BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear geno...BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.展开更多
Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. H...Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance(ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR(ARfl)or dominantly active androgen receptor splice variant 7(ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.展开更多
Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pe...Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD.Methods:Choosing cases with CHD7 variants from DSD patients in Beijing Children’s Hospital to assess for the study.Prediction software tools were used to predict variant pathogenicity in these subjects.results:Among the 113 DSD patients,22 cases had CHD7 variants.Twenty-four different CHD7 variants were identified in the 22 DSD patients.Prediction software combined with ClinVar database information and their clinical manifestations revealed that,of the 18 patients with 46,XY DSD,two had CHARGE syndrome and two had Kallmann syndrome.Seven of the variants were highly categorized as“likely to be pathogenic”and seven as“suspected to be pathogenic”.Of the four patients with 46,XX DSD,three had ovotesticular DSD(c.305A>G,c.2788G>A,and c.3098G>A)and one had testicular DSD(c.2831G>A).Interpretation:A high frequency of CHD7 variants was found in the DSD patients,especially those with 46,XY DSD.Thus,the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46,XY DSD patients,but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis.This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients.Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46,XX DSD,and the accumulation of these data is essential and necessary for DSD research.展开更多
文摘BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.
基金supported by the National Natural Science Foundation of China (Nos. 81903656 and 81673468)the National Key New Drug Innovation Program, the Ministry of Science and Technology of China (No. 2018ZX09201017-006)+3 种基金Natural Science Foundation of Jiangsu Province (No. BK20180560, China)China Postdoctoral Science Foundation (No. 2018M632430)“Double First-Class” University project (Nos. CPU2018GF10 and CPU2018GY46, China)the Scientific Startup Foundation for High level Scientists of China Pharmaceutical University (No. 3154070026, China)
文摘Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance(ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR(ARfl)or dominantly active androgen receptor splice variant 7(ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.
文摘Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD.Methods:Choosing cases with CHD7 variants from DSD patients in Beijing Children’s Hospital to assess for the study.Prediction software tools were used to predict variant pathogenicity in these subjects.results:Among the 113 DSD patients,22 cases had CHD7 variants.Twenty-four different CHD7 variants were identified in the 22 DSD patients.Prediction software combined with ClinVar database information and their clinical manifestations revealed that,of the 18 patients with 46,XY DSD,two had CHARGE syndrome and two had Kallmann syndrome.Seven of the variants were highly categorized as“likely to be pathogenic”and seven as“suspected to be pathogenic”.Of the four patients with 46,XX DSD,three had ovotesticular DSD(c.305A>G,c.2788G>A,and c.3098G>A)and one had testicular DSD(c.2831G>A).Interpretation:A high frequency of CHD7 variants was found in the DSD patients,especially those with 46,XY DSD.Thus,the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46,XY DSD patients,but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis.This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients.Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46,XX DSD,and the accumulation of these data is essential and necessary for DSD research.
