OBJECTIVE Intracellular aggre⁃gation ofα-synuclein(SNCA)is one of the core pathological features of neurodegenerative disor⁃ders including Parkinson disease,whilst the detailed mechanism for consequently neuron loss ...OBJECTIVE Intracellular aggre⁃gation ofα-synuclein(SNCA)is one of the core pathological features of neurodegenerative disor⁃ders including Parkinson disease,whilst the detailed mechanism for consequently neuron loss has not been fully illustrated.Since the altered phospholipid homeostasis has been suggested to play a role in synucleinopathy,this study aims to depict the fully-featured status of phospholip⁃ids and the targets reposingα-synuclein-related neurotoxicity.METHODS SNCAA53T transgenic mice were utilized as the model of Parkinson disease.Behavioral tests including pole test,rotarod test and gait analysis were conducted to assess the motor features of Parkinsonism.Tyro⁃sine hydroxylase were determined by immunohis⁃tochemistry.Glutathione,dopamine,3,4-dihy⁃droxyphenylacetic acid and homovanillic acid were determined by HPLC-ECD analysis.Assess⁃ment of lipid peroxidation included MDA assay and Liperfluo staining.Phospholipid-omics was analyzed based on LC-MS/MS.Investigation on mechanism was relied on Western blotting and qPCR assay.The injection of AAV into midbrain was achieved by ultra-micro injection pump to obtain the target genotype.RESULTS SNCAA53T transgenic mice displayed progres⁃sively deteriorated motor coordination functions and the mechanisms were related with lipid per⁃oxidation and ferroptosis,which might help to explain the parkinsonism.These hydroperoxides were observed on plasm membrane and were further characterized by LC-MS/MS-based phos⁃pholipid-omics analysis.α-synucleinA53T trans⁃genic mice displayed distinct patterns of phos⁃pholipid peroxidation in midbrain regions com⁃pared to wild type littermates.Among different subtypes of oxidized phospholipids,oxidative phosphatidylcholine(PC-ox)was more promi⁃nently elevated.Phospholipid peroxidation is believed as a biomarker of ferroptosis,which is largely a specialized death program caused by insufficiency of glutathione peroxidase-4(GPX4),the only known enzyme that can reduce lipid hydroperoxides within biological membranes.The deficiency of Gpx4 was demonstrated to be responsible forα-synuclein-induced lipid peroxi⁃dation,and the cell lines and mouse models underwent genetic Gpx4 downregulation showed exacerbated dopaminergic neuron loss and par⁃kinsonism.On the other hand,the potentiation of Gpx4 expression remarkably inhibited dopami⁃nergic ferroptotic death and behavioral deficits in a mouse model with synucleinopathy.CONCLU⁃SION A cellular pathway that Gpx4 deficit-medi⁃ated phospholipid peroxidation and behavioral consequence participated in synucleinopathy,suggesting a potential strategy targeting Gpx4 to alleviate PD symptoms.展开更多
目的:对穿刺活检单针阳性前列腺癌术后病理升级的危险因素进行分析,并尝试构建预测穿刺单针阳性前列腺癌患者术后病理升级的数学模型。方法:回顾分析2015年1月至2020年8月期间于北京大学第一医院诊断为前列腺癌且接受根治性前列腺切除...目的:对穿刺活检单针阳性前列腺癌术后病理升级的危险因素进行分析,并尝试构建预测穿刺单针阳性前列腺癌患者术后病理升级的数学模型。方法:回顾分析2015年1月至2020年8月期间于北京大学第一医院诊断为前列腺癌且接受根治性前列腺切除术的患者1 349例,选取其中穿刺活检单针阳性患者的临床资料,将其分为术后病理较穿刺病理升级组及未升级组,比较两组的年龄、体重指数、临床分期、前列腺影像报告和数据系统(prostate imaging reporting and data system, PI-RADS)评分、磁共振成像(magnetic resonance imaging, MRI)报告的前列腺体积、前列腺穿刺活检的Gleason评分、穿刺前及术前血清前列腺特异性抗原(prostate specific antigen, PSA)、手术方式、术后病理分期的差异,将单因素分析中P<0.1的术前变量纳入多因素Logistic回归并绘制列线图,通过受试者工作特征曲线对模型进行评价。结果:共有71例患者符合纳入排除标准,其中术后病理升级组34例,未升级组37例,两组患者的年龄(P=0.585)、体重指数(P=0.165)、手术方式(P=0.08)、MRI前列腺体积(P=0.067)、临床分期(P=0.678)、PI-RADS评分(P=0.203)、穿刺前PSA(P=0.359)、术前PSA(P=0.739)、PSA密度差(P=0.063)、穿刺Gleason评分(P=0.068)差异均无统计学意义,两组患者穿刺阳性针中肿瘤组织占比(P=0.007)、术后病理分期(P<0.001)及术后Gleason评分(P<0.001)差异有统计学意义。将单因素分析中P<0.1的术前变量,即MRI前列腺体积、PSA密度差、穿刺阳性针中的肿瘤组织占比、穿刺Gleason评分纳入多因素Logistic回归分析,只有MRI前列腺体积组间差异有统计学意义。进一步根据多因素Logistic回归结果绘制列线图,受试者工作特征曲线的曲线下面积为0.773。结论:对于穿刺病理单针阳性的前列腺癌患者,若前列腺体积较小或穿刺阳性针中肿瘤组织占比较少,需警惕术后病理较穿刺病理升级的可能;对于可能出现病理升级的患者,需谨慎考虑术前的危险分层。本模型可初步用于预测穿刺活检单针阳性前列腺癌患者术后病理升级的可能性。展开更多
基金National Key Research and Development Program of China(2017YFC1700404)Natural Science Foundation of China(81873209)+8 种基金Natural Science Foundation of China(U1801284)Natural Science Foundation of China(81903821)Natural Science Foundation of China(81973718)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036)GDUPS(2019),Fun⁃damental Research Funds for the Central Univer⁃sities(21620448)Natural Science Foundation of Guangdong Province(2019A 1515010909)Nat⁃ural Science Foundation of Guangdong Prov⁃ince(2021A1515011297)Science and Tech⁃nology Program of Guangzhou(201903010062)Science and Technology Program of Guang⁃zhou(907158833068),and the Innovation Team Project of Guangdong Provincial Department of Education(2020KCXT D003)。
文摘OBJECTIVE Intracellular aggre⁃gation ofα-synuclein(SNCA)is one of the core pathological features of neurodegenerative disor⁃ders including Parkinson disease,whilst the detailed mechanism for consequently neuron loss has not been fully illustrated.Since the altered phospholipid homeostasis has been suggested to play a role in synucleinopathy,this study aims to depict the fully-featured status of phospholip⁃ids and the targets reposingα-synuclein-related neurotoxicity.METHODS SNCAA53T transgenic mice were utilized as the model of Parkinson disease.Behavioral tests including pole test,rotarod test and gait analysis were conducted to assess the motor features of Parkinsonism.Tyro⁃sine hydroxylase were determined by immunohis⁃tochemistry.Glutathione,dopamine,3,4-dihy⁃droxyphenylacetic acid and homovanillic acid were determined by HPLC-ECD analysis.Assess⁃ment of lipid peroxidation included MDA assay and Liperfluo staining.Phospholipid-omics was analyzed based on LC-MS/MS.Investigation on mechanism was relied on Western blotting and qPCR assay.The injection of AAV into midbrain was achieved by ultra-micro injection pump to obtain the target genotype.RESULTS SNCAA53T transgenic mice displayed progres⁃sively deteriorated motor coordination functions and the mechanisms were related with lipid per⁃oxidation and ferroptosis,which might help to explain the parkinsonism.These hydroperoxides were observed on plasm membrane and were further characterized by LC-MS/MS-based phos⁃pholipid-omics analysis.α-synucleinA53T trans⁃genic mice displayed distinct patterns of phos⁃pholipid peroxidation in midbrain regions com⁃pared to wild type littermates.Among different subtypes of oxidized phospholipids,oxidative phosphatidylcholine(PC-ox)was more promi⁃nently elevated.Phospholipid peroxidation is believed as a biomarker of ferroptosis,which is largely a specialized death program caused by insufficiency of glutathione peroxidase-4(GPX4),the only known enzyme that can reduce lipid hydroperoxides within biological membranes.The deficiency of Gpx4 was demonstrated to be responsible forα-synuclein-induced lipid peroxi⁃dation,and the cell lines and mouse models underwent genetic Gpx4 downregulation showed exacerbated dopaminergic neuron loss and par⁃kinsonism.On the other hand,the potentiation of Gpx4 expression remarkably inhibited dopami⁃nergic ferroptotic death and behavioral deficits in a mouse model with synucleinopathy.CONCLU⁃SION A cellular pathway that Gpx4 deficit-medi⁃ated phospholipid peroxidation and behavioral consequence participated in synucleinopathy,suggesting a potential strategy targeting Gpx4 to alleviate PD symptoms.
文摘目的:对穿刺活检单针阳性前列腺癌术后病理升级的危险因素进行分析,并尝试构建预测穿刺单针阳性前列腺癌患者术后病理升级的数学模型。方法:回顾分析2015年1月至2020年8月期间于北京大学第一医院诊断为前列腺癌且接受根治性前列腺切除术的患者1 349例,选取其中穿刺活检单针阳性患者的临床资料,将其分为术后病理较穿刺病理升级组及未升级组,比较两组的年龄、体重指数、临床分期、前列腺影像报告和数据系统(prostate imaging reporting and data system, PI-RADS)评分、磁共振成像(magnetic resonance imaging, MRI)报告的前列腺体积、前列腺穿刺活检的Gleason评分、穿刺前及术前血清前列腺特异性抗原(prostate specific antigen, PSA)、手术方式、术后病理分期的差异,将单因素分析中P<0.1的术前变量纳入多因素Logistic回归并绘制列线图,通过受试者工作特征曲线对模型进行评价。结果:共有71例患者符合纳入排除标准,其中术后病理升级组34例,未升级组37例,两组患者的年龄(P=0.585)、体重指数(P=0.165)、手术方式(P=0.08)、MRI前列腺体积(P=0.067)、临床分期(P=0.678)、PI-RADS评分(P=0.203)、穿刺前PSA(P=0.359)、术前PSA(P=0.739)、PSA密度差(P=0.063)、穿刺Gleason评分(P=0.068)差异均无统计学意义,两组患者穿刺阳性针中肿瘤组织占比(P=0.007)、术后病理分期(P<0.001)及术后Gleason评分(P<0.001)差异有统计学意义。将单因素分析中P<0.1的术前变量,即MRI前列腺体积、PSA密度差、穿刺阳性针中的肿瘤组织占比、穿刺Gleason评分纳入多因素Logistic回归分析,只有MRI前列腺体积组间差异有统计学意义。进一步根据多因素Logistic回归结果绘制列线图,受试者工作特征曲线的曲线下面积为0.773。结论:对于穿刺病理单针阳性的前列腺癌患者,若前列腺体积较小或穿刺阳性针中肿瘤组织占比较少,需警惕术后病理较穿刺病理升级的可能;对于可能出现病理升级的患者,需谨慎考虑术前的危险分层。本模型可初步用于预测穿刺活检单针阳性前列腺癌患者术后病理升级的可能性。
