Strategies that regulate LSD1 for novel therapeutics

Histone methylation plays crucial roles in regulating chromatin structure and gene transcrip-tion in epigenetic modifications.Lysine-specific demethylase 1(LSD1),the first identified histone de-methylase,is universally overexpressed in various diseases.LSD1 dysregulation is closely associated with cancer,viral infections,and neurodegenerative diseases,etc.,making it a promising therapeutic target.Several LSD1 inhibitors and two small-molecule degraders(UM171 and BEA-17)have entered the clinical stage.LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9(H3K4 or H3K9),resulting in either transcription repression or activation.While the roles of LSD1 in transcrip-tional regulation are well-established,studies have revealed that LSDl can also be dynamically regulated by other factors.For example,the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1.Moreover,some post-transcriptional modifica-tions and cellular metabolites can also regulate LSD1 expression or its demethylase activity.Therefore,in this review,we will systematically summarize how proteins involved in the transcriptional corepressor complex,various post-translational modifications,and metabolites act as regulatory factors for LSD1 ac-tivity.

Ischaemic stroke etiological classification system: the agreement analysis of CISS, SPARKLE and TOAST

Background and purpose The ideal stroke classification system needs to have validity,high reliability and applicability among different stroke research settings.The Chinese Ischemic Stroke Subclassification(CISS)and the Subtypes of Ischemic Stroke Classification System(SPARKLE)have emerged recently but have not been tested using agreement analysis.As a result,the objective of this study is to investigate the level of agreement among stroke subtype classifications using CISS,SPARKLE and Trial of Org 10172 in Acute Stroke Treatment(TOAST).We also analyse the inter-rater reliability of CISS.Methods The data include 623 inpatients who have had an ischaemic stroke,accrued from Beijing Tiantan Hospital between 1 October 2015 and 19 April 2016.According to the diagnostic standards of the three subtype classification systems,299 inpatients who satisfied the requirements of our study were independently classified with etiological subtypes,and we compared the three subclassifications.Results There was substantial overall agreement among the three classification systems:CISS versus SPARKLE(kappa value=0.684,p<0.001),CISS versus TOAST(kappa value=0.615,p<0.001)and SPARKLE versus TOAST(kappa value=0.675,p<0.001).The inter-rater reliability of CISS was excellent(kappa value=0.857,p<0.001).Furthermore,among the three subtype classification systems,the variance analysis results of the etiological subtypes were not uniform.Conclusion There were generally substantial agreements among three ischaemic stroke etiological classification systems.CISS is a valid and reliable classification system,with which different stroke research centres can apply and compare data.