Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation a...Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.展开更多
目的观察咳喘镇定汤在小儿咳嗽变异性哮喘治疗中的作用及对患儿嗜酸性粒细胞计数(eosinophil count,EOS)、白介素-23(interleukin-23,IL-23)/辅助性T细胞17(helper T cells17,Th17)轴的影响。方法选取2020年8月—2023年2月收治的小儿咳...目的观察咳喘镇定汤在小儿咳嗽变异性哮喘治疗中的作用及对患儿嗜酸性粒细胞计数(eosinophil count,EOS)、白介素-23(interleukin-23,IL-23)/辅助性T细胞17(helper T cells17,Th17)轴的影响。方法选取2020年8月—2023年2月收治的小儿咳嗽变异性哮喘患儿104例,将患儿采用简单随机法分为两组。常规组给予止咳化痰、抗炎、平喘等常规治疗,咳喘镇定汤组在常规组基础上采用咳喘镇定汤辅助治疗。检测组间及组内T淋巴亚群、EOS、巨噬细胞炎症蛋白-1α(macrophage inflammatory protein-1α,MIP-1α)、Clara细胞分泌蛋白16(clara cell secreted protein 16,CC-16)、嗜酸细胞活化趋化因子(Eotaxin)、IL-23/Th17轴、小气道功能水平。评估组间及组内咳嗽症状评分、中医证候评分差异。统计组间疗效和不良反应。结果治疗前T淋巴亚群、CC-16、Eotaxin等差异无统计学意义(P>0.05)。两组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin降低,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)升高,咳喘镇定汤组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin低于常规组,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)高于常规组(P<0.05)。治疗前比较IL-23/Th17轴差异无统计学意义(P>0.05)。两组治疗后IL-23、Th17、白介素-17(interleukin-17,IL-17)降低,咳喘镇定汤组治疗后IL-23/Th17轴低于常规组(P<0.05)。治疗前相关评分无差异(P>0.05)。两组治疗后咳嗽症状评分、中医证候评分降低,咳喘镇定汤组治疗后咳嗽症状评分、中医症候评分低于常规组(P<0.05)。治疗前小气道功能无差异(P>0.05)。两组治疗后小气道功能升高,咳喘镇定汤组治疗后小气道功能高于常规组(P<0.05)。咳喘镇定汤组治愈13例,显效和有效共35例,总有效率92.31%高于常规组,差异有统计学意义(P<0.05)。结论咳喘镇定汤可通过调控小儿咳嗽变异性哮喘患儿IL-23/Th17轴,改善T淋巴亚群和小气道功能,减轻咳嗽症状,提高疗效。展开更多
Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutati...Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.展开更多
基金the National Natural Science Foundation of China,GrantNos.82100321 and 82370353.
文摘Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.
文摘目的观察咳喘镇定汤在小儿咳嗽变异性哮喘治疗中的作用及对患儿嗜酸性粒细胞计数(eosinophil count,EOS)、白介素-23(interleukin-23,IL-23)/辅助性T细胞17(helper T cells17,Th17)轴的影响。方法选取2020年8月—2023年2月收治的小儿咳嗽变异性哮喘患儿104例,将患儿采用简单随机法分为两组。常规组给予止咳化痰、抗炎、平喘等常规治疗,咳喘镇定汤组在常规组基础上采用咳喘镇定汤辅助治疗。检测组间及组内T淋巴亚群、EOS、巨噬细胞炎症蛋白-1α(macrophage inflammatory protein-1α,MIP-1α)、Clara细胞分泌蛋白16(clara cell secreted protein 16,CC-16)、嗜酸细胞活化趋化因子(Eotaxin)、IL-23/Th17轴、小气道功能水平。评估组间及组内咳嗽症状评分、中医证候评分差异。统计组间疗效和不良反应。结果治疗前T淋巴亚群、CC-16、Eotaxin等差异无统计学意义(P>0.05)。两组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin降低,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)升高,咳喘镇定汤组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin低于常规组,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)高于常规组(P<0.05)。治疗前比较IL-23/Th17轴差异无统计学意义(P>0.05)。两组治疗后IL-23、Th17、白介素-17(interleukin-17,IL-17)降低,咳喘镇定汤组治疗后IL-23/Th17轴低于常规组(P<0.05)。治疗前相关评分无差异(P>0.05)。两组治疗后咳嗽症状评分、中医证候评分降低,咳喘镇定汤组治疗后咳嗽症状评分、中医症候评分低于常规组(P<0.05)。治疗前小气道功能无差异(P>0.05)。两组治疗后小气道功能升高,咳喘镇定汤组治疗后小气道功能高于常规组(P<0.05)。咳喘镇定汤组治愈13例,显效和有效共35例,总有效率92.31%高于常规组,差异有统计学意义(P<0.05)。结论咳喘镇定汤可通过调控小儿咳嗽变异性哮喘患儿IL-23/Th17轴,改善T淋巴亚群和小气道功能,减轻咳嗽症状,提高疗效。
基金supported by funds from Changping Laboratory,the National Natural Science Foundation of China(NSFC 31930016)Beijing Advanced Innovation Center for Genomics at Peking University,and the Peking-Tsinghua Center for Life Sciences(to W.W.)+2 种基金Additional support was provided by the China Postdoctoral Science Foundation(2020M670031,to Y.L2020M670053,to Y-S.L.)the Taishan Scholarship(tsqn202312362,to Y-S.L.).
文摘Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.
