Hepatology最新文献

Background and aims: Hepatoblastoma (HB) is the most common malignant liver tumor in children. Despite advances in multimodal treatment, chemoresistance and relapses remain major clinical challenges. NEDDylation, a post-translational modification involving the ubiquitin-like molecule NEDD8, has been implicated in cancer, but its role in HB remains poorly understood. This study investigates the functional relevance of the deNEDDylase NEDP1 and its downstream target CAND1 in HB progression and therapy response.

Approach and results: Transcriptomic and proteomic analyses of HB patient samples, cell lines, patient-derived xenograft (PDX) cells, and transgenic mouse models revealed a significant reduction in NEDP1 expression and activity, accompanied by global hyper-NEDDylation. Functional studies demonstrated that NEDP1 overexpression restored deNEDDylation, induced apoptosis, impaired tumor cell proliferation and metabolism, and significantly restrained tumor growth and metastasis in both in vivo mouse models and in the chorioallantoic membrane (CAM) assay. Proteomic profiling identified CAND1 as a key NEDDylated substrate regulated by NEDP1. High CAND1 expression was associated with aggressive molecular HB subtypes (C2-pure, Epi-CB) and poor clinical outcomes, including reduced overall survival. Rescue experiments confirmed that CAND1 overexpression counteracted the antitumor effects of NEDP1.

Conclusions: NEDP1 acts as a tumor suppressor in HB by modulating the NEDDylation status of key regulatory proteins, particularly CAND1. Restoration of NEDP1 activity suppresses tumorigenesis and metastasis, underscoring the NEDDylation pathway as a promising therapeutic target. CAND1 is proposed as a potential prognostic biomarker and actionable oncogenic driver in HB.

Background and aims: An effective vaccine against hepatitis C virus (HCV) infection is required to achieve viral eradication. A previous viral vectored vaccine encoding a genotype-1b T cell antigen suppressed peak viral RNA but failed to prevent chronic infection. Previous studies showed dominant vaccine-induced T cell responses were not cross-reactive with common HCV strains, possibly contributing to vaccine failure. To address this, we evaluated 2 novel HCV vaccine strategies designed to elicit T cells targeting multiple HCV genotypes.

Approach and results: HCV genetic segments highly conserved between genotypes 1-6 were encoded in chimpanzee adenoviral (ChAd-Gt1-6) and Modified Vaccinia virus Ankara (MVA-Gt1-6) vectors and tested in prime-boost regimens. This was compared with vaccinating with an ancestral genotype-1a non-structural antigen encoded in ChAd (ChAd-Bole1a-NS) boosted with a genotype-3a non-structural antigen encoded in MVA (MVA-Gt3a-NS). Immunogenicity was evaluated in C57BL/6 and transgenic HLA-A*02:01 mice. Splenocytes were stimulated with genotype-1a, genotype-1b, or genotype-3a peptide pools in ex vivo IFNγ ELISpot and intracellular cytokine assays. Priming with ChAd-Gt1-6 elicited broad T cell responses toward all genotypes, whereas ChAd-Bole1a-NS generated a focused response to genotype-1a. Boosting ChAd-Bole1a-NS with MVA-Gt3a-NS generated cross-reactive T cells targeting multiple genotypes, though some responses were genotype-specific. In contrast, ChAd-Gt1-6 and MVA-Gt1-6 prime-boost generated high-magnitude responses that were all cross-reactive between genotypes.

Conclusions: Vaccinating with conserved regions of genotypes 1-6 or sequentially vaccinating with genotype-1a and genotype-3a immunogens are 2 novel approaches to generate cross-reactive T cells. The proportion of intergenotypic cross-reactive T cells generated was higher using the conserved region antigen.