BACKGROUND The NaV1.1 sodium channel alpha subunit,encoded by SCN1A,is crucial for initiating and propagating action potentials in neurons.SCN1A gene has long been an established target in the etiology and therapy of ...BACKGROUND The NaV1.1 sodium channel alpha subunit,encoded by SCN1A,is crucial for initiating and propagating action potentials in neurons.SCN1A gene has long been an established target in the etiology and therapy of epilepsy.However,very few studies have investigated the relevance of genetic variations in epilepsy and anti-epileptic drug resistance.AIM To investigate associations between polymorphisms,rs121917953 T/A and rs121918623 C/T,and drug resistance in epilepsy patients in the north Indian population.METHODS A total of 100 age-and sex-matched epilepsy patients(50 drug responsive and 50 drug resistant subjects)were recruited and SCN1A rs121918623 C/T*and rs121917953 T/A*polymorphisms were analyzed by the allele specific-PCR technique.χ^(2)and Fisher’s exact test were used to estimate differences between the distribution of SCN1A rs121918623 and rs121917953 gene polymorphisms among various groups.The association between distinct rs121917953 genotypes and drug resistance was analyzed using logistic regression analysis.RESULTS For the SCN1A rs121917953 T/A*(D188V)polymorphism,a significantly higher proportion of individuals with AT genotype were observed in the drug-resistant group as compared to the drug-responsive group.Additionally,a higher risk association was exhibited by AT genotype for drug resistance with an odds ratio of 3.51 and P value=0.017.For the SCN1A rs121918623 C/T*(T875M)polymorphism,no significant difference in genotype distribution was observed between the drug-resistant and drug-sensitive groups.CONCLUSION Our findings indicate that the SCN1A polymorphism D188V is associated with a higher risk of drug resistance for the AT variant as compared to the homozygous TT wild-type.Further research is needed at the functional level and in larger cohorts to determine the potential of these genes as a therapeutic target in epilepsy subjects.展开更多
目的:通过生物信息学的方法分析电压门控钠通道α亚基7 (Sodium Voltage-Gated Channel Alpha Subunit 7, SCN7A)基因在肺腺癌(lung adenocarcinoma, LUAD)和邻近非癌组织中的差异表达,探讨其与肺腺癌患者临床病理特征和预后的相关性,...目的:通过生物信息学的方法分析电压门控钠通道α亚基7 (Sodium Voltage-Gated Channel Alpha Subunit 7, SCN7A)基因在肺腺癌(lung adenocarcinoma, LUAD)和邻近非癌组织中的差异表达,探讨其与肺腺癌患者临床病理特征和预后的相关性,分析其可能调控的信号通路和在肿瘤免疫微环境中的作用,并通过细胞实验验证SCN7A在肺腺癌细胞中的生物学功能。方法:从癌症基因组图谱(The Cancer Genome Atlas, TCGA)数据库和基因型组织表达(Genotype-Tissue Expression, GTEx)数据库下载并整理33种肿瘤患者的基因表达数据进行SCN7A泛癌分析。利用TCGA数据库探讨SCN7A基因在肺腺癌及正常肺组织中的表达差异情况,并使用临床样本qRT-PCR对结果进行验证。ROC曲线评估SCN7A的诊断价值。从人类蛋白质图谱(The Human Protein Atlas, HPA)数据库下载LUAD患者及健康人群免疫组织化学数据。Cox回归分析寻找LUAD独立预后因素。临床相关性分析揭示SCN7A与LUAD患者临床病理特征的相关性。采用Kaplan-Meier Plotter数据库进行生存分析。通过功能注释工具分析SCN7A及其互作基因的功能。通过肿瘤免疫系统相互作用数据库(Tumor Immune System Interaction Database, TISIDB)分析SCN7A与肺癌肿瘤免疫浸润之间的关系。体外培养人正常肺上皮细胞BEAS-2B、肺腺癌细胞A549、H1395、H1975,qRT-PCR检测以上4株细胞中SCN7A的表达。构建SNC7A过表达质粒,转染至A549细胞中。采用cell counting kit8 (CCK8)、划痕试验、Transwell方法检测SCN7A基因过表达对肺腺癌A549细胞增殖、迁移及侵袭的影响。结果:SCN7A在肺腺癌中的表达显著低于正常肺组织(P Objective: This study aimed to analyze the expression differences of Sodium Voltage-Gated Channel Alpha Subunit 7 (SCN7A) in lung adenocarcinoma (LUAD) and adjacent non-tumor tissues, investigating its correlation with the clinical pathological characteristics and outcomes of LUAD patients. It also analyzes the potential signaling pathways regulated by SCN7A and its role in the tumor immune microenvironment. The biological function of SCN7A in lung adenocarcinoma cells was investigated by cell experiments. Methods: Gene expression profiles of 33 tumor types were downloaded from the Human Protein Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) databases for pan-cancer analysis of SCN7A. The expression difference of SCN7A gene in lung adenocarcinoma and adjacent normal tissues was investigated by using TCGA database, and the results were verified by qRT-PCR of clinical samples. ROC curve was employed to evaluate the diagnostic value of SCN7A. The immunohistochemical data of LUAD patients and healthy individuals were obtained from the Human Protein Atlas (HPA) database. Cox regression analysis was conducted to identify the independent prognostic factors. Clinical correlation analysis revealed the correlation between SCN7A and clinicopathological features of LUAD patients. Kaplan-Meier Plotter database was used for survival analysis. The function of SCN7A and its interacting genes was analyzed by functional annotation tools. The relationship between SCN7A and tumor immune infiltration in lung adenocarcinoma was analyzed through the Tumor Immune System Interaction Database (TISIDB). Human normal lung epithelial cells BEAS-2B, lung adenocarcinoma cells A549, H1395, H1975 were cultured in vitro. The expression of SCN7A in the above 4 cell lines was detected by qRT-PCR. SCN7A overexpression plasmid was constructed and transfected into A549 cells. The effects of SCN7A overexpression on the proliferation, migration and invasion of A549 cells were detected by Cell counting kit 8 (CCK8), scratch test and Transwell methods. Results: The expression of SCN7A in lung adenocarcinoma was significantly lower than in adjacent normal lung tissues (P < 0.001), and was negatively correlated with T stage, pathological grade, and overall survival (OS) (P < 0.05). Cox regression analysis revealed that low SCN7A expression was an independent risk factor for the prognosis of LUAD (P < 0.05). Patients with low SCN7A expression had a significantly reduced overall survival (OS) time and first progression (FP) time (P < 0.001). Function enrichment analysis suggested that SCN7A mainly participates in E2f targets, G2m checkpoint, etc. related pathways. Immune infiltration analysis showed that SCN7A expression correlated with mast cell, dendritic cell, macrophage, and follicular helper T cell infiltration in LUAD. The expression of SCN7A in A549, H1395 and H1975 cells was significantly lower than in BEAS-2B cells. After overexpression of SCN7A, proliferation, migration and invasion of A549 cells were significantly decreased (P < 0.01). Conclusion: The low expression level of the SCN7A gene is closely associated with poor prognosis and immune cell infiltration in lung adenocarcinoma patients, suggesting its potential to be established as a novel biomarker for the diagnosis and treatment of lung adenocarcinoma.展开更多
Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes.However,therapeutic decision-making is relatively complex for epilepsies associated with channelopathy.Therefore,in the pres...Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes.However,therapeutic decision-making is relatively complex for epilepsies associated with channelopathy.Therefore,in the present study,we used a patient-derived organoid model with a novel SCN2A mutation(p.E512K)to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds.The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation.Immunofluorescence staining of patient-derived cortical organoids(COs)displayed normal neurodevelopment.Multielectrode array(MEA)recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts.Moreover,the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine.Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.展开更多
目的:分析SCN1A、SCN2A基因多态性对丙戊酸钠治疗癫痫患儿的疗效影响。方法:采用PCR和Sanger测序法检测128例丙戊酸钠规范治疗的癫痫患儿(有效组76例、无效组52例)外周血SCN1A(rs10188577、rs2298771、rs3812718、rs1813502)、SCN2A(rs2...目的:分析SCN1A、SCN2A基因多态性对丙戊酸钠治疗癫痫患儿的疗效影响。方法:采用PCR和Sanger测序法检测128例丙戊酸钠规范治疗的癫痫患儿(有效组76例、无效组52例)外周血SCN1A(rs10188577、rs2298771、rs3812718、rs1813502)、SCN2A(rs2304016、rs17183814)多态性。采用非条件Logistic回归分析基因型、等位基因频率与丙戊酸钠疗效的关系,分析不同基因型患者丙戊酸钠血药浓度的差异。结果:SCN1A基因rs3812718位点多态性与丙戊酸钠治疗效果有关。携带GA和AA基因型的患者采用丙戊酸钠治疗有效(GG vs GA:OR=1.186,95%CI 0.965~2.304,P=0.015;GG vs AA:OR=1.252,95%CI 1.007~3.254,P=0.002)。有效组SCN1A基因rs3812718位点A等位基因频率明显高于无效组(OR=1.452,95%CI 1.052~2.695,P=0.010)。其余基因位点组间比较差异均无统计学意义(P>0.05)。结论:SCN1A基因rs3812718位点多态性可能与丙戊酸钠抗癫痫效应有关。展开更多
据Mich JK 2025年3月19日[Sci Transl Med,2025,17(790):eadn5603-eadn5603.]报道,美国艾伦研究所和西雅图儿童研究所的研究人员在Dravet综合征小鼠模型中合作开发了一种新的基因替代疗法。这种疗法缓解了症状,并导致了长期康复,没有毒...据Mich JK 2025年3月19日[Sci Transl Med,2025,17(790):eadn5603-eadn5603.]报道,美国艾伦研究所和西雅图儿童研究所的研究人员在Dravet综合征小鼠模型中合作开发了一种新的基因替代疗法。这种疗法缓解了症状,并导致了长期康复,没有毒性、副作用和死亡。对于治疗Dravet综合征是一项突破性的进展。展开更多
采用超声悬浮无容器处理技术,并结合高速摄影实时分析方法,研究了丁二腈-樟脑(SCN-DC)共晶型合金在不同声场条件下的液态过冷能力及其结晶过程.实验发现,SCN-10%DC亚共晶、SCN-23.6%DC共晶和SCN-40%DC过共晶合金熔体获得的最大过冷度分...采用超声悬浮无容器处理技术,并结合高速摄影实时分析方法,研究了丁二腈-樟脑(SCN-DC)共晶型合金在不同声场条件下的液态过冷能力及其结晶过程.实验发现,SCN-10%DC亚共晶、SCN-23.6%DC共晶和SCN-40%DC过共晶合金熔体获得的最大过冷度分别达22.5 K (0.07T_(L)),16 K (0.05T_(E))和32.5 K (0.1T_(L)),相应的晶体生长速度各为27.91,0.21和0.45 mm/s.随着声压的增强,合金液滴的径厚比逐渐增大.其过冷度随径厚比的增大先升高后逐渐降低,最后基本保持不变.强声场引起的表面形核率增加以及合金液滴振动是阻碍深过冷的主要因素.展开更多
文摘BACKGROUND The NaV1.1 sodium channel alpha subunit,encoded by SCN1A,is crucial for initiating and propagating action potentials in neurons.SCN1A gene has long been an established target in the etiology and therapy of epilepsy.However,very few studies have investigated the relevance of genetic variations in epilepsy and anti-epileptic drug resistance.AIM To investigate associations between polymorphisms,rs121917953 T/A and rs121918623 C/T,and drug resistance in epilepsy patients in the north Indian population.METHODS A total of 100 age-and sex-matched epilepsy patients(50 drug responsive and 50 drug resistant subjects)were recruited and SCN1A rs121918623 C/T*and rs121917953 T/A*polymorphisms were analyzed by the allele specific-PCR technique.χ^(2)and Fisher’s exact test were used to estimate differences between the distribution of SCN1A rs121918623 and rs121917953 gene polymorphisms among various groups.The association between distinct rs121917953 genotypes and drug resistance was analyzed using logistic regression analysis.RESULTS For the SCN1A rs121917953 T/A*(D188V)polymorphism,a significantly higher proportion of individuals with AT genotype were observed in the drug-resistant group as compared to the drug-responsive group.Additionally,a higher risk association was exhibited by AT genotype for drug resistance with an odds ratio of 3.51 and P value=0.017.For the SCN1A rs121918623 C/T*(T875M)polymorphism,no significant difference in genotype distribution was observed between the drug-resistant and drug-sensitive groups.CONCLUSION Our findings indicate that the SCN1A polymorphism D188V is associated with a higher risk of drug resistance for the AT variant as compared to the homozygous TT wild-type.Further research is needed at the functional level and in larger cohorts to determine the potential of these genes as a therapeutic target in epilepsy subjects.
文摘目的:通过生物信息学的方法分析电压门控钠通道α亚基7 (Sodium Voltage-Gated Channel Alpha Subunit 7, SCN7A)基因在肺腺癌(lung adenocarcinoma, LUAD)和邻近非癌组织中的差异表达,探讨其与肺腺癌患者临床病理特征和预后的相关性,分析其可能调控的信号通路和在肿瘤免疫微环境中的作用,并通过细胞实验验证SCN7A在肺腺癌细胞中的生物学功能。方法:从癌症基因组图谱(The Cancer Genome Atlas, TCGA)数据库和基因型组织表达(Genotype-Tissue Expression, GTEx)数据库下载并整理33种肿瘤患者的基因表达数据进行SCN7A泛癌分析。利用TCGA数据库探讨SCN7A基因在肺腺癌及正常肺组织中的表达差异情况,并使用临床样本qRT-PCR对结果进行验证。ROC曲线评估SCN7A的诊断价值。从人类蛋白质图谱(The Human Protein Atlas, HPA)数据库下载LUAD患者及健康人群免疫组织化学数据。Cox回归分析寻找LUAD独立预后因素。临床相关性分析揭示SCN7A与LUAD患者临床病理特征的相关性。采用Kaplan-Meier Plotter数据库进行生存分析。通过功能注释工具分析SCN7A及其互作基因的功能。通过肿瘤免疫系统相互作用数据库(Tumor Immune System Interaction Database, TISIDB)分析SCN7A与肺癌肿瘤免疫浸润之间的关系。体外培养人正常肺上皮细胞BEAS-2B、肺腺癌细胞A549、H1395、H1975,qRT-PCR检测以上4株细胞中SCN7A的表达。构建SNC7A过表达质粒,转染至A549细胞中。采用cell counting kit8 (CCK8)、划痕试验、Transwell方法检测SCN7A基因过表达对肺腺癌A549细胞增殖、迁移及侵袭的影响。结果:SCN7A在肺腺癌中的表达显著低于正常肺组织(P Objective: This study aimed to analyze the expression differences of Sodium Voltage-Gated Channel Alpha Subunit 7 (SCN7A) in lung adenocarcinoma (LUAD) and adjacent non-tumor tissues, investigating its correlation with the clinical pathological characteristics and outcomes of LUAD patients. It also analyzes the potential signaling pathways regulated by SCN7A and its role in the tumor immune microenvironment. The biological function of SCN7A in lung adenocarcinoma cells was investigated by cell experiments. Methods: Gene expression profiles of 33 tumor types were downloaded from the Human Protein Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) databases for pan-cancer analysis of SCN7A. The expression difference of SCN7A gene in lung adenocarcinoma and adjacent normal tissues was investigated by using TCGA database, and the results were verified by qRT-PCR of clinical samples. ROC curve was employed to evaluate the diagnostic value of SCN7A. The immunohistochemical data of LUAD patients and healthy individuals were obtained from the Human Protein Atlas (HPA) database. Cox regression analysis was conducted to identify the independent prognostic factors. Clinical correlation analysis revealed the correlation between SCN7A and clinicopathological features of LUAD patients. Kaplan-Meier Plotter database was used for survival analysis. The function of SCN7A and its interacting genes was analyzed by functional annotation tools. The relationship between SCN7A and tumor immune infiltration in lung adenocarcinoma was analyzed through the Tumor Immune System Interaction Database (TISIDB). Human normal lung epithelial cells BEAS-2B, lung adenocarcinoma cells A549, H1395, H1975 were cultured in vitro. The expression of SCN7A in the above 4 cell lines was detected by qRT-PCR. SCN7A overexpression plasmid was constructed and transfected into A549 cells. The effects of SCN7A overexpression on the proliferation, migration and invasion of A549 cells were detected by Cell counting kit 8 (CCK8), scratch test and Transwell methods. Results: The expression of SCN7A in lung adenocarcinoma was significantly lower than in adjacent normal lung tissues (P < 0.001), and was negatively correlated with T stage, pathological grade, and overall survival (OS) (P < 0.05). Cox regression analysis revealed that low SCN7A expression was an independent risk factor for the prognosis of LUAD (P < 0.05). Patients with low SCN7A expression had a significantly reduced overall survival (OS) time and first progression (FP) time (P < 0.001). Function enrichment analysis suggested that SCN7A mainly participates in E2f targets, G2m checkpoint, etc. related pathways. Immune infiltration analysis showed that SCN7A expression correlated with mast cell, dendritic cell, macrophage, and follicular helper T cell infiltration in LUAD. The expression of SCN7A in A549, H1395 and H1975 cells was significantly lower than in BEAS-2B cells. After overexpression of SCN7A, proliferation, migration and invasion of A549 cells were significantly decreased (P < 0.01). Conclusion: The low expression level of the SCN7A gene is closely associated with poor prognosis and immune cell infiltration in lung adenocarcinoma patients, suggesting its potential to be established as a novel biomarker for the diagnosis and treatment of lung adenocarcinoma.
基金supported by the National Key R&D Program of China(2022YFC2503802)the National Natural Science Foundation of China(82271499 and 32450530)+1 种基金the Joint Project of the Yangtze River Delta Science and Technology Innovation Community(2024CSJZN00600)the National Key Research and Development Program of China(2024YFA1108000).
文摘Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes.However,therapeutic decision-making is relatively complex for epilepsies associated with channelopathy.Therefore,in the present study,we used a patient-derived organoid model with a novel SCN2A mutation(p.E512K)to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds.The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation.Immunofluorescence staining of patient-derived cortical organoids(COs)displayed normal neurodevelopment.Multielectrode array(MEA)recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts.Moreover,the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine.Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.
文摘目的:分析SCN1A、SCN2A基因多态性对丙戊酸钠治疗癫痫患儿的疗效影响。方法:采用PCR和Sanger测序法检测128例丙戊酸钠规范治疗的癫痫患儿(有效组76例、无效组52例)外周血SCN1A(rs10188577、rs2298771、rs3812718、rs1813502)、SCN2A(rs2304016、rs17183814)多态性。采用非条件Logistic回归分析基因型、等位基因频率与丙戊酸钠疗效的关系,分析不同基因型患者丙戊酸钠血药浓度的差异。结果:SCN1A基因rs3812718位点多态性与丙戊酸钠治疗效果有关。携带GA和AA基因型的患者采用丙戊酸钠治疗有效(GG vs GA:OR=1.186,95%CI 0.965~2.304,P=0.015;GG vs AA:OR=1.252,95%CI 1.007~3.254,P=0.002)。有效组SCN1A基因rs3812718位点A等位基因频率明显高于无效组(OR=1.452,95%CI 1.052~2.695,P=0.010)。其余基因位点组间比较差异均无统计学意义(P>0.05)。结论:SCN1A基因rs3812718位点多态性可能与丙戊酸钠抗癫痫效应有关。
文摘据Mich JK 2025年3月19日[Sci Transl Med,2025,17(790):eadn5603-eadn5603.]报道,美国艾伦研究所和西雅图儿童研究所的研究人员在Dravet综合征小鼠模型中合作开发了一种新的基因替代疗法。这种疗法缓解了症状,并导致了长期康复,没有毒性、副作用和死亡。对于治疗Dravet综合征是一项突破性的进展。
文摘采用超声悬浮无容器处理技术,并结合高速摄影实时分析方法,研究了丁二腈-樟脑(SCN-DC)共晶型合金在不同声场条件下的液态过冷能力及其结晶过程.实验发现,SCN-10%DC亚共晶、SCN-23.6%DC共晶和SCN-40%DC过共晶合金熔体获得的最大过冷度分别达22.5 K (0.07T_(L)),16 K (0.05T_(E))和32.5 K (0.1T_(L)),相应的晶体生长速度各为27.91,0.21和0.45 mm/s.随着声压的增强,合金液滴的径厚比逐渐增大.其过冷度随径厚比的增大先升高后逐渐降低,最后基本保持不变.强声场引起的表面形核率增加以及合金液滴振动是阻碍深过冷的主要因素.
