Comprehensive clinicopathological significance and putative transcriptional mechanisms of Forkhead box M1 factor in hepatocellular carcinoma.

BACKGROUND: The Forkhead box M1 factor (FOXM1) is a crucial activator for cancer cell proliferation. While FOXM1 has been shown to promote hepatocellular carcinoma (HCC) progression, its transcriptional mechanisms remain incompletely understood. METHODS: We performed an in-house tissue microarray on 313 HCC and 37 non-HCC tissue samples, followed by immunohistochemical staining. Gene chips and high throughput sequencing data were used to assess FOXM1 expression and prognosis. To identify candidate targets of FOXM1, we comprehensively reanalyzed 41 chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets. We predicted FOXM1 transcriptional targets in HCC by intersecting candidate FOXM1 targets with HCC overexpressed genes and FOXM1 correlation genes. Enrichment analysis was employed to address the potential mechanisms of FOXM1 underlying HCC. Finally, single-cell RNA sequencing analysis was performed to confirm the transcriptional activity of FOXM1 on its predicted targets. RESULTS: This study, based on 4235 HCC tissue samples and 3461 non-HCC tissue samples, confirmed the upregulation of FOXM1 in HCC at mRNA and protein levels (standardized mean difference = 1.70 [1.42, 1.98]), making it the largest multi-centered study to do so. Among HCC patients, FOXM1 was increased in Asian and advanced subgroups, and high expression of FOXM1 had a strong ability to differentiate HCC tissue from non-HCC tissue (area under the curve = 0.94, sensitivity = 88.72%, specificity = 87.24%). FOXM1 was also shown to be an independent exposure risk factor for HCC, with a pooled hazard ratio of 2.00 [1.77, 2.26]. The predicted transcriptional targets of FOXM1 in HCC were predominantly enriched in nuclear division, chromosomal region, and catalytic activity acting on DNA. A gene cluster encoding nine transcriptional factors was predicted to be positively regulated by FOXM1, promoting the cell cycle signaling pathway in HCC. Finally, the transcriptional activity of FOXM1 and its targets was supported by single-cell analysis of HCC cells. CONCLUSIONS: This study not only confirmed the upregulation of FOXM1 in HCC but also identified it as an independent risk factor. Moreover, our findings enriched our understanding of the complex transcriptional mechanisms underlying HCC pathogenesis, with FOXM1 potentially promoting HCC progression by activating other transcription factors within the cell cycle pathway.

Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression.

Resveratrol (RSV) is known to possess anticancer properties in many types of cancers like breast cancer, in which POLD1 may serve as a potential target. However, the anticancer mechanism of RSV on triple negative breast cancer (TNBC) remains unclear. In the present study, the antitumor effects and mechanism of RSV on TNBC cells were analyzed by RNA sequencing (RNA-seq), which was then verified via cell counting kit-8 (CCK8), immunofluorescence, immunohistochemistry, Western Blot (WB), flow cytometry, and hematoxylin-eosin (HE) staining. According to the corresponding findings, the survival rate of MDA-MB-231 cells gradually decreased as RSV treatment concentration increased. The RNA-seq analysis results demonstrated that genes affected by RSV treatment were mainly involved in apoptosis and the p53 signaling pathway. Moreover, apoptosis of MDA-MB-231 cells induced by RSV was observed to be mainly mediated by POLD1. When treated with RSV, the expression levels of full length PARP1, PCNA, and BCL-2 were found to be significantly reduced, and the expression level of Cleaved-PARP1 as well as Cleaved-Caspase3 increased significantly. Additionally, the mRNA expression of POLD1 was significantly reduced after treatment with RSV, and the protein expression level was also inhibited by RSV in a concentration-dependent manner. The prediction of domain interaction suggested that RSV may bind to at least five functional domains of the POLD1 protein (6s1m, 6s1n, 6s1o, 6tny and 6tnz). Furthermore, after RSV treatment, the anti-apoptotic index (PCNA, BCL-2) of MDA-MB-231 cells was found to decrease while the apoptosis index (caspase3) increased. Moreover, the overexpression of POLD1 reduced the extent of apoptosis observed in MDA-MB-231 cells following RSV treatment. Moreover, animal experimental results showed that RSV had a significant inhibitory effect on the growth of live tumors, while POLD1 overexpression was shown to antagonize this inhibitory effect. Accordingly, this study's findings reveal that RSV may promote the apoptosis of TNBC cells by reducing the expression of POLD1 to activate the apoptotic pathway, which may serve as a potential therapy for the treatment of TNBC.

Usefulness of serum interleukin-33 as a prognostic marker of severe traumatic brain injury.

BACKGROUND: Interleukin-33 is recently identified as a brain injury biomarker. We determined whether serum interlerukin-33 concentrations are associated with inflammation, severity and prognosis after traumatic brain injury (TBI). METHODS: We detected serum interlerukin-33 concentrations of 102 healthy controls and 102 severe TBI patients, as well as serum concentrations of 3 inflammatory biomarkers (interleukin-6, tumor necrosis factor-alpha and C-reactive protein) and 7 cell-specific proteins (myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, Tau and ubiquitin carboxyl-terminal hydrolase L1) in 102 severe TBI patients. The recorded poor prognosis variables included acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction and six-month mortality and poor outcome (Glasgow score of 1-3). RESULTS: Median interlerukin-33 concentration of patients (692 pg/mL) was substantially raised, as compared to controls. Interlerukin-33 concentrations were significantly correlated with Glasgow coma scale (GCS) score and the preceding biomarkers concentrations. Interlerukin-33 concentration > 692 pg/mL emerged as an independent prognostic predictor and its discriminatory capability exceeded those of the above-mentioned inflammatory biomarkers concentrations and was in the range of GCS scores and the aforementioned cell-specific proteins concentrations. CONCLUSION: Ascending serum interlerukin-33 concentrations could reflect inflammation, severity and worse prognosis following TBI.

Prognostic significance of serum translocator protein in patients with traumatic brain injury.

BACKGROUND: Translocator protein (TP) is related to inflammation and is involved in brain injury. The objective of this study was to ascertain whether serum TP concentrations are associated with the severity and prognosis of traumatic brain injury (TBI). METHODS: We quantified the serum concentrations of TP in 106 healthy controls and 106 patients with severe TBI. Recorded prognostic variables included acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction, 6-month mortality and 6-month poor outcome (Glasgow Outcome Scale score of 1-3). Trauma severity was assessed by Glasgow coma scale (GCS) score. Extent of inflammatory response was indicated by serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a) and C-reactive protein (CRP) concentrations. RESULTS: Patients had significantly higher serum TP concentrations than controls. Among patients, serum TP concentrations strongly and independently correlated with GCS score and serum IL-6, TNF-a and CRP concentrations. Serum TP was identified as an independent predictor for the preceding prognostic variables, its prognostic predictive ability was similar to that of GCS score and it also significantly improved prognostic predictive ability of GCS score. CONCLUSION: Serum TP may be intimately linked with in inflammation, disease progression and poor prognosis in TBI patients.

Serum ST2 as a potential prognostic biomarker for traumatic brain injury.

BACKGROUND: ST2, a receptor of interleukin-33, is involved in inflammation. We discerned the relationship between serum soluble ST2 (sST2) concentrations, inflammation, severity and prognosis following traumatic brain injury (TBI). METHODS: We measured serum sST2, interleukin-6, tumor necrosis factor-alpha, C-reactive protein, myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, Tau and ubiquitin carboxyl-terminal hydrolase L1 concentrations in 106 healthy controls and 106 severe TBI patients. We recorded long-term prognosis (i.e., 6-month mortality and functional outcome) and in-hospital major adverse events, including in-hospital mortality, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction. RESULTS: sST2 concentrations were significantly higher in patients than in controls and were significantly correlated with Glasgow coma scale (GCS) score and the preceding biomarkers concentrations. Serum sST2 was an independent prognostic predictor and its predictive ability significantly exceeded those of serum interleukin-6, tumor necrosis factor-alpha and C-reactive protein concentrations and was similar to those of GCS scores and serum concentrations of other remaining biomarkers. Moreover, sST2 concentrations significantly improved predictive ability of GCS score. CONCLUSION: Increased serum sST2 concentrations are significantly related to inflammation, severity and prognosis, substantialized ST2 as a potential prognostic biomarker for TBI.

Plasma visfatin, associated with a genetic polymorphism -1535C>T, is correlated with C-reactive protein in Chinese Han patients with traumatic brain injury.

Visfatin is a newly identified pro-inflammatory adipokine and a genetic polymorphism -1535 C>T located in the visfatin gene promoter has been suggested to be associated with the regulation of visfatin expression in some inflammatory illness. However, there were some conflicting results regarding whether this variant is functional or not. This study aimed to examine the relations of the -1535 C>T single nucleotide polymorphism (SNP) of visfatin gene to the plasma visfatin and C-reactive protein concentrations in traumatic brain injury (TBI). 318 Chinese Han patients with TBI were recruited in this study. Plasma visfatin and C-reactive protein levels were significantly different between the genotypes in the SNP-1535 C>T even after adjustment for age, sex and body mass index. The genotype C-C had the highest plasma visfatin and C-reactive protein concentrations. The plasma visfatin and C-reactive protein concentrations between the variant genotypes C-T and T-T did not differ significantly. Plasma visfatin level was significantly associated with plasma C-reactive protein level using multivariate linear regression. Thus, the SNP-1535 C>T of visfatin gene seemed to be potentially involved in the inflammatory component of TBI through a decreased production of visfatin.

Change in plasma visfatin level after severe traumatic brain injury.

Higher plasma visfatin concentration has been associated with ischemic stroke. Thus, we sought to investigate change in plasma visfatin level after traumatic brain injury and to evaluate its relation with disease outcome. Seventy-six healthy controls and 98 patients with acute severe traumatic brain injury were recruited. Twenty-seven patients (27.6%) died and 48 patients (49.0%) suffered from unfavorable outcome (Glasgow outcome scale score of 1-3) in 6 months. On admission, plasma visfatin level was increased in patients than in healthy controls and was highly correlated with Glasgow Coma Scale score. A multivariate analysis identified plasma visfatin level as an independent predictor for 6-month mortality and unfavorable outcome. According to receiver operating characteristic curve analysis, the predictive value of the plasma visfatin concentration was similar to Glasgow Coma Scale score's. In a combined logistic-regression model, visfatin did not improve the predictive value of Glasgow Coma Scale score. Thus, increased plasma visfatin level is associated with 6-month clinical outcomes after severe traumatic brain injury.