCs and TEXs can potentially activate transcription factors downstream via ANGPTL4-SDC1/SDC4, this activation plays a role in regulating the epithelial-mesenchymal transition (EMT) program and facilitates the development of LM, the results of cell-based in vitro experiments have provided confirmation of this conclusion. We also developed and validated a prognostic risk model composed of 12 machine learning algorithms. CONCLUSION: This study elucidates the potential molecular mechanisms underlying the occurrence of LM from various angles through single-cell multi-omics analysis in CRC. It also constructs a network illustrating the role of senescent or exhausted immune cells in regulating EMT.

Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma.

Background: The challenge of systemic treatment for hepatocellular carcinoma (HCC) stems from the development of drug resistance, primarily driven by the interplay between cancer stem cells (CSCs) and the tumor microenvironment (TME). However, there is a notable dearth of comprehensive research investigating the crosstalk between CSCs and stromal cells or immune cells within the TME of HCC. Methods: We procured single-cell RNA sequencing (scRNA-Seq) data from 16 patients diagnosed with HCC. Employing meticulous data quality control and cell annotation procedures, we delineated distinct CSCs subtypes and performed multi-omics analyses encompassing metabolic activity, cell communication, and cell trajectory. These analyses shed light on the potential molecular mechanisms governing the interaction between CSCs and the TME, while also identifying CSCs' developmental genes. By combining these developmental genes, we employed machine learning algorithms and RT-qPCR to construct and validate a prognostic risk model for HCC. Results: We successfully identified CSCs subtypes residing within malignant cells. Through meticulous enrichment analysis and assessment of metabolic activity, we discovered anomalous metabolic patterns within the CSCs microenvironment, including hypoxia and glucose deprivation. Moreover, CSCs exhibited aberrant activity in signaling pathways associated with lipid metabolism. Furthermore, our investigations into cell communication unveiled that CSCs possess the capacity to modulate stromal cells and immune cells through the secretion of MIF or MDK, consequently exerting regulatory control over the TME. Finally, through cell trajectory analysis, we found developmental genes of CSCs. Leveraging these genes, we successfully developed and validated a prognostic risk model (APCS, ADH4, FTH1, and HSPB1) with machine learning and RT-qPCR. Conclusions: By means of single-cell multi-omics analysis, this study offers valuable insights into the potential molecular mechanisms governing the interaction between CSCs and the TME, elucidating the pivotal role CSCs play within the TME. Additionally, we have successfully established a comprehensive clinical prognostic model through bulk RNA-Seq data.

Does proton pump inhibitors use increase risk of digestive tumors?: A 2-sample Mendelian randomization study.

The objective of this study was to explore the causal relationship between the use of proton pump inhibitors (PPIs) and 16 types of digestive system tumors. We utilized a 2-sample Mendelian randomization (MR) approach to investigate this relationship. We obtained exposure and outcome data from the UK Biobank and the Finland Biobank, respectively. The genetic data used in the analysis were derived from genome-wide association studies (GWAS) studies conducted on European populations. We screened single nucleotide polymorphisms significantly associated with the use of omeprazole, a commonly used PPIs, as instrumental variables. We then performed MR analyses using the inverse variance weighting (IVW) method, MR-Egger regression, and the weighted median method to evaluate the causal effect of omeprazole use on the 16 types of digestive system tumors. Our MR analysis revealed a significant causal relationship between the use of omeprazole and pancreatic malignancies, but not with any other types of digestive system tumors. The IVW analysis showed an odds ratio of 4.33E-05 (95%CI: [4.87E-09, 0.38], P = .03) and the MR-Egger analysis showed an odds ratio of 5.81E-11 (95%CI: [2.82E-20, 0.12], P = .04). We found no significant heterogeneity or pleiotropy, and sensitivity analysis confirmed the robustness of our results. Furthermore, statistical power calculations suggested that our findings were reliable. Conclusion The use of PPIs is a protective factor for pancreatic malignancies, but no causal relationship has been found with other digestive system tumors.

Oxeiptosis core genes and their multi-omics analysis in hepatocellular carcinoma.

Oxeiptosis is a recently discovered caspase-independent, non-inflammatory programmed cell death modality. Current studies suggest that oxeiptosis has crucial effects on biological processes in a variety of diseases. However, the mechanism of oxeiptosis in hepatocellular carcinoma (HCC) remains unclear and no relevant studies have been published. Therefore, this study is intended to investigate the mechanism and prognostic role of oxeiptosis-related genes in HCC. We explored the mechanisms and molecular phenotypes underlying the role of oxeiptosis in HCC through multi-omics analysis. Firstly, we obtained RNA-sequencing and clinical data from public database and divided the samples into trial and validation cohorts in subsequent analyses. We then screened oxeiptosis core genes (OCGs) and screened prognosis-related genes. Based on different molecular markers, we identified the molecular phenotypes of HCC, and the potential OCGs molecular mechanisms were explored. Subsequently, we construct a prognostic prediction system for HCC. Finally, we analyzed the tumor microenvironment and the immune escape phenomenon. We screened a total of 69 OCGs, most of which were prognostic risk factors for HCC. A majority of OCGs were enriched in cell cycle regulation and mitotic processes, which were related to both tumor cell proliferation and death. We identified 2 different molecular typing options with significant differences in prognosis, function, and signaling pathway enrichment between different molecular subtypes. The prognostic prediction model combined with molecular phenotypes and had a good predictive effect. Finally, we found CD4 + T-cell exhaustion in samples with specific molecular phenotypes. Through multi-omics analysis of OCGs, we not only revealed the possible molecular mechanisms of OCGs in HCC but also provided a prognostic prediction system for clinical application through molecular typing and risk scoring model. Meanwhile, we found immune escape mechanisms in HCC.

The central helicase domain holds the major conformational epitopes of melanoma differentiation-associated gene 5 autoantibodies.

OBJECTIVES: Autoantibodies against MDA5 serve as a biomarker for dermatomyositis (DM) and a risk factor for interstitial lung disease (ILD). MDA5 is a protein responsible for sensing RNA virus infection and activating signalling pathways against it. However, little is known about antigen epitopes on MDA5 autoantibodies. We aimed to determine the interaction of the MDA5 autoantibody-antigen epitope. METHODS: Cell-based assays (CBAs), immunoprecipitation-immunoblot assays, and various immunoblotting techniques were used in the study. RESULTS: We demonstrate that DM patient autoantibodies recognize MDA5 epitopes in a native conformation-dependent manner. Furthermore, we identified the central helicase domain formed by Hel1, Hel2i, Hel2, and pincer (3Hel) as the major epitopes. As proof of principle, the purified 3Hel efficiently absorbed MDA5 autoantibodies from patient sera through immunoprecipitation-immunoblot assay. CONCLUSION: Our study uncovers the nature of antigen epitopes on MDA5 and provides guidance for diagnosis and targeted therapeutic approach development.

A novel rare variant of CNPY3 from familial NMOSD impairs the TLR-mediated immune response.

Toll-like receptors (TLRs) are a class of proteins that play essential roles in innate and adaptive immune responses. Recently, accumulating evidence has demonstrated that impairments in the TLR signalling pathway contribute to the development and progression of neuroimmune diseases, such as neuromyelitis optica spectrum disorder (NMOSD). However, the cellular and molecular mechanisms are still largely unknown. In this study, we report a novel variant, C52Y, of canopy FGF signalling regulator 3 (CNPY3) from patients with familial NMOSD and demonstrate that this variant shows a stronger interaction with GP96 and TLRs than with wild-type CNPY3. We find that C52Y has dominant negative effects on TLR4 surface expression. Importantly, the TLR4 surface expression level is decreased in RAW264.7 cells infected with the C52Y virus upon LPS stimulation. We further demonstrate that bone marrow-derived macrophages (BMDMs) from CNPY3C52Y/+ transgenic mice secrete less tumour necrosis factor (TNF) and interleukin (IL)-6 than BMDMs from wild-type mice upon stimulation with LPS. These data suggest that impairment of TLR trafficking may contribute to the development of neuroimmune disorders.

In Silico and In Vitro Studies on the Mechanisms of Chinese Medicine Formula (Yiqi Jianpi Jiedu Formula) in the Treatment of Hepatocellular Carcinoma.

Objective: Traditional Chinese medicine (TCM) is an important part of the comprehensive treatment of hepatocellular carcinoma (HCC), and Chinese materia medica formulas with the effect of "Yiqi Jianpi" (replenishing qi and strengthening spleen) or "Jiedu" (removing toxicity) have been proved to be effective in treating HCC. However, mechanisms of these formulas in treating HCC remain unclear. In this paper, our goal is to explore the antitumor activity and its molecular mechanisms of Yiqi Jianpi Jiedu (YQJPJD) formula against HCC. Methods: The bioactive ingredients and targets of YQJPJD formula and HCC targets were screened by five Chinese materia medicas and two disease databases, respectively. The network pharmacology was utilized to construct the relationship network between YQJPJD formula and HCC, and the mechanisms were predicted by the protein-protein interaction (PPI) network, pathway enrichment analysis, bioinformatics, and molecular docking. Numerous in vitro assays were performed to verify the effect of YQJPJD formula on HCC cells, cancer-associated targets, and PI3K/Akt pathway. Results: The network relationship between YQJPJD formula and HCC suggested that YQJPJD formula mainly regulated the potential therapeutic targets of HCC by several key bioactive ingredients (e.g., quercetin, luteolin, baicalein, and wogonin). PPI network, bioinformatics, and molecular docking analyses displayed that YQJPJD formula may play an anti-HCC effect through key targets such as MAPK3, RAC1, and RHOA. Additionally, pathway analysis demonstrated that YQJPJD formula could play an anti-HCC effect via multiple pathways (e.g., PI3K-Akt and hepatitis B). Experimental results showed that YQJPJD formula could effectively inhibit the proliferation, migration, and invasion of HCC cells and promote HCC cell apoptosis in a concentration-dependent manner. Moreover, YQJPJD formula could decrease the mRNA expression of ß-catenin, MAPK3, and RHOA and the protein expression of phosphorylated PI3K and Akt. Conclusion: YQJPJD formula mainly exerts its anti-HCC effect through multiple bioactive ingredients represented by quercetin, as well as multiple pathways and targets represented by PI3K/Akt pathway, ß-catenin, MAPK3, and RHOA.

Analysis of the association of HLA subtypes with cryptococcal meningitis in HIV-negative immunocompetent patients.

Objective: We aimed to study the possible relationship between cryptococcal meningitis (CM) and HLA genotypes in HIV-negative immunocompetent patients. Methods: HLA loci of 53 HIV-negative immunocompetent Han Chinese CM patients were compared with those in 481 healthy individuals. Results: We found a significant association between DQB1*05:02 and CM patients compared with controls. There were no significant differences in the frequencies of HLA alleles between CM with and without postinfectious inflammatory response syndrome and controls. Correlation analysis showed DQB1*05:02 was correlated with susceptibility to CM. CM patients carrying the DQB1*05:02 allele had more severe focal neurological deficit, higher initial modified Rankin Scale and British Medical Research Council staging scores. Conclusion: This study provides the first evidence for the interaction between specific HLA class II alleles and HIV-negative immunocompetent CM patients.

Cryptococcus neoformans is a pathogen that mainly causes infections in patients with a weakened immune system. The most common manifestation of C. neoformans infection is cryptococcal meningitis (CM), inflammation of the membranes that surround the brain and spinal cord. CM is a leading fungal cause of human disease and death worldwide. It mainly occurs in patients who are HIV positive, but is also an important cause of disease in individuals with immune systems that are working normally. However, little is known about the cause and development of the disease in HIV-negative individuals who have normally functioning immune systems. Human proteins called HLA molecules are associated with various infectious diseases, so we wondered whether HLA subtypes are associated with CM. Our study found that an HLA subtype called HLA-DQB1*05:02 was involved in C. neoformans infections that lead to CM. Patients with HLA-DQB1*05:02 had a significantly worse level of disability and problems with nerve, spinal cord or brain function. This study will be useful for exploring the influence of different forms of the HLA molecule on susceptibility to CM in HIV-negative individuals with a normally functioning immune system.

Immune Checkpoint Inhibitor Associated Autoimmune Encephalitis, Rare and Novel Topic of Neuroimmunology: A Case Report and Review of the Literature.

Immune checkpoint inhibitors (ICIs) are being used in patients with various advanced malignancies, and patient outcomes have improved considerably. Although ICIs can effectively treat tumors, 30-60% of patients experience immune-related adverse events (irAEs). Autoimmune encephalitis (AE) is a rare irAE that has become a novel topic in neuroimmunology and has received increasing attention in recent years. Herein, we report a rare case of GAD65-antibody-associated AE after metastatic small cell lung cancer treatment with pembrolizumab. The patient received IVIg therapy for AE and continuous pembrolizumab therapy without suspension of tumor treatment. At 1 year follow-up, both the patient's AE symptoms and tumors were stable. We consider that the treatment of ICI-associated AE should be more individualized with prudent decision-making and should balance the tumor progression and AE treatment. In addition, we have also comprehensively reviewed the literature of ICI-associated AE, and summarized the clinical features, treatment, and prognosis of AE caused by ICI, thus broadening our understanding of the neurological complications caused by ICI.

Anti-IgLON5 Encephalopathy with Concomitant Herpes Virus Encephalitis.

Anti-IgLON5 encephalopathy is a new and rare autoimmune encephalitis with unclear pathophysiology. In this study, we reported an unusual case of anti-IgLON5 encephalopathy with concomitant herpes virus encephalitis. A 51-year-old man with HLA-DQB1*05:01 and HLA-DRB1*10:01, who suffered from an episode of acute encephalitis, mental disorders, and memory impairment was admitted to our hospital. Human alpha herpes virus 1, human gamma herpes virus 4 (Epstein-Barr virus), and IgLON5-IgG were detected in the cerebrospinal fluid, indicating anti-IgLON5 encephalopathy with concomitant herpes virus encephalitis of this patient. Brain magnetic resonance imaging revealed T2 hyperintensities in the left temporal lobe and enhancement in the hippocampus. A mild sleep disorder was also found by video polysomnography. The patient was then treated with antiviral drugs, intravenous immunoglobulins, methylprednisolone, and protein A immunoadsorption. After treatment, the patient's clinical symptoms were partially improved. This is the first reported case of anti-IgLON5 encephalopathy with concomitant herpes virus encephalitis.

Expanding the clinical spectrum of anti-IgLON5 disease: A multicenter retrospective study.

BACKGROUND: We conducted this study to describe detailed the clinical characteristics, ancillary test results and treatment response of a group of Chinese patients with anti-IgLON5 disease. METHODS: We recruited 13 patients with positive IgLON5 antibodies in serum and/or cerebrospinal fluid from nine tertiary referral centers. Patients were enrolled from February 2017 to July 2021. We retrospectively collected information on the presenting and main symptoms, treatment response and follow-up outcomes. RESULTS: The median age of onset for symptoms was 60 (range: 33-73) years and six of the 13 patients were females. The predominant clinical presentations included sleep disturbance (eight patients) and cognitive impairment (seven patients), followed by movement disorders (six patients). Parainfectious cause seemed plausible. Notably, we identified the first case of possible Epstein-Barr virus (EBV)-related anti-IgLON5 disease. Coexisting neural autoantibodies were identified in two patients. Furthermore, two patients had other autoimmune diseases. The IgG subclass was determined in four patients, including two with dominant IgG4 subtype and two with dominant IgG1 subtype. Additionally, 10 patients were treated with immunotherapy and four patients exhibited improvement. Overall, six of 10 patients for whom follow-up results were assessable had favorable clinical outcomes (modified Rankin Scale score ≤2). CONCLUSIONS: The clinical spectrum of anti-IgLON5 disease is variable. Our results highlight a boarder spectrum of anti-IgLON5 disease.

Comprehensive Analysis of LPCATs Highlights the Prognostic and Immunological Values of LPCAT1/4 in Hepatocellular Carcinoma.

BACKGROUND: The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains poor. Lipid remodeling modulators are considered promising therapeutic targets of cancers, owing to their functions of facilitating cancer cells' adaption to the limited environment. Lysophosphatidylcholine acyltransferases (LPCATs) are enzymes regulating bio-membrane remodeling, whose roles in HCC have not been fully illuminated. METHODS: Multiple bioinformatic tools were applied to comprehensively evaluate the expression, genetic alterations, clinical relevance, prognostic values, DNA methylation, biological functions, and correlations with immune infiltration of LPCATs in HCC. RESULTS: We found LPCAT1 was significantly overexpressed and the most frequently altered in HCC. The high-expression of LPCAT1/4 indicated clinicopathological advancements and poor prognoses of HCC patients. Even though the global DNA methylation of LPCATs in HCC showed no significant difference with that in normal liver, the hypermethylation of numerous CpG sites of them implied worse survivals of HCC patients. Thirty LPCATs' interactive genes were identified, which were generally membrane components and partook in phospholipid metabolism pathways. Finally, we found the expression of LPCATs was extensively positively correlated with the infiltration of various stimulatory and suppressive tumor-infiltrating immune cells (TIICs) in the tumor microenvironment. CONCLUSION: This study addressed LPCAT1/4 were potential prognostic and immunotherapeutic biomarkers of HCC targeting bio-membrane lipid remodeling.

Roles of HMGBs in Prognosis and Immunotherapy: A Pan-Cancer Analysis.

Background: High mobility group box (HMGB) proteins are DNA chaperones involved in transcription, DNA repair, and genome stability. Extracellular HMGBs also act as cytokines to promote inflammatory and immune responses. Accumulating evidence has suggested that HMGBs are implicated in cancer pathogenesis; however, their prognostic and immunological values in pan-cancer are not completely clear. Methods: Multiple tools were applied to analyze the expression, genetic alternations, and prognostic and clinicopathological relevance of HMGB in pan-cancer. Correlations between HMGB expression and tumor immune-infiltrating cells (TIICs), immune checkpoint (ICP) expression, microsatellite instability (MSI), and tumor mutational burden (TMB) in pan-cancer were investigated to uncover their interactions with the tumor immune microenvironment (TIME). Gene set enrichment analysis (GSEA) was conducted for correlated genes of HMGBs to expound potential mechanisms. Results: HMGB expression was significantly elevated in various cancers. Both prognostic and clinicopathological significance was observed for HMGB1 in ACC; HMGB2 in ACC, LGG, LIHC, and SKCM; and HMGB3 in ESCA. Prognostic values were also found for HMGB2 in KIRP and MESO and HMGB3 in BRCA, SARC, SKCM, OV, and LAML. The global alternation of HMGBs showed prognostic significance in ACC, KIRC, and UCEC. Furthermore, HMGBs were significantly correlated with TIIC infiltration, ICP expression, MSI, and TMB in various cancers, indicating their regulations on the TIME. Lastly, results of GSEA-illuminated genes positively correlated with HMGBs which were similarly chromosome components participating in DNA activity-associated events. Conclusion: This study demonstrated that HMGBs might be promising predictive biomarkers for the prognosis and immunotherapeutic response, also immunotherapy targets of multiple cancers.

ZWINT is a Promising Therapeutic Biomarker Associated with the Immune Microenvironment of Hepatocellular Carcinoma.

BACKGROUND: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is still poor, effective therapeutic targets are needed. ZW10 interacting kinetochore protein (Zwint) is an essential component of the mitotic spindle checkpoint and is upregulated in cancers. Disappointing, the role of ZWINT in HCC has not been fully illuminated. METHODS: Multiple tools, including TIMER2.0, Oncomine, GEPIA2, UALCAN, LinkedOmics, Kaplan-Meier Plotter, cBioPortal, and MethSurv, etc. were applied to comprehensively analyze the expression, genetic alternations, clinicopathological relevance, prognostic value, and DNA methylation of ZWINT, along with its correlations with immune infiltration in HCC. Besides, gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) analysis were performed for the correlated genes of ZWINT, closely interconnected clusters and hub proteins in the PPI network were discovered to learn the underlying biological mechanisms. RESULTS: We found ZWINT was significantly upregulated in diverse cancers including HCC, compared with the corresponding normal controls. ZWINT upregulation was significantly associated with unfavorable clinicopathological features and survivals of HCC patients. Genetic alternations of ZWINT frequently occurred, which were linked to worse outcomes of HCC patients. The results of GSEA displayed ZWINT and its correlated genes might be components of condensed chromosomes and spindles, which participated in biological processes and signaling pathways involving DNA replication, cytokinesis, and cell cycle checkpoint, etc. Three highly interconnected clusters and 10 hub proteins were identified from the PPI network constructed with the correlated genes of ZWINT. Moreover, ZWINT expression was found positively correlated with infiltration levels of various immune cells, especially myeloid-derived suppressor cells. CONCLUSION: This study demonstrated ZWINT might be a promising unfavorable prognostic biomarker and a therapeutic target of HCC, which could regulate HCC progression through cell division and immunosuppression.

Potential Role of NEU1 in Hepatocellular Carcinoma: A Study Based on Comprehensive Bioinformatical Analysis.

Background: Aberrant expression of NEU1 has been identified in many malignancies. Nevertheless, the clinical significance of NEU1 in hepatocellular carcinoma (HCC) has not been fully elucidated. Methods: In our study, multiple databases, including ONCOMINE, The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), Cancer Cell Line Encyclopedia (CCLE), Human Protein Atlas (HPA), Kaplan-Meier (KM) plotter, MethSurv, Gene Expression Profiling Interactive Analysis (GEPIA), and Metascape, etc., were utilized to investigate the expression, prognostic value, and function of NEU1 in HCC. Results: ONCOMINE, GEO, and TCGA analyses revealed that NEU1 was more highly expressed in HCC compared to normal tissues. Additionally, the mRNA and protein expression levels of NEU1 were increased in liver cancer cell lines and HCC tissues, respectively. Moreover, a trend toward increased NEU1 expression with advanced stage or grade was found. Furthermore, higher mRNA expression of NEU1 was found to be remarkably correlated with worse survival in HCC patients, and multivariate Cox analysis indicated that high mRNA expression of NEU1 was an independent prognostic factor for poor prognosis of HCC patients. Also, 21 methylated CpGs were found to be significantly related to HCC prognosis. Besides, functional enrichment analyses indicated that high NEU1 expression group had lower levels of B cells, CD8+ T cells, NK cells, and T helper cells, etc. than the low NEU1 expression group, and NEU1 may regulate a variety of tumor-related proteins and pathways, including lysosome, spliceosome, mTOR signaling pathway and so on. Conclusion: High expression level of NEU1 was positively correlated with unfavorable prognosis of HCC patients, which may be related to the regulation of cancer-associated pathways and the inhibition of immune function by NEU1. Thus, NEU1 could be used as a potential prognostic biomarker and target for HCC.

CXCL2/10/12/14 are prognostic biomarkers and correlated with immune infiltration in hepatocellular carcinoma.

BACKGROUND: C-x-C motif chemokine ligands (CXCLs) are critical regulators of cancer immunity and angiogenesis, which affect disease progression and treatment responses. The character of each CXCL in the prognosis and immune infiltration of hepatocellular carcinoma (HCC) patients is unclear yet. METHODS: Differentially expressed CXCLs between HCC and normal control were screened by Oncomine and GEPIA2. Genetic alternations of CXCLs in HCC were analyzed by cBioPortal. Clinicopathological relevance of CXCLs in HCC patients was analyzed using UALCAN. The prognostic value of CXCLs was evaluated using univariate and multivariate analyses. Correlations of CXCLs' expression with immune infiltration, chemokines and their receptors were assessed integrating TIMER, TISIDB, and GEPIA2. The co-expressed genes of CXCLs were discovered, and functional enrichment analysis was performed for them. RESULTS: CXCL9/10 was significantly higher expressed while CXCL2/12/14 was lower expressed in HCC than normal tissues, but they didn't show significant clinicopathological relevance in HCC patients. High-expression of CXCL2/10/12/14 indicated favorable outcomes of HCC patients. The expression of CXCL9/10/12/14 was significantly positively correlated with not only the infiltration and biomarkers' expression of various tumor-infiltrating immune cells but also the abundance of chemokines and their receptors. The co-expressed genes of the five CXCLs were extracellular components and regulated immune or inflammatory responses and signaling pathways of chemokine, Toll-like receptor and tumor necrosis factor might be involved. CONCLUSION: The present study proposed CXCL2/10/12/14 might predict outcomes of HCC patients and were extensively related with the immune microenvironment in HCC. It would be a prospective therapeutic strategy for HCC to enhance effective immunity surveillance through intervening in these CXCLs.

Human Gastric Cancer Stem Cell (GCSC) Markers Are Prognostic Factors Correlated With Immune Infiltration of Gastric Cancer.

The prognosis of patients with gastric cancer (GC) is still unsatisfying. Numerous markers of gastric cancer stem cells (GCSCs) have been identified and were thought to be related to cancer aggressiveness. However, the roles of GCSC markers in GC patients' prognosis and immune infiltration remain unknown. Expression of GCSC markers was analyzed using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). Their associations with clinicopathological parameters were analyzed using UALCAN and LinkedOmics. Alternations and protein expression of GCSC markers were analyzed by cBioPortal and the Human Protein Atlas databases, respectively. The prognostic significance of GCSC markers was evaluated using Kaplan-Meier plotter. Correlations between the expression of GCSC markers and immune infiltration along with biomarkers of tumor-infiltrating immune cells (TIICs) were assessed combined Tumor Immune Estimation Resource and GEPIA. GeneMANIA was used to discover the interactive genes of GCSC markers, and enrichment analysis was performed using Database for Annotation, Visualization, and Integrated Discovery server. We identified six GCSC markers significantly up-expressed in GC, compared with normal stomach tissues. Among them, the overexpression of ICAM1, THY1, and CXCR4 significantly indicated adverse, while EPCAM indicated beneficial clinicopathological features of GC patients. The up-regulation of CXCR4 showed unfavorable prognostic significance, whereas EPCAM and TFRC showed the opposite. The six GCSC markers were all correlated with the infiltration and activation of distinct TIICs. Especially, ICAM1, THY1, and CXCR4 showed strongly positive correlations with tumor-associated macrophages. Besides, chemokine, Toll-like receptor, NF-kappa B, and HIF-1 signaling pathways might be involved in the regulation of GCSC markers on cancer development. This study proposed that GCSC markers might be promising targets of GC treatment to weaken cancer stem-like properties and strengthen anticancer immunity.

Identification of prognostic biomarkers associated with the occurrence of portal vein tumor thrombus in hepatocellular carcinoma.

The occurrence of portal vein tumor thrombus (PVTT) is strongly correlated to the staging and poor prognosis of hepatocellular carcinoma (HCC) patients. However, the mechanisms of PVTT formation remain unclear. This study aimed to investigate differentially expressed genes (DEGs) between primary tumor (PT) and PVTT tissues and comprehensively explored the underlying mechanisms of PVTT formation. The DEGs between PT and paired PVTT tissues were analyzed using transcriptional data from the Gene Expression Omnibus (GEO) database. The expression, clinical relevance, prognostic significance, genetic alternations, DNA methylation, correlations with immune infiltration, co-expression correlations, and functional enrichment analysis of the DEGs were explored using multiple databases. As result, 12 DEGs were commonly down-expressed in PVTT compared with PT tissues among three datasets. The expression of DCN, CCL21, IGJ, CXCL14, FCN3, LAMA2, and NPY1R was progressively decreased from normal liver, PT, to PVTT tissues, whose up-expression associated with favorable survivals of HCC patients. The genetic alternations and DNA methylation of the DEGs frequently occurred, and several methylated CpG sites of the DEGs significantly correlated with outcomes of HCC patients. The immune infiltration in the tumor microenvironment of HCC was correlated with the expression level of the DEGs. Besides, the DEGs and their co-expressive genes participated in the biological processes of extracellular matrix (ECM) organization and focal adhesion. In summary, this study indicated the dysregulation of ECM and focal adhesion might contribute to the formation of PVTT. And the above seven genes might serve as potential biomarkers of PVTT occurrence and prognosis of HCC patients.