Comprehensive assessment of osteoporosis in lumbar spine using compositional MR imaging of trabecular bone.

OBJECTIVES: To comprehensively assess osteoporosis in the lumbar spine, a compositional MR imaging technique is proposed to quantify proton fractions for all the water components as well as fat in lumbar vertebrae measured by a combination of a 3D short repetition time adiabatic inversion recovery prepared ultrashort echo time (STAIR-UTE) MRI and IDEAL-IQ. METHODS: A total of 182 participants underwent MRI, quantitative CT, and DXA. Lumbar collagen-bound water proton fraction (CBWPF), free water proton fraction (FWPF), total water proton fraction (TWPF), bone mineral density (BMD), and T-score were calculated in three vertebrae (L2-L4) for each subject. The correlations of the CBWPF, FWPF, and TWPF with BMD and T-score were investigated respectively. A comprehensive diagnostic model combining all the water components and clinical characteristics was established. The performances of all the water components and the comprehensive diagnostic model to discriminate between normal, osteopenia, and osteoporosis cohorts were also evaluated using receiver operator characteristic (ROC). RESULTS: The CBWPF showed strong correlations with BMD (r = 0.85, p < 0.001) and T-score (r = 0.72, p < 0.001), while the FWPF and TWPF showed moderate correlations with BMD (r = 0.65 and 0.68, p < 0.001) and T-score (r = 0.47 and 0.49, p < 0.001). The high area under the curve values obtained from ROC analysis demonstrated that CBWPF, FWPF, and TWPF have the potential to differentiate the normal, osteopenia, and osteoporosis cohorts. At the same time, the comprehensive diagnostic model shows the best performance. CONCLUSIONS: The compositional MRI technique, which quantifies CBWPF, FWPF, and TWPF in trabecular bone, is promising in the assessment of bone quality. KEY POINTS: • Compositional MR imaging technique is able to quantify proton fractions for all the water components (i.e., collagen-bound water proton fraction (CBWPF), free water proton fraction (FWPF), and total water proton fraction (TWPF)) in the human lumbar spine. • The biomarkers derived from the compositional MR imaging technique showed moderate to high correlations with bone mineral density (BMD) and T-score and showed good performance in distinguishing people with different bone mass. • The comprehensive diagnostic model incorporating CBWPF, FWPF, TWPF, and clinical characteristics showed the highest clinical diagnostic capability for the assessment of osteoporosis.

ABI2-mediated MEOX2/KLF4-NANOG axis promotes liver cancer stem cell and drives tumour recurrence.

Tumour recurrence and drug resistance in hepatocellular carcinoma remain challenging. Cancer stem cells (CSCs) are responsible for tumour initiation because of their stemness characteristics. CSCs accounting for drug resistance and tumour relapse are promising therapeutic targets. We report that Abelson interactor 2 (ABI2) is a novel therapeutic target of HCC CSCs. First, ABI2 was upregulated in HCC tissues compared with liver tissues and was associated with tumour size, pathological grade, liver cirrhosis, worse prognosis and a high recurrence rate. Functional studies illustrate that ABI2 knockdown suppresses cell growth, migration, invasion and sorafenib resistance in vitro. Furthermore, ABI2 knockdown inhibited HCC sphere formation and decreased the CD24+ , CD133+ and CD326+ CSCs populations, suggesting the suppression of HCC stemness characteristics. A tumour xenograft model and limiting dilution assay demonstrated the inhibition of tumorigenicity and tumour initiation. Moreover, molecular mechanism studies showed that ABI2 recruits and directly interacts with the transcription factor MEOX2, which binds to the KLF4 and NANOG promoter regions to activate their transcription. Furthermore, overexpression of MEOX2 restored HCC malignant behaviour and the CSC population. The ABI2-mediated transcriptional axis MEOX2/KLF4-NANOG promotes HCC growth, metastasis and sorafenib resistance by maintaining the CSC population, suggesting that ABI2 is a promising CSC target in HCC treatment.

GLP-1 promotes osteogenic differentiation of human ADSCs via the Wnt/GSK-3ß/ß-catenin pathway.

Glucagon-like peptide-1 (GLP-1) analogues are promising anti-diabetic drugs which had been shown to have beneficial effects on bone metabolism in clinical practice, but the molecular mechanism remains unclear. In this study, we evaluated whether GLP-1 can affect the "intestine-fat-bone axis" via the Wnt/GSK-3ß/ß-catenin pathway. We established a diabetic mouse model and then treated mice with GLP-1 analogue liraglutide. The results showed that after liraglutide treatment, glucose tolerance and insulin tolerance were significantly improved in diabetic mice as expected. Moreover, osteogenic markers such as collagenⅠ, Runx2 and OCN were upregulated; and the adipogenic differentiation markers C/EBP-α and PPAR-γ were downregulated, these results indicated that liraglutide could ameliorate the osteogenic metabolism in diabetic mice. In the cell model, human ADSCs (hADSCs) were cultured and induced to undergo osteogenic and adipogenic differentiation under high glucose conditions in vitro and then treated with GLP-1. The results showed that GLP-1 repressed the induction of adipocyte differentiation biomarkers and the secretion of GSK-3ß in a dose-dependent manner. In addition, GLP-1 enhanced the expression of osteoblastogenic biomarkers, such as OCN, Runx2 and collagenⅠ, and promoted osteoblastic mineralization. These effects were substantially suppressed by the Wnt signal recombinant human DKK-1 or activated by Wnt pathway agonist LiCl. Silencing of GSK-3ß showed that the levels of ß-catenin, GSK-3ß and Runx2 were significantly increased by 2.46-, 2.05-, 4.44-fold after GLP-1 treatment compared to that observed in the GSK-3ß lentiviral group, respectively. We conclude that GLP-1 promotes the osteogenic differentiation of hADSCs via the Wnt/GSK-3ß/ß-catenin pathway.

C14orf166 Is a Biomarker for Predicting Hepatocellular Carcinoma Recurrence.

Aim: Chromosome 14 open reading frame 166 (C14orf166) acts as a transcriptional repressor and is correlated with centrosome architecture manipulation. Nevertheless, the function of C14orf166 in hepatocellular carcinoma (HCC) progression remains unclear. We aimed to investigate the role C14orf166 plays in HCC and further compared the prognostic value of C14orf166 with that of clinicopathological features. Methods: C14orf166 expression was evaluated in a human liver cell line, HCC cell lines, HCC tissues and adjacent noncancerous liver tissues with qRT-PCR, western blot and immunohistochemistry. Patients were divided into two different groups according to C14orf166 level. The relationship between C14orf166 expression and clinicopathological features was assessed by Pearson chi-squared test and receiver operating characteristic curves. Cumulative disease-free survival (DFS) and overall survival (OS) curves were evaluated using the Kaplan-Meier method. Results: C14orf166 mRNA and protein expression is upregulated in HCC cell lines and tissues. The level of C14orf166 was correlated with serum alpha-fetoprotein level, lymph node metastasis, tumor size and recurrence, with high C14orf166 expression correlating with high HCC recurrence risk. The poor OS and DFS of HCC patients are partly due to the persistently high HCC recurrence risk. When combined with serum alpha-fetoprotein level, the predictive accuracy of C14orf166 for HCC recurrence was enhanced (AUC = 0.712, 95% CI 0.603-0.821; p = 0.001). Conclusions: This study demonstrated that C14orf166 is a high-risk biomarker and predictive factor for HCC recurrence, providing information for the selection of appropriate treatment strategies.

HIF-2α upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway.

Non-alcoholic fatty liver disease (NAFLD) is a relevant risk factor for developing hepatocellular carcinoma (HCC). Steatohepatitic HCC (SH-HCC), characterized by HCC with steatosis, is influenced by lipid metabolism disorders. A hypoxic microenvironment is common in HCC and affects lipid metabolism. However, whether hypoxia-induced HIF-2α upregulation exacerbates lipid accumulation to contribute to SH-HCC progression remains unclear. In this study, we demonstrated that HIF-2α was elevated in tissues from NAFLD-HCC patients and was associated with survival. Under hypoxic conditions, upregulated HIF-2α was accompanied by lipid accumulation and PI3K-AKT-mTOR pathway activation. HIF-2α knockdown (KD) in steatotic HCC ameliorated triglyceride accumulation and steatosis. HIF-2α-KD steatotic HCC showed minimal lipid synthesis in a hypoxic environment, which contributes to a reduction in malignant behaviours. However, treatment with MHY1485 restored these behaviours. STAM mice, a mouse model that develops NAFLD-HCC, exhibit more rapid tumour progression upon exposure to hypoxia. STAM mice treated with INK-128 presented abrogated mTOR expression and tumour progression under hypoxic conditions with lower triglycerides and steatosis. In conclusion, in a hypoxic microenvironment, HIF-2α upregulation promotes steatotic HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway. Therefore, HIF-2α can be a biomarker and target in developing specific therapeutic measures for NAFLD-HCC patients.

Hypoxia exacerbates nonalcoholic fatty liver disease via the HIF-2α/PPARα pathway.

This study aimed to investigate whether hypoxia can affect nonalcoholic fatty liver disease (NAFLD) progression and the associated mechanisms, specifically regarding the hypoxia-inducible factor (HIF)-2α/peroxisome proliferator-activated receptor (PPAR)α pathway in vitro and in vivo. Recent studies have reported that, compared with HIF-1α, HIF-2α has different effects on lipid metabolism. We propose hypoxia may exacerbate NAFLD by the HIF-2α upregulation-induced suppression of PPARα in the liver. To verify this hypothesis, a steatotic human hepatocyte (L02) cell line treated with free fatty acids and a mouse model of NAFLD fed a high-fat diet were used. Steatotic hepatocytes were treated with hypoxia, HIF-2α siRNA, PPARα agonists, and inhibitors, respectively. Meanwhile, the NAFLD mice were exposed to intermittent hypoxia or intermittent hypoxia with PPARα agonists. The relative gene expression levels of HIF-1α, HIF-2α, mitochondrial function, fatty acid ß-oxidation and lipogenesis were examined. Evidence of lipid accumulation was observed, which demonstrated that, compared with normal hepatocytes, steatotic hepatocytes exhibited higher sensitivity to hypoxia. This phenomenon was closely associated with HIF-2α. Moreover, lipid accumulation in hepatocytes was ameliorated by HIF-2α silencing or a PPARα agonist, despite the hypoxia treatment. HIF-2α overexpression under hypoxic conditions suppressed PPARα, leading to PGC-1α, NRF-1, ESRRα downregulation, and mitochondrial impairment. Additionally, ß-oxidation genes such as CPT1α, CPT2α, ACOX1, and ACOX2 were downregulated and lipogenesis genes including LXRα, FAS, and SCD1 were upregulated by hypoxia. Therefore, we concluded that HIF-2α overexpression induced by hypoxia aggravated NAFLD progression by suppressing fatty acid ß-oxidation and inducing lipogenesis in the liver via PPARα.

Potential Five-MicroRNA Signature Model for the Prediction of Prognosis in Patients with Wilms Tumor.

BACKGROUND Wilms tumor (WT) is the most common type of pediatric renal malignancy, and is associated with poor prognosis. The aim of the present study was to identify microRNA (miRNA) signatures which might predict prognosis and categorize WTs into high- and low-risk subgroups. MATERIAL AND METHODS The miRNA expression profiles of WT patients and normal samples were obtained from the Therapeutically Applicable Research to Generate Effective Treatment database. Differentially expressed miRNAs between WT patients and normal samples were identified using the EdgeR package. Subsequently, correlations between differentially expressed miRNAs and the prognosis of overall survival were analyzed. Enrichment analyses for the targeted mRNAs were conducted via the Database for Annotation, Visualization, and Integration Discovery. RESULTS A total of 154 miRNAs were identified as differentially expressed in WT. Of those, 18 miRNAs were associated with overall survival (P<0.05). A prognostic signature of 5 differentially expressed miRNAs (i.e., has-mir-149, has-mir-7112, has-mir-940, has-mir-1248, and has-mir-490) was constructed to classify the patients into high- and low-risk subgroups. The targeted mRNAs of these prognostic miRNAs were primarily enriched in Gene Ontology terms (i.e., protein autophosphorylation, protein dephosphorylation, and stress-activated MAPK cascade) and the Kyoto Encyclopedia of Genes and Genomes signaling pathways (i.e., MAPK, AMPK, and PI3K-Akt). CONCLUSIONS The 5-miRNA signature model might be useful in determining the prognosis of WT patients. As a promising prediction tool, this prognosis signature might serve as a potential biomarker for WT patients.