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It has been reported that the expression of CD44 variant 9 could be utilized as a predictive marker for the recurrence in early gastric cancer (EGC) after endoscopic submucosal dissection (ESD). And circFNDC3B was proved to increase the migration and invasion of gastric cancer (GC) cells. In this study, we recruited 96 EGC patients after ESD treatment and grouped them into High circFNDC3B expression group (High expression group) and Low circFNDC3B expression group (Low expression group). Accordingly, we found that the recurrence-free rate in the High expression group was lower than that in the Low expression group. In the High expression group, the relative expression of miR-942 and miR-510 was both suppressed while the relative expression of CDH1 mRNA and CD44 mRNA/protein was increased compared with those in the Low expression group. CircFNDC3B was found to target miR-942 and miR-510 and suppress their expressions respectively. Moreover, miR-942 was found to target CD44 mRNA while miR-510 was found to target CDH1 mRNA. The overexpression of circFNDC3B led to the down-regulation of miR-942 and miR-510, which accordingly resulted in the up-regulation of CD44 and CDH1 in MKN28 cells. Moreover, we found H. pylori infection could promote the expression of circFNDC3B, which also resulted in up-regulated CD44 and CDH1 mRNA level in rTip-α cultivated MKN28 cells. In summary, our study demonstrated that a higher level of circFNDC3B could lead to the increased expression of CD44 and CDH1 via modulating the signaling pathways of miR-942/CD44 and miR-510/CDH1 in EGC patients. And the up-regulation of CD44 and CDH1 would accordingly result in a higher recurrence rate of EGC patients treated by ESD. [ABSTRACT FROM AUTHOR]

Aberrant epigenetic modification, including N6-methylation of adenosine (m6A), has been frequently reported in embryos derived from parthenogenetic activation (PA). However, the role of Igf2bp1 expression pattern in m6A modification and the mechanism through which Igf2bp1 function is regulated in PA embryos remains elusive. Therefore, in this study, using si-Igf2bp1 and betaine (N,N,N-trimethylglycine, a major methyl donor), we investigated the effect of Igf2bp1 expression in m6A modification on the development of PA embryos. The results indicated that the down-regulation of Igf2bp1 reduced the cleavage and blastula rates of PA embryos. Moreover, m6A expression level was markedly down-regulated following microinjection with si-Igf2bp1. However, the treatment with betaine could significantly restore the m6A level. Further bioinformatics analysis revealed Igf2bp1 as the putative target of microRNA 670 (miR-670). Thus, to confirm this finding, mimics and inhibitor of miR-670 were microinjected into PA embryos. The results demonstrated that miR-670 inhibitor augmented the expression of Igf2bp1 and rescued cleavage and blastula rates. In addition, the miR-670 inhibitor promoted the m6A expression level. TUNEL assay revealed a loss of expression of Igf2bp1 induced cell apoptosis in PA embryos. Taken together, these results demonstrated that miR-670-3p functions as the regulator of Igf2bp1 expression and plays a crucial role in PA development through m6A modification. [ABSTRACT FROM AUTHOR]

Programmed cell death 1 (PD-1) monoclonal antibodies have been approved by regulatory agencies for the treatment of various types of cancer, and the mechanism involves the restoration of T cell functions. We report herein the X-ray crystal structure of a fully human monoclonal antibody mAb059c fragment antigen-binding (Fab) in complex with the PD-1 extracellular domain (ECD) at a resolution of 1.70 Å. Structural analysis indicates 1) an epitope, comprising fragments from the C'D, BC and FG loops of PD-1, contributes to mAb059c interaction, 2) an unique conformation of the C'D loop and a different orientation of R86 enabling the capture of PD-1 by the antibody complementarity determining region (CDR) and the formation of one salt-bridge contact – ASP101(HCDR3):ARG86(PD-1), and 3) the contact of FG with light chain (LC) CDR3 is maintained by a second salt-bridge and two backbone hydrogen bonds. Interface analysis reveals that N-glycosylation sites 49, 74 and 116 on PD-1 do not contact mAb059c; while N58 in the BC loop is recognized by mAb059c heavy chain CDR1 and CDR2. Mutation of N58 attenuated mAb059c binding to PD-1. These findings and the novel anti-PD-1 antibody will facilitate better understanding of the mechanisms of the molecular recognition of PD-1 receptor by anti-PD-1 mAb and, thereby, enable the development of new therapeutics with an expanded spectrum of efficacy for unmet medical needs. [ABSTRACT FROM AUTHOR]