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AbstractHepatocellular carcinoma (HCC) is one of the high incidence cancers and third leading cause of cancer-related mortality. HBV is the top most risk factor accounting for 50–80% of the HCC cases. Kinases: Aurora kinase A (AURKA), cyclin-dependent kinase (CDK1) and Polo-like kinase 1 (PLK1), the key regulators of cell mitosis are overexpressed in varieties of cancers including HCC. However, the exact role of these genes in prognosis of HCC is not fully unveiled. In addition, there is no such an accurate prognostic biomarker for HBV-related HCC. To address this issue, we performed a multidimensional analysis of AURKA, CDK1 and PLK1 with a series of publicly available databases in multiple cancers and with experimental validation in HBV-related HCC tissues. Overexpression of AURKA, CDK1 and PLK1 was found in multiple cancers including HCC. Elevated expression of these genes could result from lowered DNA methylation and genomic alterations. Transcriptional overexpression was significantly correlated with poor prognosis of HCC patients. The expression levels were also significantly positively associated with tumor grades and stages. Furthermore, the expression levels of these genes had a strong correlation with infiltration of immune cells. Our analysis shows that AURKA, CDK1 and PLK1 are correlated with immune infiltration and are the prognostic biomarkers for HBV-induced HCC.Communicated by Ramaswamy H. Sarma

Objective: Numerous studies have indicated that excitatory amino acid toxicity, such as glutamate toxicity, is involved in glaucoma. In addition, excessive glutamate can lead to an intracellular calcium overload, resulting in regulated necrosis. Our previous studies have found that the calpastatin (CAST)-calpain pathway plays an important role in retinal neuron-regulated necrosis after glutamate injury. Although inhibition of the calpain pathway can decrease regulated necrosis, necrotic cells remain. It has been suggested that there are other molecules that participate in retinal neuron-regulated necrosis. CAST is an important regulator of dynamin-related protein 1 (Drp1)-mediated mitochondrial defects. Thus, the aim of this study was to determine whether the CAST-Drp1 pathway may be an underlying signaling axis in neuron-regulated necrosis. Methods: Using cultured retinal neurons and in an in-vivoglaucoma model induced by glutamate overload, members of the CAST-Drp1 pathway were assessed by immunofluorescence, Western blotting, Phos-tagTMSDS-PAGE, and co-immunoprecipitation assays. Moreover, the black and white box test was performed on the rats. Results: We found that more retinal neuron-regulated necrosis and Drp1 activation as well as lower CAST levels were present in the glutamate-induced glaucoma model. Rats with glutamate-induced glaucoma exhibited impaired visual function. We also observed retinal neuron-regulated necrosis and Drp1 activity decreased, and impaired vision recovered after CAST active peptide application, indicating that the CAST-Drp1 pathway plays a critical role in retinal neuron-regulated necrosis and visual function. Conclusion: The results of this study indicate that the CAST-Drp1 pathway protects against retinal neuron-regulated necrosis, which may expand the therapeutic targets for the treatment of neurodegenerative disorders involving dysfunction of glutamate metabolism, such as glaucoma.