Variants at the GTF2I repeat domain containing 1(GTF2IRD1)–GTF2I locus are associated with primary Sj?gren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis. Numerous studies have indicated that ...Variants at the GTF2I repeat domain containing 1(GTF2IRD1)–GTF2I locus are associated with primary Sj?gren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis. Numerous studies have indicated that this susceptibility locus is shared by multiple autoimmune diseases. However, until now there were no studies of the correlation between GTF2IRD1–GTF2I polymorphisms and neuromyelitis optica spectrum disorders(NMOSD). This case control study assessed this association by recruiting 305 participants with neuromyelitis optica spectrum disorders and 487 healthy controls at the Department of Neurology, from September 2014 to April 2017. Peripheral blood was collected, DNA extracteds and the genetic association between GTF2IRD1–GTF2I polymorphisms and neuromyelitis optica spectrum disorders in the Chinese Han population was analyzed by genotyping. We found that the T allele of rs117026326 was associated with an increased risk of neuromyelitis optica spectrum disorders(odds ratio(OR) = 1.364, 95% confidence interval(CI) 1.019–1.828; P = 0.037). This association persisted after stratification analysis for aquaporin-4 immunoglobulin G antibodies(AQP4-IgG) positivity(OR = 1.397, 95% CI 1.021–1.912; P = 0.036) and stratification according to coexisting autoimmune diseases(OR = 1.446, 95% CI 1.072–1.952; P = 0.015). Furthermore, the CC genotype of rs73366469 was frequent in AQP4-IgG-seropositive patients(OR = 3.15, 95% CI 1.183–8.393, P = 0.022). In conclusion, the T allele of rs117026326 was associated with susceptibility to neuromyelitis optica spectrum disorders, and the CC genotype of rs73366469 conferred susceptibility to AQP4-IgG-seropositivity in Han Chinese patients. The protocol was approved by the Ethics Committee of West China Hospital of Sichuan University, China(approval number: 2016-31) on March 2, 2016.展开更多
Through bioinformatics predictions,we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma(TC).Further,Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and ...Through bioinformatics predictions,we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma(TC).Further,Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression.Therefore,we selected them for this present study,where the effects of bone marrow mesenchymal stem cell-derived EVs(BMSDs-EVs)enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition(EMT)and stemness maintenance in TC.The under-expression of GTF2I and FAT1 was validated in TC cell lines.Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells,EMT,and stemness maintenance.Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression.MSC-EVs could shuttle GTF2I into TPC-1 cells,where GTF2I inhibited TC malignant phenotypes,EMT,and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation.In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice.Taken together,our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.展开更多
目的对比不典型A型胸腺瘤(atypical type A thymoma,AAT)与经典A型胸腺瘤(type A thymoma,TAT)在临床病理特征、分子表型及预后方面的差异,明确AAT的侵袭性本质。方法回顾性收集2016年1月—2024年11月四川大学华西医院手术切除胸腺瘤的...目的对比不典型A型胸腺瘤(atypical type A thymoma,AAT)与经典A型胸腺瘤(type A thymoma,TAT)在临床病理特征、分子表型及预后方面的差异,明确AAT的侵袭性本质。方法回顾性收集2016年1月—2024年11月四川大学华西医院手术切除胸腺瘤的AAT患者(AAT组)和经典TAT患者(TAT组)资料,分析并比较两组临床资料、组织学形态、免疫组织化学(CD20、Ki-67)及GTF2I突变状态,并进行生存分析。结果共纳入患者53例,其中AAT组22例,TAT组31例。两组年龄、性别、初诊临床症状方面差异无统计学意义(P>0.05)。相比TAT组,AAT组肿瘤直径更大[(5.6±2.7)vs.(4.1±2.0)cm,P=0.043],MasaokaⅠ期比例更低(31.6%vs.61.3%,P=0.041),生存预后更差[无进展生存期:风险比(hazard ratio,HR)=2.87,95%置信区间(confidence interval,CI)(1.42,5.81),P=0.004;总生存期:HR=1.96,95%CI(1.02,3.78),P=0.013]。病理特征方面,AAT组核分裂数更多(平均6个/2 mm^(2)),45.5%可见肿瘤性坏死,两组CD20表达率(20.0%vs.41.9%)、Ki-67指数[(11.0±6.0)%vs.(8.0±6.9)%]、GTF2I突变率(86.7%vs.92.3%)差异无统计学意义(P>0.05)。结论AAT是一种具有独特侵袭性病理特征的TAT亚型,表现为更高核分裂活性、坏死倾向及更易复发转移。病理诊断应结合形态学与分子检测,指导临床采取更积极治疗与随访策略。展开更多
Background and Aims:General transcription factor IIIC subunit 2(GTF3C2)is one of the polymerase III transcription-related factors.Previous studies have revealed that GTF3C2 is involved in regulating cell proliferation...Background and Aims:General transcription factor IIIC subunit 2(GTF3C2)is one of the polymerase III transcription-related factors.Previous studies have revealed that GTF3C2 is involved in regulating cell proliferation.However,the role of GTF3C2 in hepatocellular carcinoma(HCC)remains un-clear.This study aimed to determine its expression,biologi-cal function,and mechanism in HCC.Methods:The expres-sion of GTF3C2 in HCC and non-tumor tissues,along with its clinical significance,was investigated using public databases and clinical samples.Reverse transcription-quantitative poly-merase chain reaction and Western blot assays were per-formed to detect the expression of GTF3C2,ubiquitin specific peptidase 21(USP21),mitogen-activated protein kinase 2(MEK2),extracellular signal-regulated kinase 1/2(ERK1/2),and p-ERK1/2 in cells.A luciferase reporter assay was con-ducted to explore the regulatory effect of GTF3C2 on USP21 transcription.Cell Counting Kit-8,5-ethynyl-2′-deoxyuridine,and colony formation assays were performed to assess HCC cell proliferation.Subcutaneous injection of HCC cells into nude mice was used to evaluate tumor growth in vivo.Re-sults:GTF3C2 expression was upregulated in HCC tissues and was positively correlated with advanced tumor stages and high tumor grades.HCC patients with high GTF3C2 ex-pression had significantly worse survival outcomes.Knock-down of GTF3C2 suppressed the proliferation of Hep3B and HCCLM3 cells,while overexpression of GTF3C2 facilitated the proliferation of SNU449 and Huh7 cells.GTF3C2 promoted USP21 expression by activating its transcription,which sub-sequently increased the levels of MEK2 and p-ERK1/2 in HCC cells.Overexpression of both USP21 and MEK2 counteracted the GTF3C2 knockdown-induced inactivation of the ERK1/2 pathway.Moreover,GTF3C2 promoted HCC cell proliferation in vitro and tumor growth in vivo by regulating the USP21/MEK2/ERK1/2 pathway.Conclusions:Upregulation of GT-F3C2 is frequently observed in HCC tissues and predicts poor prognosis.GTF3C2 promotes HCC cell proliferation via the USP21/MEK2/ERK1/2 pathway.展开更多
Thymic epithelial tumors(TETs)comprise a heterogeneous group of epithelial-derived thymic neoplasms with diverse clinical behavior and underlying molecular genetic features.Owing to their rare nature,the molecular cla...Thymic epithelial tumors(TETs)comprise a heterogeneous group of epithelial-derived thymic neoplasms with diverse clinical behavior and underlying molecular genetic features.Owing to their rare nature,the molecular classification of TETs has only recently begun to be fully explored.The advent of advanced molecular studies,particularly the ability to sequence the DNA and RNA of tumors in a massively parallel fashion,has led to an increased understanding of the molecular underpinnings of thymic neoplasia.Thymomas,characterized by a heterogeneous group of molecular alterations,tend to have low mutational burdens and various copy number abnormalities including a characteristic loss of chromosomal material in the region of 6q25.2-p25.3,a recurrent,specific point mutation GTF2I p.L424H,and specific expression of certain microRNAs.Thymic carcinomas,in contrast,are generally characterized by increased tumor mutational burdens,multiple copy number alterations,and varied,non-recurrent,somatic mutations.Advances in molecular knowledge of TETs allow for more precise molecular classification of these tumors,and the presence of specific alterations aids in the diagnosis of borderline lesions.In the future,additional molecular studies will better delineate the molecular landscape of these tumors and may one day allow for more targeted treatment algorithms.This review aims to cover the current understanding of the molecular alterations thus far identified in thymomas and thymic carcinomas.展开更多
基金supported by the National Natural Science Foundation of China,No.81271321(to HYZ)a grant from the Department of Science and Technology Research Projects in Sichuan Province of China,No.2013FZ0015(to HYZ)the Fundamental Research Funds for the Central Universities,China,No.2017SCU11049(to QZ)
文摘Variants at the GTF2I repeat domain containing 1(GTF2IRD1)–GTF2I locus are associated with primary Sj?gren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis. Numerous studies have indicated that this susceptibility locus is shared by multiple autoimmune diseases. However, until now there were no studies of the correlation between GTF2IRD1–GTF2I polymorphisms and neuromyelitis optica spectrum disorders(NMOSD). This case control study assessed this association by recruiting 305 participants with neuromyelitis optica spectrum disorders and 487 healthy controls at the Department of Neurology, from September 2014 to April 2017. Peripheral blood was collected, DNA extracteds and the genetic association between GTF2IRD1–GTF2I polymorphisms and neuromyelitis optica spectrum disorders in the Chinese Han population was analyzed by genotyping. We found that the T allele of rs117026326 was associated with an increased risk of neuromyelitis optica spectrum disorders(odds ratio(OR) = 1.364, 95% confidence interval(CI) 1.019–1.828; P = 0.037). This association persisted after stratification analysis for aquaporin-4 immunoglobulin G antibodies(AQP4-IgG) positivity(OR = 1.397, 95% CI 1.021–1.912; P = 0.036) and stratification according to coexisting autoimmune diseases(OR = 1.446, 95% CI 1.072–1.952; P = 0.015). Furthermore, the CC genotype of rs73366469 was frequent in AQP4-IgG-seropositive patients(OR = 3.15, 95% CI 1.183–8.393, P = 0.022). In conclusion, the T allele of rs117026326 was associated with susceptibility to neuromyelitis optica spectrum disorders, and the CC genotype of rs73366469 conferred susceptibility to AQP4-IgG-seropositivity in Han Chinese patients. The protocol was approved by the Ethics Committee of West China Hospital of Sichuan University, China(approval number: 2016-31) on March 2, 2016.
基金supported by Shanghai Shenkang Hospital Development Center(No.SHDC12019X38).
文摘Through bioinformatics predictions,we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma(TC).Further,Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression.Therefore,we selected them for this present study,where the effects of bone marrow mesenchymal stem cell-derived EVs(BMSDs-EVs)enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition(EMT)and stemness maintenance in TC.The under-expression of GTF2I and FAT1 was validated in TC cell lines.Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells,EMT,and stemness maintenance.Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression.MSC-EVs could shuttle GTF2I into TPC-1 cells,where GTF2I inhibited TC malignant phenotypes,EMT,and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation.In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice.Taken together,our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.
文摘目的对比不典型A型胸腺瘤(atypical type A thymoma,AAT)与经典A型胸腺瘤(type A thymoma,TAT)在临床病理特征、分子表型及预后方面的差异,明确AAT的侵袭性本质。方法回顾性收集2016年1月—2024年11月四川大学华西医院手术切除胸腺瘤的AAT患者(AAT组)和经典TAT患者(TAT组)资料,分析并比较两组临床资料、组织学形态、免疫组织化学(CD20、Ki-67)及GTF2I突变状态,并进行生存分析。结果共纳入患者53例,其中AAT组22例,TAT组31例。两组年龄、性别、初诊临床症状方面差异无统计学意义(P>0.05)。相比TAT组,AAT组肿瘤直径更大[(5.6±2.7)vs.(4.1±2.0)cm,P=0.043],MasaokaⅠ期比例更低(31.6%vs.61.3%,P=0.041),生存预后更差[无进展生存期:风险比(hazard ratio,HR)=2.87,95%置信区间(confidence interval,CI)(1.42,5.81),P=0.004;总生存期:HR=1.96,95%CI(1.02,3.78),P=0.013]。病理特征方面,AAT组核分裂数更多(平均6个/2 mm^(2)),45.5%可见肿瘤性坏死,两组CD20表达率(20.0%vs.41.9%)、Ki-67指数[(11.0±6.0)%vs.(8.0±6.9)%]、GTF2I突变率(86.7%vs.92.3%)差异无统计学意义(P>0.05)。结论AAT是一种具有独特侵袭性病理特征的TAT亚型,表现为更高核分裂活性、坏死倾向及更易复发转移。病理诊断应结合形态学与分子检测,指导临床采取更积极治疗与随访策略。
基金supported by a grant from the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(Grant No.LHDMD23H300002).
文摘Background and Aims:General transcription factor IIIC subunit 2(GTF3C2)is one of the polymerase III transcription-related factors.Previous studies have revealed that GTF3C2 is involved in regulating cell proliferation.However,the role of GTF3C2 in hepatocellular carcinoma(HCC)remains un-clear.This study aimed to determine its expression,biologi-cal function,and mechanism in HCC.Methods:The expres-sion of GTF3C2 in HCC and non-tumor tissues,along with its clinical significance,was investigated using public databases and clinical samples.Reverse transcription-quantitative poly-merase chain reaction and Western blot assays were per-formed to detect the expression of GTF3C2,ubiquitin specific peptidase 21(USP21),mitogen-activated protein kinase 2(MEK2),extracellular signal-regulated kinase 1/2(ERK1/2),and p-ERK1/2 in cells.A luciferase reporter assay was con-ducted to explore the regulatory effect of GTF3C2 on USP21 transcription.Cell Counting Kit-8,5-ethynyl-2′-deoxyuridine,and colony formation assays were performed to assess HCC cell proliferation.Subcutaneous injection of HCC cells into nude mice was used to evaluate tumor growth in vivo.Re-sults:GTF3C2 expression was upregulated in HCC tissues and was positively correlated with advanced tumor stages and high tumor grades.HCC patients with high GTF3C2 ex-pression had significantly worse survival outcomes.Knock-down of GTF3C2 suppressed the proliferation of Hep3B and HCCLM3 cells,while overexpression of GTF3C2 facilitated the proliferation of SNU449 and Huh7 cells.GTF3C2 promoted USP21 expression by activating its transcription,which sub-sequently increased the levels of MEK2 and p-ERK1/2 in HCC cells.Overexpression of both USP21 and MEK2 counteracted the GTF3C2 knockdown-induced inactivation of the ERK1/2 pathway.Moreover,GTF3C2 promoted HCC cell proliferation in vitro and tumor growth in vivo by regulating the USP21/MEK2/ERK1/2 pathway.Conclusions:Upregulation of GT-F3C2 is frequently observed in HCC tissues and predicts poor prognosis.GTF3C2 promotes HCC cell proliferation via the USP21/MEK2/ERK1/2 pathway.
文摘Thymic epithelial tumors(TETs)comprise a heterogeneous group of epithelial-derived thymic neoplasms with diverse clinical behavior and underlying molecular genetic features.Owing to their rare nature,the molecular classification of TETs has only recently begun to be fully explored.The advent of advanced molecular studies,particularly the ability to sequence the DNA and RNA of tumors in a massively parallel fashion,has led to an increased understanding of the molecular underpinnings of thymic neoplasia.Thymomas,characterized by a heterogeneous group of molecular alterations,tend to have low mutational burdens and various copy number abnormalities including a characteristic loss of chromosomal material in the region of 6q25.2-p25.3,a recurrent,specific point mutation GTF2I p.L424H,and specific expression of certain microRNAs.Thymic carcinomas,in contrast,are generally characterized by increased tumor mutational burdens,multiple copy number alterations,and varied,non-recurrent,somatic mutations.Advances in molecular knowledge of TETs allow for more precise molecular classification of these tumors,and the presence of specific alterations aids in the diagnosis of borderline lesions.In the future,additional molecular studies will better delineate the molecular landscape of these tumors and may one day allow for more targeted treatment algorithms.This review aims to cover the current understanding of the molecular alterations thus far identified in thymomas and thymic carcinomas.
