Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 ...(CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant KD: 1.95 × 10-10 ± 0.21 × 10-10 M). Moreover, HBV activated SIGLEC-3 on myeloid cells and induced immunosuppression by stimulating immunoreceptor tyrosine-based inhibitory motif phosphorylation and SHP-1/-2 recruitment via α2,6-biantennary sialoglycans on HBsAg. An antagonistic anti-SIGLEC-3 mAb reversed this effect and enhanced cytokine production in response to TLR-7 agonist GS-9620 in PBMCs from CHB patients. Moreover, anti-SIGLEC-3 mAb alone was able to upregulate the expression of molecules involved in antigen presentation, such as CD80, CD86, CD40, MHC-I, MHC-II, and PD-L1 in CD14+ cells. Furthermore, SIGLEC-3 SNP rs12459419 C, which expressed a higher amount of SIGLEC-3, was associated with increased risk of hepatocellular carcinoma (HCC) in CHB patients (HR: 1.256, 95% CI: 1.027-1.535, P = 0.0266). Thus, blockade of SIGLEC-3 is a promising strategy to reactivate host immunity to HBV and lower the incidence of HCC in the CHB patient population.
Abstract
Background: The reported associations of genetic variants within the human leukocyte antigen (HLA) region with hepatis B virus (HBV)-related hepatocellular carcinoma (HCC) are not ...consistent, and the structure-function patterns involved in this disease remain unclear.
Methods: Utilizing genotype data from 706 HBV-related HCC cases and 6197 chronic HBV carriers without HCC collected from three resources in Taiwan, we imputed the classical HLA alleles at 2-field resolution and analyzed the molecular landscape of HLA complexes by deeply dissecting their genotypic configurations, functional divergence, and HBV-antigen binding capabilities in associations with the HCC risk. Logistic regression models were used, and all models were adjusted for sex, age, and population structure using the top 10 principal components. We also tested the underlying biological implications of our findings by investigating the HLA binding affinities and HLA effect on control of viral replication (i.e, HBV DNA load), viral population diversity (i.e, quasispecies), and inflammation (i.e, chemokines, cytokines, and soluble programmed cell death 1 sPD-1-associated T cell exhaustion).
Results: We found high accuracy (≥95% concordance) of HLA imputation at all HLA class I and class II alleles. The strongest evidence for an association with HCC was observed for HLA-DQB1*03:01 (adjusted OR= 1.35 in an additive genetic model, P=1.3×10-6). Three amino acids at specific positions within or near the peptide-binding groove of DQB1 molecules might explain the observed allele association, which leads to loss of binding HBV nucleocapsid protein (i.e., low binding affinity predicted by NetMHCIIpan 4.0 for HLA-DQB1*03:01). HLA-DQB1*03:01 was significantly associated with a higher HBV DNA load (P= 4.3×10-4) and an increased level of serum sPD-1 (P=6.8×10-4), but not with increased levels of chemokines, cytokines, and viral complexity (i.e., Shannon entropy for HBV quasispecies, all P values>0.05). Analysis of HLA zygosity confirmed that HLA-DQB1 heterozygosity was associated with a decreased risk of HCC (adjusted OR=0.77, P= 0.015). Analysis of HLA evolutionary divergence (HED) showed that high HED at HLA-DRB1 loci was marginally associated with a decreased risk of HCC among HLA-DQB1*03:01 non-carriers (P=0.05).
Conclusion: Our data shed light on the immunogenetic risk associated with HBV-related HCC. The effect of HLA-DQB1*03:01 could be partly explained by its low binding affinity with HBV nucleocapsid antigen, and/or its effect on viral load control and sPD-1, but not by its control on other inflammation markers (chemokines and cytokines) and viral population diversity. The association between HLA-DQB1 heterozygosity and HCC risk could be independent of the HLA-DQB1*03:01 effect, which indicates underlying mechanisms related to increased immunosurveillance in clearing potential viral antigens or neoantigens.
Citation Format: Zhiwei Liu, Chih-Jen Huang, Yu-Han Huang, Mei-Hung Pan, Mei-Hsuan Lee, Mathias Viard, Allan Hildesheim, Ruth M. Pfeiffer, Mary Carrington, Chien-Jen Chen, Tobias L. Lenz, Hwai-I Yang. The immunogenetic basis of hepatitis B virus-related hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3013.
BPR0Y007, a bis-benzylidenecyclopentanone derivative (2,5-bis- (4-hydroxy-3-methoxybenzylidene) cyclopentanone), was identified in our laboratory as a novel antineoplastic agent with a broad spectrum ...of antitumor activity against many human cancer cells. A previous study showed that BPR0Y007 inhibited DNA topoisomerase I (Top 1) activity and prevented tubulin polymerization. Notably, no cross-resistance with BPR0Y007 was observed in camptothecin-, VP-16- or vincristine-resistant cell lines. In this study, we further investigated the cellular and molecular events underlying the antitumoral function of this compound in human oral epidermoid carcinoma KB cells, focusing on the early cytotoxic effect. Treatment of KB cells with BPR0Y007-induced G
2/M phase arrest followed by sub-G
1 phase accumulation. Annexin-V–propidium iodide (PI) binding assay and DNA fragmentation assay further indicated that BPR0Y007-induced cell death proceeded through an apoptotic pathway as opposed to via necrosis. This compound produced a time-dependent activation of caspases-3 and -8, however, another caspase-3 initiator, caspase-9, was only marginally activated at later time point. We further demonstrated that the activation of the caspases cascade and nuclear fragmentation was not associated with inactivated Bcl-2 and perturbed mitochondrial membrane potential by BPR0Y007. The finding that BPR0Y007-induced apoptosis through a membrane-mediated mechanism was supported by up-regulated expression of Fas (CD95/APO-1), but not Fas-L. Furthermore, up-regulation of p53 and its affected gene, MDM2, in KB cells was found after BPR0Y007 exposure. Overall, our results demonstrated that the BPR0Y007 could induce an early cytotoxic apoptosis through a caspase-8-dependent but mitochondrial-caspase-9 independent pathway, and involving upregulation of p53.
碩士
高雄醫學大學
公共衛生學研究所碩士班
92
Background:
Once absorbed into the body, lead becomes widely distributed and interacts with a number of enzyme systems. Lead poisoning cause cardiac and vascular damage in ...experimental animals. In epidemiology, lead exposure has been related to cardiovascular dysfunctions in humans. Paraoxonase-1（PON1）is an HDL-associated serum enzyme, previously known for its ability to detoxify organophosphorus insecticides. Evidence has shown that PON1 protects low-density lipoproteins（LDL）from oxidative damage both in vitro and in vivo. The aim of this study is to investigate whether occupational lead exposure is associated with lipid profiles and how PON1 may modify the association.
Methods:
474 and 124 workers were recruited from two lead manufacturing factories, separately. Three common PON1 polymorphisms（Q192R, L55M, -108C/T）were determined by PCR-RFLP method. Serum PON1 activities were measured using a microfiter plate reader （SpectraMax, Molecular Devices）. Blood samples were analyzed for li
Abstract: The association between rotating shift work and increased occupational stress in nurses: Pei-Chen LIN, et al. Department of Public Health, College of Health Sciences, Kaohsiung Medical ...University, Taiwan - Purpose: The aim of this study was to investigate whether rotating shift work increases occupational stress in nurses. Methods: This study measured shift work scheduling and occupational stress by using the Effort-Reward Imbalance model with self-reported questionnaires in a sample of 654 female nurses. Results: Overcommitment risk was higher in nurses who worked rotating shifts than in those who worked day/non-night shifts (OR, 2.16; 95% CI, 1.03-4.66). However, an effort/reward imbalance was not directly associated with work schedules (OR, 1.88; 95% CI, 0.87-4.35). Among nurses working rotation rotating shifts, those who had 2 days off after their most recent night shifts showed an alleviated risk of overcommitment (OR, 0.52; 95% CI, 0.32-0.82), but those who had worked for at least one series of 7 consecutive work days per month had an increased risk of effort/reward imbalance (OR, 2.75; 95% CI, 1.69-4.48). Additionally, those who had little or no participation in planning working hours and shift scheduling and worked overtime at least three times per week during the preceding 2 months tended to have high stress. Conclusions: The nurses who worked rotating shifts tended to experience work-related stress, but their stress levels improved if they had at least 2 days off after their most recent night shift and if they were not scheduled to work 7 consecutive days. These empirical data can be used to optimize work schedules for nurses to alleviate work stress.
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