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Abstract Background Peroxisome proliferator-activated receptor-beta/delta (PPARδ) was considered as the key regulator involved in the evolution of various tumors. Given that PPARδ potential role in hepatocellular carcinoma (HCC) is still obscure, we comprehensively assessed its expression pattern, prognosis, functions and correlation with tumor microenvironment in HCC using public database data and in vitro studies. Methods Transcriptional data and clinical data in the TCGA and GEO database were analyzed in R software. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry were used to detect the expression level of related RNA and proteins. The malignant biological characteristics were explored by cell counting Kit-8 (CCK8), 5-Ethynyl-2ʹ-deoxyuridine (EdU) assay and wound healing assay. Results Our results illustrated that PPARδ expression was significantly higher in HCC tissues and HCC cell lines. Elevated expression of PPARδ suggested poor clinical staging and prognosis in HCC. Ligand-activated PPARδ expression promoted the proliferation and invasion of HCC cells via PDK1/AKT/GSK3β signaling pathway. The expression of PPARδ was closely related to the HCC tumor microenvironment. Conclusions PPARδ plays an important part in HCC progression, penetrating investigation of the related regulatory mechanism may shed light upon further biological and pharmacological value.

Abstract Background Misdiagnosis of multiple sclerosis (MS) and neuromyelitis optica (NMO) may delay the treatment, resulting in poor prognosis. However, the precise identification of these two diseases is still challenging in clinical practice. We aimed to evaluate the value of quantitative radiomic features extracted from the brain white matter lesions for differential diagnosis of MS and NMO. Methods We recruited 116 CNS demyelinating patients including 78 MS, and 38 NMO. Three neuroradiologists performed visual differential diagnosis based on brain MRI for comparison purpose. A multi-level scheme was designed to harness the selection of discriminative and stable radiomics features extracted from brain while mater lesions in T1-MPRAGE, T2 sequences and clinical factors. Based on the imaging phenotype composed of the selected radiomic and clinical features, Multi-parametric Multivariate Random Forest (MM-RF) model was constructed and verified with both 10-fold cross-validation and independent testing. Result interpretation was provided to build trust in diagnostic decisions. Results Eighty-six patients were randomly selected to form the training set while the rest 30 patients for independent testing. On the training set, our MM-RF model achieved accuracy 0.849 and AUC 0.826 in 10-fold cross-validation, which were significantly higher than clinical visual analysis (0.709 and 0.683, p

Abstract Recent studies have showed that IKBKE is overexpressed in several kinds of cancers and that IKBKE-knockdown inhibits tumor progression. In this article, we first verified that two glioblastoma cell lines, U87-MG and LN-229, were sensitive to CYT387 by measuring the half maximal inhibitory concentration (IC50) with a CCK-8 assay and then demonstrated that CYT387, as a potent IKBKE inhibitor, suppressed glioblastoma cell proliferation, migration and invasion. Additionally, CYT387 induced cell apoptosis and arrested the cell cycle at the G2/M checkpoint in vitro. Furthermore, we showed that CYT387 did not simply inhibit IKBKE activity but also decreased IKBKE expression at the protein level rather than at the mRNA level. We discovered that CYT387 restrained malignant tumor progression by activating the Hippo pathway in vitro. By coimmunoprecipitation (co-IP), we showed that IKBKE interacted with TEAD2 and YAP1, thus accelerating TEAD2 and YAP1 transport into the nucleus. In subsequent in vivo experiments, we found that CYT387 inhibited subcutaneous nude mouse tumor growth but had little impact on intracranial orthotopic xenografts, probably due to a limited ability to penetrate the blood–brain barrier (BBB). These results suggest that CYT387 has potential as a new antiglioblastoma drug, but an approach to allow passage through the blood–brain barrier (BBB) is needed.

Abstract Background Mutations in TP53 gene is considered a main driver of hepatocellular carcinoma (HCC). While TP53 mutations are the leading cause of p53 dysfunction, their occurrence rates may drop to approximately 10% in cohorts without hepatitis B virus and aflatoxin exposure. This observation suggests that the deactivation of wild-type p53 (p53wt) may be a critical factor in the majority of HCC cases. However, the mechanism undermining p53wt activity in the liver remains unclear. Methods Microarray analysis and luciferase assay were utilized to confirm target associations. Gain- and/or loss-of-function methods were employed to assess alterations in signaling pathways. Protein interactions were analyzed by molecular immunological methods and further visualized by confocal microscopy. Bioinformatic analysis was performed to analyze clinical significance. Tumor xenograft nude mice were used to validate the findings in vivo. Results Our study highlights the oncogenic role of Rictor, a key component of the mammalian target of rapamycin complex 2 (mTORC2), in hepatocytes. Rictor exerts its oncogenic function by binding to p53wt and subsequently blocking p53wt activity based on p53 status, requiring the involvement of mTOR. Moreover, we observed a dynamic nucleocytoplasmic distribution pattern of Rictor, characterized by its translocation from the nucleus (in precancerous lesions) to the cytoplasm (in HCCs) during malignant transformation. Notably, Rictor is directly targeted by the liver-enriched microRNA miR-192, and the disruption of the miR-192-Rictor-p53-miR-192 signaling axis was consistently observed in both human and rat HCC models. Clinical analysis associated lower miR-192/higher Rictor with shorter overall survival and more advanced clinical stages (P

Background: Hepatocellular carcinoma (HCC), a primary liver malignancy, is the most common cancer in males and fourth common cancer in females in Taiwan. HCC patients usually have a poor prognosis due to late diagnosis. It has been classified as a complex disease because of the heterogeneous phenotypic and genetic traits of the patients and a wide range of risk factors. Micro (mi)RNAs regulate oncogenes and tumor suppressor genes that are known to be dysregulated in HCC. Several studies have found an association between downregulation of miR-122, a liver-specific miRNA, and upregulation of paternally expressed gene 10 (PEG10) in HCC; however, the correlation between low miR-122 and high PEG10 levels still remains to be defined and require more investigations to evaluate their performance as an effective prognostic biomarker for HCC.Methods: An in silico approach was used to isolate PEG10, a potential miR-122 target implicated in HCC development. miR-122S binding sites in the PEG10 promoter were evaluated with a reporter assay. The regulation of PEG10 by miR-122S overexpression was examined by quantitative RT-PCR, western blotting, and immunohistochemistry in miR-122 knockout mice and liver tissue from HCC patients. The relationship between PEG10 expression and clinicopathologic features of HCC patients was also evaluated.Results: miR-122 downregulated the expression of PEG10 protein through binding to 3'-untranslated region (UTR) of the PEG10 transcript. In miR-122 knockout mice and HCC patients, the deficiency of miR-122 was associated with HCC progression. The expression of PEG10 was increased in 57.3 % of HCC as compared to paired non-cancerous tissue samples. However, significant upregulation was detected in 56.5 % of patients and was correlated with Okuda stage (P = 0.05) and histological grade (P = 0.001).Conclusions: miR-122 suppresses PEG10 expression via direct binding to the 3'-UTR of the PEG10 transcript. Therefore, while PEG10 could not be an ideal diagnostic biomarker for HCC but its upregulation in HCC tissue still has predictive value for HCC prognosis. [ABSTRACT FROM AUTHOR]

Abstract Purpose To investigate the association of serum levels of 25(OH)D and 1,25(OH)2D3 in healthy and non-healthy controls with Crohn’s disease (CD) and ulcerative colitis (UC). Methods Three electronic databases: PubMed, EMbase and EBSCOhost CINAHL, were searched for observational studies to measure the relationship between serum levels of vitamin D (VitD) and CD (or UC). Results Fifty-five studies were included in the meta-analysis. We found that mean serum 25(OH)D levels in patients with CD were significantly lower than those in healthy controls (MD: − 3.17 ng/mL; 95% CI − 4.42 to − 1.93). Results from the meta-analysis examining 1,25(OH)2D3 levels in Crohn’s patients revealed higher levels in the CD group than in healthy (MD: 3.47 pg/mL; 95% CI − 7.72 to 14.66) and UC group (MD: 5.05 pg/mL; 95% CI − 2.42 to 12.52). Serum 25(OH)D levels were lower in the UC group than in the healthy control group (MD: − 2.52 ng/mL; 95% CI − 4.02 to − 1.02). In studies investigating the level of 1,25(OH)2D3 in UC and healthy control groups, the level of 1,25(OH)2D3 in the UC groups were found to be higher than that in the control groups (MD: 3.76 pg/mL; 95% CI − 8.36 to 15.57). However, the 1,25(OH)2D3 level in patients with UC was lower than that in CD groups (MD: − 6.71 pg/mL; 95% CI − 15.30 to 1.88). No significant difference was noted between CD patients and UC patients in terms of average serum 25(OH)D levels. Conclusions This study found that VitD levels were inversely related to CD and UC. Serum levels of 25(OH)D were lower in patients with CD and UC than in healthy people, and more than half of the patients had insufficient vitamin D levels. The serum level of 1,25(OH)2D3 in both the CD and UC groups was higher than that in healthy people.