Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.
Background International Sustainable Development Goals (SDGs) for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In African populations, infant immunisation has been fundamental to reducing incident infections in children, but overall population prevalence of chronic hepatitis B (CHB) infection remains high. In high-prevalence populations, adult catch-up vaccination has sometimes been deployed, but an alternative Test and Treat (T&T) approach could be used as an intervention to interrupt transmission. Universal T&T has not been previously evaluated as a population intervention for HBV infection, despite high-profile data supporting its success with human immunodeficiency virus (HIV). Methods and findings We set out to investigate the relationship between prevalence of HBV infection and exposure in Africa, undertaking a systematic literature review in November 2019. We identified published seroepidemiology data representing the period 1995-2019 from PubMed and Web of Science, including studies of adults that reported prevalence of both hepatitis B
Background Tumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis. In this study, we examined the pan-cancer prognostic significance of oxygen-sensing genes from the 2-oxoglutarate-dependent oxygenase family. Methods A multi-cohort, retrospective study of transcriptional profiles of 20,752 samples of 25 types of cancer was performed to identify pan-cancer prognostic signatures of 2-oxoglutarate-dependent oxygenase gene family (a family of oxygen-dependent enzymes consisting of 61 genes). We defined minimal prognostic gene sets using three independent pancreatic cancer cohorts (n = 681). We identified two signatures, each consisting of 5 genes. The ability of the signatures in predicting survival was tested using Cox regression and receiver operating characteristic (ROC) curve analyses. Results Signature 1 ( KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7 ) and signature 2 ( KDM3A, P4HA1, ASPH, PLOD1, PLOD2 ) were associated with good and poor prognosis. Signature 1 was prognostic in 8 cohorts representing 6 cancer types (n = 2627): bladder urothelial carcinoma ( P = 0.039), renal papillary cell carcinoma ( P = 0.013), liver cancer ( P = 0.033 and P = 0.025), lung adenocarcinoma ( P = 0.014), pancreatic adenocarcinoma ( P < 0.001 and P = 0.040), and uterine corpus endometrial carcinoma ( P < 0.001). Signature 2 was prognostic in 12 cohorts representing 9 cancer types (n = 4134): bladder urothelial carcinoma ( P = 0.039), cervical squamous cell carcinoma and endocervical adenocarcinoma ( P = 0.035), head and neck squamous cell carcinoma ( P = 0.038), renal clear cell carcinoma ( P = 0.012), renal papillary cell carcinoma ( P = 0.002), liver cancer ( P < 0.001, P < 0.001), lung adenocarcinoma ( P = 0.011), pancreatic adenocarcinoma ( P = 0.002, P = 0.018, P < 0.001), and gastric adenocarcinoma ( P = 0.004). Multivariate Cox regression confirmed independent clinical relevance of the signatures in these cancers. ROC curve analyses confirmed superior performance of the signatures to current tumor staging benchmarks. KDM8 was a potential tumor suppressor down-regulated in liver and pancreatic cancers and an independent prognostic factor. KDM8 expression was negatively correlated with that of cell cycle regul...
BackgroundDespite much progress in cancer research, its incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.MethodsIn a retrospective bioinformatics analysis involving patients with liver cancer (n = 839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we were able to identify a second prognostic signature comprised of 8 genes. Its performance was further validated in five other cancers: head and neck (n = 520), renal papillary cell (n = 290), lung (n = 515), pancreas (n = 178) and endometrial (n = 370).ResultsThe 45-gene signature predicted overall survival in three liver cancer cohorts: hazard ratio (HR) = 1.82, P = 0.006; HR = 1.84, P = 0.008 and HR = 2.67, P = 0.003. Additionally, the reduced 8-gene signature was sufficient and effective in predicting survival in liver and five other cancers: liver (HR = 2.36, P = 0.0003; HR = 2.43, P = 0.0002 and HR = 3.45, P = 0.0007), head and neck (HR = 1.64, P = 0.004), renal papillary cell (HR = 2.31, P = 0.04), lung (HR = 1.45, P = 0.03), pancreas (HR = 1.96, P = 0.006) and endometrial (HR = 2.33, P = 0.003). Receiver operating characteristic analyses demonstrated both signatures superior performance over current tumor staging parameters. Multivariate Cox regression analyses revealed that both 45-gene and 8-gene signatures were independent of other clinicopathological features in these cancers. Combining the gene signatures with somatic mutation profiles increased their prognostic ability.ConclusionsThis study, to our knowledge, is the first to identify a gene signature uniting both tumor hypoxia and lymphocytic infiltration as a prognostic determinant in six cancer types (n = 2712). The 8-gene signature can be used for patient risk stratification by incorporating hypoxia information to aid clinical decision making.Electronic supplementary materialThe online version of this article (10.1186/s12967-019-1775-9) contains supplementary material, which is available to authorized users.
Antibody responses are important in the control of viral respiratory infection in the human host. What is not clear for SARS-CoV-2 is how rapidly this response occurs, or when antibodies with protective capability evolve. Hence, defining the events of SARS-CoV-2 seroconversion and the time frame for the development of antibodies with protective potential may help to explain the different clinical presentations of COVID-19. Furthermore, accurate descriptions of seroconversion are needed to inform the best use of serological assays for diagnostic testing and serosurveillance studies. Here, we describe the humoral responses in a cohort of hospitalised COVID-19 patients (n = 19) shortly following the onset of symptoms. Commercial and ‘in-house’ serological assays were used to measure IgG antibodies against different SARS-CoV-2 structural antigens–Spike (S) S1 sub-unit and Nucleocapsid protein (NP)–and to assess the potential for virus neutralisation mediated specifically by inhibition of binding between the viral attachment protein (S protein) and cognate receptor (ACE-2). Antibody response kinetics varied amongst the cohort, with patients seroconverting within 1 week, between 1–2 weeks, or after 2 weeks, following symptom onset. Anti-NP IgG responses were generally detected earlier, but reached maximum levels slower, than anti-S1 IgG responses. The earliest IgG antibodies produced by all patients included those that recognised the S protein receptor-binding domain (RBD) and were capable of inhibiting binding to ACE-2. These data revealed events and patterns of SARS-CoV-2 seroconversion that may be important predictors of the outcome of infection and guide the delivery of clinical services in the COVID-19 response.
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