Background . Graves’ disease (GD) is an organ-specific autoimmune disease. Accumulated data have indicated that aberrant epigenetic modifications are associated with many autoimmune disorders. However, it remains unknown whether histone methylation plays a role in the pathogenesis of GD. In the present study, we aimed to assess histone modification patterns in peripheral blood mononuclear cells (PBMCs) from GD patients. The rate (degree) of H3K4 and H3K9 methylation and the expressions of histone-modifying genes were investigated. Methods . A total of 68 GD patients and 32 healthy controls were enrolled in this study. Global histone H3K4/H3K9 methylation of PBMCs was evaluated by the EpiQuik™ global histone H3K4/H3K9 methylation assay kit. The expressions of histone methyltransferases (HMTs) and histone demethylases (HDMs) at the mRNA level were determined by real-time quantitative polymerase chain reaction. Results . Global histone H3K9 methylation in PBMCs of GD patients was significantly decreased compared with that in the healthy controls (P=0.007). The expressions of HMTs (SUV39H1 and SUV39H2) at the mRNA level were significantly decreased in PBMCs from GD patients compared with healthy controls (P<0.001), whereas the SETD1A expression at the mRNA level was significantly increased in GD patients compared with healthy controls (P=0.004). In addition, the expressions of HDMs, including JHDM2A and JMJD2A, at the mRNA level were significantly increased in GD patients compared with healthy controls (P<0.001; P=0.007). Moreover, the mRNA expression levels of JARID1A and LSD1 did not significantly differ in GD patients and healthy controls (P>0.05). Conclusions . These findings firstly suggested that the histone methylation was aberrant in PBMCs of GD patients, which could be possibly attributed to the deregulation of epigenetic modifier genes. Abnormal histone methylation modification may be involved in the pathogenesis of GD.
Background: The adverse impact of thyroid dysfunction on cardiovascular system is well established, but the relationship between the level of thyroid stimulating hormone (TSH) and the risk of hypertension in euthyroid individuals is still inconclusive. Methods: We carried out a population-based, cross-sectional study to evaluate the relationship between TSH and hypertension risk in euthyroid individuals, and logistic regression analysis was utilized. In addition, a dose–response meta-analysis of relevant cohort or cross-sectional studies was carried out to further assess the impact of TSH on hypertension risk among euthyroid individuals. Results: A total of 2289 euthyroid individuals without thyroid diseases were recruited in our cross-sectional study. Serum TSH level within the upper reference range was associated with higher risk of hypertension [odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.04–1.61, P = 0.023], and the OR for hypertension was still statistically significant after adjustment for confounding factors (OR = 1.32, 95% CI 1.01–1.72, P = 0.041). Moreover, meta-analysis suggested an obvious dose–response relationship between TSH and hypertension risk in euthyroid individuals, and the OR for hypertension associated with per 1 mIU/l increase in TSH level was 1.09 (95% CI 1.04–1.14, P < 0.001). Meta-analysis also showed that the β-coefficients of SBP and DBP associated with per 1 mIU/l increase in TSH level were 0.78 (95% CI 0.37–1.18, P < 0.001) and 0.45 (95% CI 0.15–0.76, P = 0.004), respectively. Conclusion: The current study provides strong evidence for the dose–response relationship between serum TSH level and hypertension risk in euthyroid individuals. Euthyroid individuals with higher normal TSH level are at higher risk of developing hypertension than those with lower normal TSH level.
Abstract Previous studies have shown associations of polymorphisms in the tumor necrosis factor (TNF) receptor super family member 1A (TNFRSF1A) gene with several groups of inflammatory and autoimmune related diseases, but associations of TNFRSF1A polymorphisms with autoimmune thyroid diseases (AITD), mainly including two sub-types of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), in the Chinese Han population is unclear. A case-control study of 1812 subjects (965 AITD patients and 847 unrelated healthy controls) was conducted to assess AITD associations with five single nucleotide polymorphisms (SNPs), including rs4149576, rs4149577, rs4149570, rs1800693, and rs767455 in the TNFRSF1A gene locus. Genotyping was performed and evaluated using the platform of ligase detection reaction. No significant difference was observed in the allele and genotype frequencies between HT or GD patients and controls in any of the five SNPs in the TNFRSF1A gene (all p values >0.05). However, a moderate association of rs4149570 with HT was found after adjusting for age and gender [odds ratio (OR)=1.40, p=0.03]. No obvious difference was found in the haplotype distribution of any of the five SNPs in the TNFRSF1A gene between the AITD patients and controls. These data suggest that these five SNPs in the TNFRSF1A gene are not associated with AITD in the Chinese Han population, but rs4149570 shows a weak association with HT after adjusting for gender and age.
The IKZF3 gene encodes a zinc-finger protein that plays an important role in the proliferation and differentiation of B lymphocytes. Autoimmune thyroid diseases (AITDs), mainly include Graves' disease (GD) and Hashimoto's thyroiditis (HT), are probably caused by the aberrant proliferation of B cells. The objective of this study was to explore the association between IKZF3 polymorphisms and AITDs.We examined 915 AITD patients (604 GD and 311 HT) and 814 healthy controls. IKZF3 variants (rs2941522, rs907091, rs1453559, rs12150079 and rs2872507) were tested by PCR-ligase detection reaction.It was manifested that that the minor alleles of the five loci increased susceptibility to GD (p<0.05 for rs2941522, and p<0.01 for rs907091, rs1453559, rs12150079 and rs2872507) but in HT patients, these loci showed no significant difference compared with controls. Similarly, the genotype distributions of GD patients manifested obvious differences in all these loci compared with the control group, whereas no statistical differences were observed between HT patients and controls. Furthermore, bioinformatics tools were used to analyze rs1453559, rs12150079 and rs907091. These variants were believed to be the transcription regulator.It is the first time we reported the association between the IKZF3 polymorphisms and GD, indicating that IKZF3 gene tends to bean important risk factor for the development of GD.
The dynamic mechanical property of silicone rubbers with different phenyl units and phenyl contents were comprehensively investigated by means of experiments combined with molecular dynamics (MD) simulation. Experimentally, the results indicate that the phenyl units are randomly distributed in the polymer chains and the damping capacity is considerably improved with the augment of phenyl contents. Compared with methylphenyl units, diphenyl units endow the silicone rubber with enhanced mechanical stability, which leads to a wider glass transition region and effective damping temperature range. Furthermore, the MD simulation reveals the equilibrium structures and local dynamics by monitoring the changes of molecular interactions, bond rotation, conformational transition and molecular diffusion during the cooling process, which correlates the dynamic mechanical response to the molecular relaxation behavior. This work provides a deeper insight into the relationship among the composition, microstructure and damping property, which may promote theoretical predictions and scientific basis for the designs of silicone rubber with desired performances.
Pembrolizumab is a monoclonal antibody against programmed death-1. It can inhibit the binding of programmed death-1 with its ligands, then stimulate anti-tumor effect in the body. Pembrolizumab significantly prolonged the survival of patients with malignant melanoma in several clinical trials and was approved by the US FDA for the treatment of unresectable or metastatic melanoma. In this paper, the research progress of Pembrolizumab in treatment of malignant melanoma is reviewed.
Key words:
Antibodies, monoclonal; Melanoma; Immunotherapy
Programmed death-1 (PD-1) and its ligand (PD-L) are a pair of co-inhibitory molecules popularly studied recently. The signal transduced via PD-1 after binding its ligands acts on regulation of T-cell activity and maintenance of peripheral tolerance by suppressing T-cell proliferation. Therefore, PD-1 plays an important role in preventing onset and progression of autoimmune diseases. The role of PD-1/PD-L in immune regulation makes them new target molecules in the treatment of autoimmune diseases.
Key words:
Autoimmune diseases; Lupus erythematosus, systemic; Arthritis, rheumatoid; Diabetes mellitus, type 1; Programmed death-1; Programmed death-1 ligand
Previous studies propose that hypothyroidism might play a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), but findings from published studies on the relationship between hypothyroidism and NAFLD are still controversial. Our study aimed to make a comprehensive evaluation of the relationship between hypothyroidism and NAFLD through a meta-analysis.PubMed, China Dissertation Database, and EMBASE databases were searched to find observational studies assessing the relationship between hypothyroidism and NAFLD. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to evaluate the strength of the relationship between hypothyroidism and NAFLD through meta-analysis.Thirteen articles were ultimately included in our meta-analysis. Meta-analysis of the 13 studies found a high correlation between hypothyroidism and NAFLD (OR = 1.52, 95% CI 1.24-1.87, P < 0.001). Meta-analysis of 9 studies providing adjusted ORs found that hypothyroidism was independently correlated with NAFLD (OR = 1.72, 95% CI 1.32-2.23, P < 0.001). Subgroup analysis found that both overt hypothyroidism and subclinical hypothyroidism were significantly correlated with NAFLD, and the pooled ORs were 1.70 (95% CI 1.23-2.36, P = 0.002) and 1.40 (95% CI 1.10-1.77, P = 0.006), respectively. Besides, meta-analysis of studies providing adjusted ORs also found that both overt hypothyroidism and subclinical hypothyroidism were independently correlated with NAFLD, and the pooled ORs were 1.81 (95% CI 1.30-2.52, P < 0.001) and 1.63 (95% CI 1.19-2.24, P = 0.002), respectively.The meta-analysis provides strong epidemiological evidence for the relationship between hypothyroidism and NAFLD. Both individuals with subclinical and overt hypothyroidism are at higher risk for NAFLD than euthyroid subjects.
Part B: Applied Biomaterials is a highly interdisciplinary peerreviewed journal serving the needs of biomaterials professionals who design, develop, produce and apply biomaterials and medical devices.It has the common focus of biomaterials applied to the human body and covers all disciplines where medical devices are used.Papers are published on biomaterials related to medical device development and manufacture, degradation in the body, nano-and biomimetic-biomaterials interactions, mechanics of biomaterials, implant retrieval and analysis, tissue-biomaterial surface interactions, wound healing, infection, drug delivery, standards and regulation of devices, animal and pre-clinical studies of biomaterials and medical devices, and tissue-biopolymer-material combination products.
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