Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy

The effect of anti-programmed cell death 1(anti-PD-1)immunotherapy is limited in patients with hepatocellular carcinoma(HCC).Yes-associated protein 1(YAP1)expression increased in liver tumor cells in early HCC,and Akkermansia muciniphila abundance decreased in the colon.The response to anti-PD-1 treatment is associated with A.muciniphila abundance in many tumors.However,the interaction between A.muciniphila abundance and YAP1 expression remains unclear in HCC.Here,anti-PD-1 treatment decreased A.muciniphila abundance in the colon,but increased YAP1 expression in the tumor cells by mice with liver tumors in situ.Mechanistically,hepatocyte-specific Yap1 knockout(Yap1^(LKO))maintained bile acid homeostasis in the liver,resulting in an increased abundance of A.muciniphila in the colon.Yap1 knockout enhanced anti-PD-1 efficacy.Therefore,YAP1 inhibition is a potential target for increasing A.muciniphila abundance to promote anti-PD-1 efficacy in liver tumors.Dihydroartemisinin(DHA),acting as YAP1 inhibitor,increased A.muciniphila abundance to sensitize anti-PD-1 therapy.A.muciniphila by gavage increased the number and activation of CD8^(+)T cells in liver tumor niches during DHA treatment or combination with anti-PD-1.Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

Clinical analysis of CHD2 gene mutations in pediatric patients with epilepsy

Importance:CHD2 is a member of the chromodomain helicase DNA-binding(CHD)family of proteins,which have important roles in the regulation of gene expression.Dysregulation of this protein may lead to various disorders.Objective:To delineate the genotypes and phenotypes of CHD2-related epilepsy.Methods:We analyzed the medical history,magnetic resonance imaging findings,and video-electroencephalogram recordings of 17 patients withCHD2 mutations in the Neurology Department of Beijing Children’s Hospital from June 2016 to June 2021.Results:Age at seizure onset ranged from 6 months to 10 years;the median age at onset was 4 years.Generalized tonic-clonic,myoclonic,eyelid myoclonic,atonic,atypical absence,myoclonic-atonic,and spasm seizures were observed.Ten of the 17 patients had multiple types of seizures.One patient exhibited photosensitivity epilepsy and one patient exhibited grid image-induced visual reflex epilepsy.Developmental disability was present in 14 patients,while autism features were present in five patients.Sixteen patients hadde novo mutations ofCHD2;one patient had an inherited variant.Eleven mutations were novel.One patient had two mutations;that patient exhibited development delay and refractory epilepsy.Seizures were controlled in eight patients,improved in seven patients,and resistant to treatment in two patients.Interpretation:Phenotype severity in patients withCHD2 variants ranged from drug-responsive seizures to severe epileptic encephalopathy.Most patients exhibited developmental disorders.