Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1, 995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction

ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells

Aging and inflammation: aging cells express interferon-stimulated genes in a non-canonical pathway Aging cells express many kinds of inflammation-related genes called SASP (senescence-associated secretary-phenotype), which are involved in aging-associated phenotypes. However, the underlying molecular mechanisms how such inflammatory gene expression is induced in aging cells are unclear. A team led by Motoyuki Otsuka at the University of Tokyo found that using senescent human fibroblasts interferon-stimulated genes do not express in a canonical interferon-related intracellular signaling pathway. Normally, interferon-stimulated genes are expressed through the phosphorylation of STAT proteins triggered by interferon stimulation. In contrast, in senescent cells, interferon-stimulated genes were highly expressed without interferon stimulation and the representative STAT phosphorylation was not induced. These findings indicate that the interferon-stimulated genes in aging cells are expressed in a mechanism different from a canonical interferon-related pathway. Further research into these phenomena may develop a way to intervene the senescence-associated phenotypes in aging

Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx–DDB1 InteractionSummary

Background & Aims: Hepatitis B virus (HBV) infection is a major health concern worldwide. Although currently used nucleos(t)ide analogs efficiently inhibit viral replication, viral proteins transcribed from the episomal viral covalently closed circular DNA (cccDNA) minichromosome continue to be expressed long-term. Because high viral RNA or antigen loads may play a biological role during this chronicity, the elimination of viral products is an ultimate goal of HBV treatment. HBV regulatory protein X (HBx) was recently found to promote transcription of cccDNA with degradation of Smc5/6 through the interaction of HBx with the host protein DDB1. Here, this protein–protein interaction was considered as a new molecular target of HBV treatment. Methods: To identify candidate compounds that target the HBx–DDB1 interaction, a newly constructed split luciferase assay system was applied to comprehensive compound screening. The effects of the identified compounds on HBV transcription and cccDNA maintenance were determined using HBV minicircle DNA, which mimics HBV cccDNA, and the natural HBV infection model of human primary hepatocytes. Results: We show that nitazoxanide (NTZ), a thiazolide anti-infective agent that has been approved by the FDA for protozoan enteritis, efficiently inhibits the HBx–DDB1 protein interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system and in human primary hepatocytes naturally infected with HBV. Conclusions: These results indicate that NTZ, which targets an HBV-related viral–host protein interaction, may be a promising new therapeutic agent and a step toward a functional HBV cure. Keywords: Drug Screening, Minicircle, Primary Hepatocyte Infectio