Mutations occur during cell division in all somatic lineages due to the unavoidable DNA replication errors. Because neural stem cells continue to undergo cell division throughout human life, somatic mutations in human brain can arise during development and accumulate with the aging process. Although somatic diversity is an evident feature of the brain, the extent of somatic mutations affecting the neuronal structure and function and their contribution to neurological disorders remain largely unexplored. Recently, we have provided the molecular genetic evidence that brain somatic mutations indeed lead to the structural and functional abnormalities of the brain observed in neurodevelopmental disorders, brain tumors, and neurodegenerative disorders. In this symposium, I will present our recent findings regarding brain somatic mutations as potential molecular lesions underlying various human brain disorders, thereby providing a new insight into the molecular pathogenesis and therapeutics for the related disorders.
Monitoring of Non-human Glycan Motif in Biotherapeutics for Immunogenicity Prediction
Abstract
Glycosylation of biotherapeutics plays a pivotal role in determining physicochemical properties as well as bioactivities. Especially, sialic acid affects pharmacokinetics and pharmacodynamics properties by prolongation of serum half-life of biotherapeutics, and modulating receptor binding affinity of biotherapeutics. However, biotherapeutics were frequently contaminated by NeuGc, non-human sialic acid, which specifically binds to anti-NeuGc antibody circulated in human blood and generates immune complex. As a result, NeuGc-sialylated biotherapeutics, produced in mammalian cell line except human cells, could show reduced efficacy, and generate immune responses. Therefore, NeuGc contents, considered as a critical quality attribute (CQA), must be precisely analyzed and controlled to ensure quality and to regulate potential immunogenicity in process development and manufacturing procedure of biotherapeutics. In this study, we developed highly sensitive analytical platform for monitoring of NeuGc expressed in biotherapeutics for prediction of immunogenicity using UHPLC/MRM MS.
University of Ulsan College of Medicine, ASAN Medical Center
Title
Defining the molecular mechanism of the UBA6-USE1 in lung cancer
Abstract
The UBA6-USE1 ubiquitin enzyme cascade is a poorly characterized arm of the ubiquitin-proteasome system. We found that USE1 proteins are frequently overexpressed in lung cancer patients (92.45%, n = 106). Stable overexpression of USE1 significantly increased cell proliferation, migration, and invasiveness in lung cancer cells and xenograft models, whereas their knockdown significantly reduced cell proliferation, migration, and invasion. USE1 has a conserved D-box domain and the level of the protein was regulated by the anaphase-promoting complex (APC/C) through its interaction with CDC20 and CDH1. Furthermore, five missense mutations in USE1 identified in patients prolong the half-life and stability of the protein. These data reveal an unexpected role for USE1 in lung cancer promotion, migration, and invasion.
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