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Summary: Background: Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). Aims: To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. Methods: This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg‐positive, normal ALT and HBV DNA ≤106 IU/ml (GZ‐A); HBeAg‐positive, elevated ALT and HBV DNA ≤2 × 104 IU/ml (GZ‐B); HBeAg‐negative, normal ALT and HBV DNA ≥2 × 103 IU/ml (GZ‐C) and HBeAg‐negative, elevated ALT and HBV DNA ≤2 × 103 IU/ml (GZ‐D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. Results: Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg‐positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg‐negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ‐D (42.6%) was the dominant category, followed by GZ‐C (38.8%), GZ‐A (10.3%) and GZ‐B (8.3%). The highest proportion of significant histological disease was observed patients in GZ‐B (100.0%), followed by GZ‐A (84.0%), GZ‐D (69.9%) and GZ‐C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg‐negative GZ. Conclusions: Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg‐positive and HBeAg‐negative GZ CHB patients with high PT. [ABSTRACT FROM AUTHOR]

Objectives: To identify semiologic features of automatisms correlating to different seizure onset zones (SOZ).Methods: In total, 204 seizures from 74 patients with either oral or manual automatisms were assessed. Patients were divided into four groups depending on the SOZ into frontal, posterior, neocortical temporal, and mesial temporal cortex groups. A k-means analysis was applied on 11 semiologic features on a multi-criteria scale. Then, the resulting clinical patterns were correlated with the SOZs determined by presurgical anatomy-electroclinical data (25 cases with stereo-EEG).Results: Four clinical patterns of automatisms with different accompanying symptoms were identified. The clinical features of clusters 1 and 4 were mostly found in temporal epilepsy whereas clusters 2 and 3 were more frequent in extratemporal epilepsy. Cluster 1 was significantly correlated with mesial temporal lobe epilepsy (p = .017) and was characterised by aura, postictal confusion, short automatisms delay. Cluster 3 included 1/3 patients with frontal lobe epilepsy and was characterised by emotionality. Cluster 4 was related to neocortical temporal lobe epilepsy and characterised by dystonia and short automatism delay (p = .011).Conclusion: The distinct semiologic patterns of automatisms may provide information which may allow clinicians to define the SOZs. These findings could improve diagnostic accuracy and surgical outcome. [ABSTRACT FROM AUTHOR]

Background: Liver cancer is one of the most commonly diagnosed cancers and the fourth leading cause of cancer-related death worldwide. Broad-spectrum kinase inhibitors like sorafenib and lenvatinib provide only modest survival benefit to patients with hepatocellular carcinoma (HCC). This study aims to identify novel therapeutic strategies for HCC patients. Methods: Integrated bioinformatics analyses and a non-biased CRISPR loss of function genetic screen were performed to identify potential therapeutic targets for HCC cells. Whole-transcriptome sequencing (RNA-Seq) and time-lapse live imaging were performed to explore the mechanisms of the synergy between CDC7 inhibition and ATR or CHK1 inhibitors in HCC cells. Multiple in vitro and in vivo assays were used to validate the synergistic effects. Results: Through integrated bioinformatics analyses using the Cancer Dependency Map and the TCGA database, we identified ATR-CHK1 signaling as a therapeutic target for liver cancer. Pharmacological inhibition of ATR or CHK1 leads to robust proliferation inhibition in liver cancer cells having a high basal level of replication stress. For liver cancer cells that are resistant to ATR or CHK1 inhibition, treatment with CDC7 inhibitors induces strong DNA replication stress and consequently such drugs show striking synergy with ATR or CHK1 inhibitors. The synergy between ATR-CHK1 inhibition and CDC7 inhibition probably derives from abnormalities in mitosis inducing mitotic catastrophe. Conclusions: Our data highlights the potential of targeting ATR-CHK1 signaling, either alone or in combination with CDC7 inhibition, for the treatment of liver cancer. [ABSTRACT FROM AUTHOR]