目的对2021年1月陆军军医大学第二附属医院接诊的1例Schmid型干骺端软骨发育不全(Schmid type metaphyseal chondrodysplasia,SMCD)家系进行疾病表型与基因型分析,结合文献复习探讨其防治手段。方法对先证者进行家系调查及系谱分析,收...目的对2021年1月陆军军医大学第二附属医院接诊的1例Schmid型干骺端软骨发育不全(Schmid type metaphyseal chondrodysplasia,SMCD)家系进行疾病表型与基因型分析,结合文献复习探讨其防治手段。方法对先证者进行家系调查及系谱分析,收集先证者及家系成员的临床资料,采用全外显子组测序明确突变基因,并通过Sanger测序验证和家系共分离分析,同时结合ACMG指南进行生物信息学分析来评价变异的致病性。结果在家系患者中发现COL10A1基因存在新的杂合错义突变c.1843T>G(p.Tyr615Asp),该位点所在区域在不同物种之间高度保守,此突变可能通过影响X型胶原(α1)蛋白的三聚化及其与细胞外基质分子结合导致疾病发生。结论发现了1种SMCD的新突变,丰富了SMCD患者的突变谱,为SMCD的预防、诊断及治疗提供理论依据。展开更多
目的探讨超声造影定性及定量参数与乳腺癌患者新辅助化疗疗效及CBL proto-oncogene家族蛋白成员CBL原癌基因C(CBL proto-oncogene C,CBLC)蛋白、X型胶原蛋白(type X collagen,COL10)成员COL10A1表达水平的相关性。方法选取2019年6月至2...目的探讨超声造影定性及定量参数与乳腺癌患者新辅助化疗疗效及CBL proto-oncogene家族蛋白成员CBL原癌基因C(CBL proto-oncogene C,CBLC)蛋白、X型胶原蛋白(type X collagen,COL10)成员COL10A1表达水平的相关性。方法选取2019年6月至2021年6月于新疆医科大学第二附属医院接受全程新辅助化疗并进行保乳或全乳切除术治疗的192例乳腺癌患者作为研究对象,术中取乳腺癌组织和癌旁正常组织。化疗前,采用飞利浦iU22彩色多普勒超声诊断仪对病灶进行检查,观察并记录定性和定量参数。新辅助化疗结束后行肿块切除术,由2位病理学副主任及以上医师依据Miller and Payne改良病理反应分级标准评估疗效,分为病理完全应答(pathological complete response,PCR)组(102例)和非PCR组(90例);采用免疫组织化学法检测组织中的CBLC、COL10A1表达水平。结果单因素分析结果表明,非PCR组的增强边界不清晰、出现灌注缺损、周围放射状增强和增强不均匀的比例显著高于PCR组,非PCR组的峰值强度(peak intensity,PI)和曲线下面积(area under curve,AUC)均显著高于PCR组(均P<0.05);CBLC高表达者出现高增强、增强边界不清晰、灌注缺损、增强不均匀的比例显著低于低表达者,PI和AUC均显著低于低表达者(均P<0.05);COL10A1高表达者出现高增强、周围放射状增强、增强不均匀的比例显著高于低表达者,PI和AUC均显著高于低表达者,而达峰时间(time to peak,TTP)显著低于低表达者(均P<0.05)。多因素Logistic回归分析结果显示,增强边界不清晰、PI及AUC增大是出现非PCR的独立危险因素(均P<0.05);高增强、增强边界不清晰、PI及AUC增大是CBLC低表达的独立危险因素(均P<0.05);高增强、PI增大及TTP减小是COL10A1高表达的独立危险因素(均P<0.05)。结论超声造影定性及定量参数可用于预测乳腺癌患者新辅助化疗疗效及CBLC、COL10A1表达水平,有助于选择治疗方案和预测患者预后。展开更多
BACKGROUND Gastric cancer(GC)remains an aggressive malignancy with a high rate of mortality,being the third leading cause of cancer-related death.More than one million newly diagnosed cases and 782685 deaths due to GC...BACKGROUND Gastric cancer(GC)remains an aggressive malignancy with a high rate of mortality,being the third leading cause of cancer-related death.More than one million newly diagnosed cases and 782685 deaths due to GC were reported in 2018.GC is characterized by limited effective treatment options and the lack of consistent biomarkers for the diagnosis and prognosis of these patients.The discovery of new biomarkers useful in the early diagnosis of GC is mandatory.AIM To evaluate the potential of COL10A1 as a circulating biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients.METHODS Plasma and tissue obtained from 49 patients with gastric adenocarcinoma have been used in exploring the expression of COL10A1.Real-time PCR and western blot techniques were used to evaluate COL10A1 level in gastric tumor tissue compared to normal adjacent tissue.The circulating level of COL10A1 was also evaluated by ELISA in plasma of gastric adenocarcinoma patients.Survival analysis was made in order to evaluate the potential of COL10A1 as a biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients.RESULTS Our results showed a significant increase in COL10A1 gene expression and protein levels in gastric tumor tissue compared to adjacent normal tissue(P<0.05).COL10A1 seems to show an elevated expression from the beginning of carcinogenesis,in the early stages,and its increased level remains elevated during cancer progression.A significant increase of COL10A1 plasma level in gastric adenocarcinoma patients was also identified.Moreover,increased COL10A1 plasma level was associated with poor survival of the patients.Plasma COL10A1 performed a diagnostic value in GC with area under the receiver operating characteristic curve(AUC)of 0.9171(P=0.0002),sensitivity of 87.76%,and specificity of 100.0%.Furthermore,this study demonstrated the potential role of plasma COL10A1 in the early detection of GC,as in the early stage,we obtained an AUC of 0.8789(P=0.0030),sensitivity of 81.25%,and specificity of 100.0%.CONCLUSION Circulating expression level of COL10A1 is significantly increased in gastric adenocarcinoma patients being associated with poor survival and is a potential biomarker for early detection of GC.展开更多
目的对一个Schmid型干骺端软骨发育不良(Schmid type metaphyseal chondrodysplasia,SMCD)三代家系进行致病基因分析并探讨该突变在SMCD发病机制中的潜在作用,并探索SMCD基因型与表型的关系。方法回顾性分析1例SMCD患儿的临床资料并定...目的对一个Schmid型干骺端软骨发育不良(Schmid type metaphyseal chondrodysplasia,SMCD)三代家系进行致病基因分析并探讨该突变在SMCD发病机制中的潜在作用,并探索SMCD基因型与表型的关系。方法回顾性分析1例SMCD患儿的临床资料并定期随访,抽取患儿及家系成员的外周血进行全外显子组测序分析,针对可疑变异进行Sanger测序验证和生物信息学预测突变的致病性,并对突变蛋白质的三维结构进行建模,分析突变蛋白三级结构的变化。通过构建野生型和突变型COL10A1质粒,进行体外功能研究。通过PubMed数据库查询1997年1月至2021年8月既往报道对SMCD所有病例进行的文献综述和基因型-表型分析,总结COL10A1突变基因型-表型关系。结果经全外显子测序检测到患儿COL10A1基因存在杂合突变(c.1863_1866delAATG,p.M622Tfs*54),为未报道过的新变异。经家系验证分析,家系成员均未检测出此突变。生物信息学软件预测可能为有害变异。SWISS-MODEL同源建模显示该突变位于NC1结构域,预测突变蛋白产生截短的Ⅹ型胶原α-1(X)链,引起Ⅹ型胶原蛋白α-1(X)亚基的错误折叠和三聚体不正确组装。体外功能实验发现突变体α-1(X)链表达降低,α-1(X)链三聚体降低,而α-1(X)链二聚体水平明显升高。基因型-表型分析结果显示,携带截短突变或NC1结构域突变的患者比携带非截短突变或非NC1结构域突变的患者发病年龄更早,临床表型更严重。结论COL10A1基因新发突变(p.M622Tfs*54)引起X胶原α-1(X)链三聚化及组装异常,导致SMCD。COL10A1蛋白NC1结构域是SMCD的热点突变区域,携带NC1结构域突变患者发病年龄较早且临床症状更严重。展开更多
Osteoarthritis(OA)has been considered non-reversible as articular cartilage wears down with limited repair capacity.Enhanced chondrocyte hypertrophy and increased type X collagen gene(COL10A1)expression have been asso...Osteoarthritis(OA)has been considered non-reversible as articular cartilage wears down with limited repair capacity.Enhanced chondrocyte hypertrophy and increased type X collagen gene(COL10A1)expression have been associated with OA.Therefore,regulators controlling collagen X expression and chondrocyte hypertrophy may play a role in OA intervention.Here,we investigated how Distal-less homeobox 5(DLX5),the distal-less homeobox family member,controls murine Col10a1 gene expression and chondrocyte hypertrophy in chondrogenic cell models and its role in a murine OA model.Through qRT-PCR and Western blot analyses,we detected significantly increased levels of COL10A1 and DLX5 in hypertrophic MCT and ATDC5 cells compared to their proliferative stage.Forced expression of Dlx5 further increases,while knockdown of Dlx5 decreases COL10A1 expression in hypertrophic MCT cells.We have performed dual-luciferase reporter and ChiP assays and demonstrated that DLX5 promotes reporter activity through direct interaction with Col10a1 cis-enhancer.We established a murine OA model and detected markedly increased COL10A1 and DLX5 in the articular cartilage and subchondral bone of the OA mice compared with the controls.Notably,forced overexpression of DLX5 in hypertrophic MCT cells up-regulates RUNX2,and adjacent DLX5 and RUNX2 binding sites have previously been found within the Col10a1 cis-enhancer.Together,our data suggest that DLX5 may cooperate with RUNX2 to control cell-specific Col10a1 expression and chondrocyte hypertrophy and is involved in OA pathogenesis.展开更多
目的对2021年10月我院接诊的1例Schmid型干骺端软骨发育不全(Schmid type metaphyseal chondrodysplasia,SMCD)患儿的临床资料进行回顾性分析。方法收集先证者及其家系成员临床资料并分析其临床特点。对先证者父母、妹妹及其进行家系全...目的对2021年10月我院接诊的1例Schmid型干骺端软骨发育不全(Schmid type metaphyseal chondrodysplasia,SMCD)患儿的临床资料进行回顾性分析。方法收集先证者及其家系成员临床资料并分析其临床特点。对先证者父母、妹妹及其进行家系全外显子测序。结果先证者,男,14岁,因发现身材矮小7余年,来院就诊。双下肢全长X线片提示双侧髋臼变浅拉长,双侧股骨颈变短增粗,颈干角变小,大粗隆升高且增大,坐骨较细小,闭孔扁长;双膝关节各骨对位尚可,双侧股骨远端及胫腓骨近端干骺端骨质形态欠规则,密度欠均匀,多发硬化边;双踝关节各骨对位好,双侧胫腓骨远端干骺端骨质欠规整,密度自然,符合干骺端软骨发育不全。完善基因检测提示在COL10A1基因(OMIM编号:156500)外显子区域发现一处杂合突变c.53G>A(鸟嘌呤>腺嘌呤),导致氨基酸改变p.Gly18Glu(甘氨酸>谷氨酸),目前国内尚未见报道。结合患儿临床表现及检查结果,诊断为SMCD。结论该病例扩展了COL1OA1基因的突变位点,并提示临床医师对怀疑SMCD的患儿尽快完善X线片及基因检测,对遗传倾向的家族应完善遗传咨询。展开更多
文摘目的对2021年1月陆军军医大学第二附属医院接诊的1例Schmid型干骺端软骨发育不全(Schmid type metaphyseal chondrodysplasia,SMCD)家系进行疾病表型与基因型分析,结合文献复习探讨其防治手段。方法对先证者进行家系调查及系谱分析,收集先证者及家系成员的临床资料,采用全外显子组测序明确突变基因,并通过Sanger测序验证和家系共分离分析,同时结合ACMG指南进行生物信息学分析来评价变异的致病性。结果在家系患者中发现COL10A1基因存在新的杂合错义突变c.1843T>G(p.Tyr615Asp),该位点所在区域在不同物种之间高度保守,此突变可能通过影响X型胶原(α1)蛋白的三聚化及其与细胞外基质分子结合导致疾病发生。结论发现了1种SMCD的新突变,丰富了SMCD患者的突变谱,为SMCD的预防、诊断及治疗提供理论依据。
文摘目的探讨超声造影定性及定量参数与乳腺癌患者新辅助化疗疗效及CBL proto-oncogene家族蛋白成员CBL原癌基因C(CBL proto-oncogene C,CBLC)蛋白、X型胶原蛋白(type X collagen,COL10)成员COL10A1表达水平的相关性。方法选取2019年6月至2021年6月于新疆医科大学第二附属医院接受全程新辅助化疗并进行保乳或全乳切除术治疗的192例乳腺癌患者作为研究对象,术中取乳腺癌组织和癌旁正常组织。化疗前,采用飞利浦iU22彩色多普勒超声诊断仪对病灶进行检查,观察并记录定性和定量参数。新辅助化疗结束后行肿块切除术,由2位病理学副主任及以上医师依据Miller and Payne改良病理反应分级标准评估疗效,分为病理完全应答(pathological complete response,PCR)组(102例)和非PCR组(90例);采用免疫组织化学法检测组织中的CBLC、COL10A1表达水平。结果单因素分析结果表明,非PCR组的增强边界不清晰、出现灌注缺损、周围放射状增强和增强不均匀的比例显著高于PCR组,非PCR组的峰值强度(peak intensity,PI)和曲线下面积(area under curve,AUC)均显著高于PCR组(均P<0.05);CBLC高表达者出现高增强、增强边界不清晰、灌注缺损、增强不均匀的比例显著低于低表达者,PI和AUC均显著低于低表达者(均P<0.05);COL10A1高表达者出现高增强、周围放射状增强、增强不均匀的比例显著高于低表达者,PI和AUC均显著高于低表达者,而达峰时间(time to peak,TTP)显著低于低表达者(均P<0.05)。多因素Logistic回归分析结果显示,增强边界不清晰、PI及AUC增大是出现非PCR的独立危险因素(均P<0.05);高增强、增强边界不清晰、PI及AUC增大是CBLC低表达的独立危险因素(均P<0.05);高增强、PI增大及TTP减小是COL10A1高表达的独立危险因素(均P<0.05)。结论超声造影定性及定量参数可用于预测乳腺癌患者新辅助化疗疗效及CBLC、COL10A1表达水平,有助于选择治疗方案和预测患者预后。
基金Supported by the Romanian National Authority for Scientific Research and Innovation,CNCS-UEFISCDI,No.PN-III-P4-IDPCCF-2016-0158(contract PCCF 17/2018),within PNCDI III.
文摘BACKGROUND Gastric cancer(GC)remains an aggressive malignancy with a high rate of mortality,being the third leading cause of cancer-related death.More than one million newly diagnosed cases and 782685 deaths due to GC were reported in 2018.GC is characterized by limited effective treatment options and the lack of consistent biomarkers for the diagnosis and prognosis of these patients.The discovery of new biomarkers useful in the early diagnosis of GC is mandatory.AIM To evaluate the potential of COL10A1 as a circulating biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients.METHODS Plasma and tissue obtained from 49 patients with gastric adenocarcinoma have been used in exploring the expression of COL10A1.Real-time PCR and western blot techniques were used to evaluate COL10A1 level in gastric tumor tissue compared to normal adjacent tissue.The circulating level of COL10A1 was also evaluated by ELISA in plasma of gastric adenocarcinoma patients.Survival analysis was made in order to evaluate the potential of COL10A1 as a biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients.RESULTS Our results showed a significant increase in COL10A1 gene expression and protein levels in gastric tumor tissue compared to adjacent normal tissue(P<0.05).COL10A1 seems to show an elevated expression from the beginning of carcinogenesis,in the early stages,and its increased level remains elevated during cancer progression.A significant increase of COL10A1 plasma level in gastric adenocarcinoma patients was also identified.Moreover,increased COL10A1 plasma level was associated with poor survival of the patients.Plasma COL10A1 performed a diagnostic value in GC with area under the receiver operating characteristic curve(AUC)of 0.9171(P=0.0002),sensitivity of 87.76%,and specificity of 100.0%.Furthermore,this study demonstrated the potential role of plasma COL10A1 in the early detection of GC,as in the early stage,we obtained an AUC of 0.8789(P=0.0030),sensitivity of 81.25%,and specificity of 100.0%.CONCLUSION Circulating expression level of COL10A1 is significantly increased in gastric adenocarcinoma patients being associated with poor survival and is a potential biomarker for early detection of GC.
文摘目的对一个Schmid型干骺端软骨发育不良(Schmid type metaphyseal chondrodysplasia,SMCD)三代家系进行致病基因分析并探讨该突变在SMCD发病机制中的潜在作用,并探索SMCD基因型与表型的关系。方法回顾性分析1例SMCD患儿的临床资料并定期随访,抽取患儿及家系成员的外周血进行全外显子组测序分析,针对可疑变异进行Sanger测序验证和生物信息学预测突变的致病性,并对突变蛋白质的三维结构进行建模,分析突变蛋白三级结构的变化。通过构建野生型和突变型COL10A1质粒,进行体外功能研究。通过PubMed数据库查询1997年1月至2021年8月既往报道对SMCD所有病例进行的文献综述和基因型-表型分析,总结COL10A1突变基因型-表型关系。结果经全外显子测序检测到患儿COL10A1基因存在杂合突变(c.1863_1866delAATG,p.M622Tfs*54),为未报道过的新变异。经家系验证分析,家系成员均未检测出此突变。生物信息学软件预测可能为有害变异。SWISS-MODEL同源建模显示该突变位于NC1结构域,预测突变蛋白产生截短的Ⅹ型胶原α-1(X)链,引起Ⅹ型胶原蛋白α-1(X)亚基的错误折叠和三聚体不正确组装。体外功能实验发现突变体α-1(X)链表达降低,α-1(X)链三聚体降低,而α-1(X)链二聚体水平明显升高。基因型-表型分析结果显示,携带截短突变或NC1结构域突变的患者比携带非截短突变或非NC1结构域突变的患者发病年龄更早,临床表型更严重。结论COL10A1基因新发突变(p.M622Tfs*54)引起X胶原α-1(X)链三聚化及组装异常,导致SMCD。COL10A1蛋白NC1结构域是SMCD的热点突变区域,携带NC1结构域突变患者发病年龄较早且临床症状更严重。
基金supported by the Jiangsu Provincial Key Research and Development Program(China)(No.BE2020679 to Q.Z.)the Innovation Team(leader)of Jiangsu Province,China(2017,QZ)the National Natural Science Foundation of China(No.82001576 to L.Q.)。
文摘Osteoarthritis(OA)has been considered non-reversible as articular cartilage wears down with limited repair capacity.Enhanced chondrocyte hypertrophy and increased type X collagen gene(COL10A1)expression have been associated with OA.Therefore,regulators controlling collagen X expression and chondrocyte hypertrophy may play a role in OA intervention.Here,we investigated how Distal-less homeobox 5(DLX5),the distal-less homeobox family member,controls murine Col10a1 gene expression and chondrocyte hypertrophy in chondrogenic cell models and its role in a murine OA model.Through qRT-PCR and Western blot analyses,we detected significantly increased levels of COL10A1 and DLX5 in hypertrophic MCT and ATDC5 cells compared to their proliferative stage.Forced expression of Dlx5 further increases,while knockdown of Dlx5 decreases COL10A1 expression in hypertrophic MCT cells.We have performed dual-luciferase reporter and ChiP assays and demonstrated that DLX5 promotes reporter activity through direct interaction with Col10a1 cis-enhancer.We established a murine OA model and detected markedly increased COL10A1 and DLX5 in the articular cartilage and subchondral bone of the OA mice compared with the controls.Notably,forced overexpression of DLX5 in hypertrophic MCT cells up-regulates RUNX2,and adjacent DLX5 and RUNX2 binding sites have previously been found within the Col10a1 cis-enhancer.Together,our data suggest that DLX5 may cooperate with RUNX2 to control cell-specific Col10a1 expression and chondrocyte hypertrophy and is involved in OA pathogenesis.
文摘目的对2021年10月我院接诊的1例Schmid型干骺端软骨发育不全(Schmid type metaphyseal chondrodysplasia,SMCD)患儿的临床资料进行回顾性分析。方法收集先证者及其家系成员临床资料并分析其临床特点。对先证者父母、妹妹及其进行家系全外显子测序。结果先证者,男,14岁,因发现身材矮小7余年,来院就诊。双下肢全长X线片提示双侧髋臼变浅拉长,双侧股骨颈变短增粗,颈干角变小,大粗隆升高且增大,坐骨较细小,闭孔扁长;双膝关节各骨对位尚可,双侧股骨远端及胫腓骨近端干骺端骨质形态欠规则,密度欠均匀,多发硬化边;双踝关节各骨对位好,双侧胫腓骨远端干骺端骨质欠规整,密度自然,符合干骺端软骨发育不全。完善基因检测提示在COL10A1基因(OMIM编号:156500)外显子区域发现一处杂合突变c.53G>A(鸟嘌呤>腺嘌呤),导致氨基酸改变p.Gly18Glu(甘氨酸>谷氨酸),目前国内尚未见报道。结合患儿临床表现及检查结果,诊断为SMCD。结论该病例扩展了COL1OA1基因的突变位点,并提示临床医师对怀疑SMCD的患儿尽快完善X线片及基因检测,对遗传倾向的家族应完善遗传咨询。
