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Introduction: Compared with multivariate risk assessment, traditional category-based risk assessment (CRA) approaches for neonatal early-onset sepsis (EOS) screening are usually straightforward to use, do not require electronic devices, but are associated with higher rates of antibiotic use. This study aims to evaluate the performance of a novel enhanced CRA (eCRA) framework on EOS admissions and antibiotic use and to investigate whether a modified version with adjustments in risk factor weighting can allow its performance to match the EOS calculator while remaining easy to implement. Method: This is a prospective, single-center, two-phase observational study. Infants of all gestations delivered in a tertiary hospital in Hong Kong with risk factors or clinical features of EOS were recruited. Phase I: A novel eCRA framework (period 2) was compared with the CDC 2010-based protocol (period 1). Phase II: A modified eCRA framework was compared theoretically with the EOS calculator. EOS-specific admissions and antibiotic use were measured. Results: Phase I: 1,025 at-risk infants were recruited during period 2 and compared with 757 infants of period 1. Admissions and antibiotic use decreased from 45.8% to 29.4% and 41.1% to 28.2%, respectively. Antibiotics among those at-risk but well-appearing infants decreased from 25.3% to 16.3% (p < 0.001 for all). Phase II: antibiotic use was similar (7.3 vs. 6.4%, p = 0.42) between the modified eCRA framework and the EOS calculator. Conclusions: An eCRA framework can effectively and safely provide individualized guidance for EOS screening without the need for tools such as the EOS calculator. [ABSTRACT FROM AUTHOR]

Background and Aims: HCC is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence., Approach and Results: Clinical traits and RNA-seq of patients with HCC in The Cancer Genome Atlas were used for weighted gene coexpression network analysis, where 1 module was significantly correlated with advanced pathological stage and stem cell population maintenance. Further analysis of this module by integrating data obtained from HCC patient nonresponders to tyrosine kinase inhibitors identified 361 commonly deregulated genes. Intriguingly, these genes are significantly enriched in the intracellular signal transduction pathway, with diacylglycerol kinase eta (DGKH) ranked as the most enriched gene in poorly differentiated HCC tumors. Clinically, DGKH was elevated in tumor tissues compared to nontumor tissues. Patients with higher DGKH expression exhibited a more undifferentiated state and were less responsive to tyrosine kinase inhibitors. Functional assays using DGKH-manipulated HCC cell lines demonstrated that DGKH augmented aggressive features, including cancer stemness, therapy resistance, and metastasis. Upstream of DGKH , we discovered that the E1A-associated protein p300 (EP300) binds to DGKH's promoter region, thereby increasing its transcriptomic expression. Mechanistically, DGKH promotes mTOR signaling by producing phosphatidic acid. In an immunocompetent mouse model, cotreatment with sorafenib and liver-directed AAV8-mediated Dgkh depletion significantly reduced tumor burden, self-renewal, phosphatidic acid production, and mTOR signaling., Conclusions: Our research demonstrated that DGKH is a crucial oncometabolic regulator of cancer stemness and therapy resistance, suggesting that inhibiting DGKH may lead to more effective HCC treatment., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Cancer stem cells (CSCs) are now recognized as one of the major root causes of therapy failure and tumor recurrence in hepatocellular carcinoma (HCC). Early studies in the field focused primarily on the intrinsic regulators of CSC maintenance, but in recent years, mounting evidence has demonstrated the presence and role of extrinsic regulators in the tumor microenvironment (TME) in the control of liver CSCs. In addition to direct interaction with cellular components, noncellular components, including the extracellular matrix, hypoxia, nutrient deprivation, and secreted molecules within the tumor stroma and hepatitis viruses, also play a critical role in shaping the CSC niche. In this review, we highlight how various noncellular components in the TME play a role in regulating CSCs and how CSCs secrete components to interact with the TME to generate their own niche, working hand in hand to drive tumor physiology in HCC. In addition, we describe the potential clinical applications of these findings and propose perspectives on future research of noncellular components in the liver CSC niche., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)