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Dedifferentiation of cell identity to a progenitor-like or stem cell-like state with increased cellular plasticity is frequently observed in cancer formation. During this process, a subpopulation of cells in tumours acquires a stem cell-like state partially resembling to naturally occurring pluripotent stem cells that are temporarily present during early embryogenesis. Such characteristics allow these cancer stem cells (CSCs) to give rise to the whole tumour with its entire cellular heterogeneity and thereby support metastases formation while being resistant to current cancer therapeutics. Cancer development and progression are demarcated by transcriptional dysregulation. In this article, we explore the epigenetic mechanisms shaping gene expression during tumorigenesis and cancer stem cell formation, with an emphasis on 3D chromatin architecture. Comparing the pluripotent stem cell state and epigenetic reprogramming to dedifferentiation in cellular transformation provides intriguing insight to chromatin dynamics. We suggest that the 3D chromatin architecture could be used as a target for re-sensitizing cancer stem cells to therapeutics.
ABSTRACT
Objective@#To analyze molecular feature of rabies virus (RABV) epidemic strains in Sichuan province during 2011 to 2017, and explore differences at nucleotide, amino acid and protein modification between these street strains and vaccine strains.@*Methods@#Nucleoprotein(N) and glycoprotein(G) genes were amplified by RT-PCR using specific primers for 23 antigen-positive canine brain specimens collected from 2011 to 2017. The evolutionary relationship and immune antigenicity of N and G genes was analyzed. Bioinformatics software was used to analyze and organize data.@*Results@#We obtained the N and G genes sequences of 23 RABV strains by sequencing. Genetic evolution relationship analysis showed that all the 23 RABV strains belonged to rabies virus species and could be divided into three branches, which had apparent geographically specific characteristics but some Sichuan strains co-circulated with the epidemic strains in the eastern and northern regions of China.The N genes of Sichuan strains had nucleotide and amino acid homology of 97.4% to 100% and 99.6%-100%. The nucleotide and amino acid homology between Sichuan strains and reference strains were 72.1%-99.8% and 81.6%-100%, respectively. There were some differences in antigenic sites, cell epitopes and signal peptide sequences between vaccine strain and Sichuan strains but no significant change was found in antigenicity, organizational preference and virulence.@*Conclusions@#The 23 strains of RABV of Sichuan belonged to rabies virus species and had no obvious differences. There were few differences between Sichuan strain and vaccine strain in amino acid sequences of G, but the virulence did not change.
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Objective To investigate the inhibitory effects of IBI302 on experimental choroidal neovascularization (CNV).Methods Affinity of IBI302 to vascular endothelial growth factor (VEGF) family cytokines (including VEGF-A165,VEGF-A121 and placental growth factor PlGF) and complements (C3b,C4b) was determined by enzyme-linked immunosorbent assay (ELISA).The antagonist effect of IBI302 on VEGF was measured by proliferation,migration and tube formation tests of human umbilical vein endothelial cells (HUVEC).The anti-complement activity of IBI302 was measured by hemolysis test mediated by complement classical pathway and alternative pathway.Rhesus laser-induced CNV model was divided into 5 groups including model control group,bevacizumab group,IBI302 0.25 mg group,IBI302 0.50 mg group and IBI302 1.25 mg group.Fluorescein angiography and optical coherence tomography were performed on these monkeys at 14 and 28 days after drug delivery to observe the fluorescein leakage area and retinal thickness.The aqueous VEGF concentration was measured at 29 days after drug delivery.Results IBI302 showed good affinity to VEGF-A165,VEGF-A121 and PlGF,as well as C3b and C4b.IBI302 significantly inhibited the proliferation,migration and tube formation of HUVEC induced by VEGF-A165.IBI302 inhibited the hemolysis induced by complements obviously.At 14 and 28 days after drug delivery,the area of fluorescein leakage and retinal thickness in IBI302 0.25 mg group,IBI302 0.50 mg group,IBI302 1.25 mg group were reduced.The differences of the area of fluorescein leakage and retinal thickness in three IBI302 groups were not significant (P＞0.05).At 29 days after drug delivery,the VEGF concentration in the aqueous of rhesus monkey in bevacizumab group [(38.644 ± 6.521) pg/ml] was decreased than that in model control group [(94.203± 17.360) pg/ml],the difference was significant (P＜ 0.05).The VEGF concentration in the aqueous of rhesus monkey in three IBI302 groups were less than 31.300 pg/ml.Conclusion IBI302 inhibited experimental CNV through blocking the activity of VEGF and complement.