Cornelia de Lange综合征(Cornelia de Lange syndrome,CdLS)在1933年由荷兰儿科医生Cornelia首次描述,该病是一种伴有多系统发育异常的遗传缺陷综合征,呈常染色体显性或X连锁显性方式遗传,发病率介于1/10000~1/30000活产新生儿,常表现...Cornelia de Lange综合征(Cornelia de Lange syndrome,CdLS)在1933年由荷兰儿科医生Cornelia首次描述,该病是一种伴有多系统发育异常的遗传缺陷综合征,呈常染色体显性或X连锁显性方式遗传,发病率介于1/10000~1/30000活产新生儿,常表现为成比例的身材矮小、宫内及出生后发育迟缓、特定的面部特征、多器官系统畸形(特别是心脏、胃肠道和肌肉骨骼系统)以及认知和行为方面的异常等。该病常见的突变基因有NIPBL、SMC1A、SMC3、RAD21、BRD4、HDAC8和ANKRD11,所有这些基因表达的蛋白都参与组成黏连蛋白复合物或影响其调节功能[1-2]。本团队对1例CdLS患儿及其家系成员进行基因突变检测,发现患儿携带HDAC8基因c.111+3A>T新发突变,既往未见报道,并统计中国目前报道的HDAC8基因突变所致CdLS患者基因型及临床表现,具体报告如下。展开更多
目的探讨Cornelia de Lange综合征(CdLS)的临床表型及基因型特点。方法回顾分析1例确诊CdLS患儿的临床资料,并总结分析国内已报道病例的情况。结果女性患儿,1岁2月龄,有特殊外貌,智力及运动发育落后,合并四肢畸形及听力异常。基因检测...目的探讨Cornelia de Lange综合征(CdLS)的临床表型及基因型特点。方法回顾分析1例确诊CdLS患儿的临床资料,并总结分析国内已报道病例的情况。结果女性患儿,1岁2月龄,有特殊外貌,智力及运动发育落后,合并四肢畸形及听力异常。基因检测发现患儿HDAC8基因c.675C>A(p.Y 225X)存在新发杂合无义变异,根据ACMG指南预测为致病性变异,确诊CdLS。通过对万方、维普、中国知网及PubMed数据库搜索,发现国内报道CdLS病例46例。其中26例行基因检查,20例(76.9%)存在NIPBL基因变异,3例(11.5%)HDAC8基因变异,1例(3.8%)SCM1A基因变异,2例未发现与临床吻合的致病性基因变异,表型各异。结论CdLS患儿存在特殊外貌、生长发育迟缓、多器官受累、听力障碍,多数可通过典型临床表型诊断,基因检测有助于非典型患者的早期诊断。展开更多
Background: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant primary tumor in the liver, and the rates of incidence and mortality are rapidly increasing globally. Histone deacetylase 8 (HDAC8) is a transcri...Background: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant primary tumor in the liver, and the rates of incidence and mortality are rapidly increasing globally. Histone deacetylase 8 (HDAC8) is a transcriptional regulator and is associated with tumorigenesis of several tumor types. This study aimed to evaluate the correlation between HDAC8 expression and clinicopathological parameters in ICC patients. Methods: ICC tissues and corresponding nonmalignant bile duct tissues were obtained from 60 patients. HDAC8 and Ki-67 expression were evaluated by immunohistochemistry staining. HDAC8 expression and the clinicopathological features and prognosis of the patients were analyzed. The mRNA level of HDAC8 in ICC was further analyzed using data from The Cancer Genome Atlas (TCGA). Results: The expression of HDAC8 were lower in ICC tissues (39/60, 65%) than in the corresponding nonmalignant bile duct tissues (54/60, 90%)( P = 0.001). Low HDAC8 expression in ICC was significantly associated with lymph node metastases (47.6% vs. 17.9%, P = 0.015). In addition, the positive cells rate of HDAC8 was statistically and negatively correlated with the Ki-67 index in ICC lesions ( r =?0.7660, P < 0.001). Importantly, the overall survival rate and recurrence-free survival rate in ICC patients with low HDAC8 expression were lower than those with high HDAC8 expression ( P = 0.008 and P = 0.011, respectively). Conclusions: Decreased HDAC8 expression in ICC is related to poor prognosis, and HDAC8 may be an independent prognostic indicator of ICC patients after curative resection.展开更多
Objective： Multiple myeloma is a kind of malignant plasma cell disease that originated from B lymphocyte and secrete great amount of monoclonal immunoglobulin. It is still one of the refractory diseases at present. N...Objective： Multiple myeloma is a kind of malignant plasma cell disease that originated from B lymphocyte and secrete great amount of monoclonal immunoglobulin. It is still one of the refractory diseases at present. Numerous studies show that there is an intensive relationship between the disequilibrium of histone acetylation and the occurance of multiple myeloma. Here we investigated the effect of triptolide（TPL） on the proliferation, apoptosis, histone H3 and H4 acetylation and expression of histone deacetylase 8 （HDAC8） in vitro, to explore its anti- myeloma mechanism. Methods： The effect of triptolide on the growth of RPMI8226 was studied by 3-（4,5-Dimethyl-2-thiazolyl） -2,5-diphenyl-2H-tetrazolium（MTT） assay. Apoptosis was detected by Hoechst 33258 staining. The protein expressions of acetyl-histone H3 and H4 were determined by Western blot, and the expression of HDAC8 was assessed by RT-PCR, Western blot and confocal microscopy. Results： Triptolide inhibited the proliferation of RPMI8226 and induced apoptosis in a time- and dosedependent manner. The 36h IC50 value was （105.370 ± 0.189）nmol/L. Triptolide increased the acetylation of histone H3 and H4 greatly. Furthermore, triptolide significantly down-regulated the mRNA and protein expression of HDAC8. Conclusion： Triptolide can inhibit proliferation and induce apoptosis of RPMI8226 significantly. Triptolide reduces the expression of HDAC8 in order to increase the histone H3 and H4 acetylation, which is possibly the anti-myeloma mechanism of triptolide.展开更多
目的对1例临床表现为先天发育异常、生后反应差、足月小样儿的新生儿进行临床及遗传学分析。方法对患儿进行临床及实验室检查指标分析。抽取患儿及其父母外周血,提取全基因组DNA,应用二代测序技术进行基因突变检测、生物信息学预测及San...目的对1例临床表现为先天发育异常、生后反应差、足月小样儿的新生儿进行临床及遗传学分析。方法对患儿进行临床及实验室检查指标分析。抽取患儿及其父母外周血,提取全基因组DNA,应用二代测序技术进行基因突变检测、生物信息学预测及Sanger测序验证。结果测序结果显示患儿携带X染色体上HDAC8基因(NM_018486.2)的c.556G>A(p.E186K)突变,软件预测该突变为疑似致病性变异。结论患儿为Cornelia de Lange综合征5型,HDAC8基因c.556G>A突变可能导致患儿发病。展开更多
HDAC8 is an important target for the treatment of many cancers and other diseases. To develop potent and selective HDAC8 inhibitors, molecular docking and molecular dynamics(MD) simulations were employed for investiga...HDAC8 is an important target for the treatment of many cancers and other diseases. To develop potent and selective HDAC8 inhibitors, molecular docking and molecular dynamics(MD) simulations were employed for investigation of the mechanism of HDAC8 inhibitions containing hydroxamic acid group. Compound 1 with high activity and compound 2 with low activity were selected for comparative study. Compound 1 formed a stronger chelation with Zn ion and was more stable in the HDAC8 pocket than compound 2. Residues HIS-180, ASP-178, ASP-267, and GLY-140 played a critical role in securing the position of compound 1. Both the head and tail of compound 1 formed strong hydrogen bonds with ASP-178, facilitating the ZBG of compound 1 close to the Zn ion so that they formed permanent chelation during the simulation period. The Cap group of the compounds with branch and long chains was advantageous to form interaction with active pocket opening. What’s more, based on the results of this study, three innovative recommendations for the design of highly active HDAC8 inhibitors were presented, which will be useful for the development of new HDAC8 inhibitors.展开更多
目的对3例Cornelia de Lange综合征(CdLS)患儿的临床表型及基因检测结果进行分析,明确其致病原因。方法选取2020年3月12日、8月14日、12月5日于甘肃省妇幼保健院医学遗传中心就诊的3例CdLS患儿为研究对象。收集患儿及其父母的临床资料,...目的对3例Cornelia de Lange综合征(CdLS)患儿的临床表型及基因检测结果进行分析,明确其致病原因。方法选取2020年3月12日、8月14日、12月5日于甘肃省妇幼保健院医学遗传中心就诊的3例CdLS患儿为研究对象。收集患儿及其父母的临床资料,采集外周血样进行家系高通量测序分析。结果3例患儿的主要临床表现包括发育迟缓、智力低下、特殊面容和其他伴随症状。根据国际诊断共识标准,3例患儿被拟诊为CdLS。通过家系全外显子组测序及生物信息学分析,确诊CdLS。患儿1携带NIPBL基因c.5567_5569delGAAinsTAT错义变异,患儿2携带SMC1A基因c.607A>G错义变异,患儿3携带HDAC8基因c.628+1G>A剪接变异。3例患儿均为新发变异。结论3例患儿均确诊CdLS,并发现了致病基因变异位点,其中NIPBL基因c.5567_5569delGAAinsTAT及HDAC8基因c.628+1G>A变异位点既往未见报道,丰富了CdLS的变异谱。展开更多
Objective To investigate the relationship between the expression of histone acetylation enzyme 2(HDAC2),interleukin-8(IL-8),tumor necrosis factor-α(TNF-α)in lung adenocarcinoma tissues and smoking.Methods A total of...Objective To investigate the relationship between the expression of histone acetylation enzyme 2(HDAC2),interleukin-8(IL-8),tumor necrosis factor-α(TNF-α)in lung adenocarcinoma tissues and smoking.Methods A total of 73 cases of lung adenocarcinoma confirmed by pathological examination after surgical展开更多
文摘Cornelia de Lange综合征(Cornelia de Lange syndrome,CdLS)在1933年由荷兰儿科医生Cornelia首次描述,该病是一种伴有多系统发育异常的遗传缺陷综合征,呈常染色体显性或X连锁显性方式遗传,发病率介于1/10000~1/30000活产新生儿,常表现为成比例的身材矮小、宫内及出生后发育迟缓、特定的面部特征、多器官系统畸形(特别是心脏、胃肠道和肌肉骨骼系统)以及认知和行为方面的异常等。该病常见的突变基因有NIPBL、SMC1A、SMC3、RAD21、BRD4、HDAC8和ANKRD11,所有这些基因表达的蛋白都参与组成黏连蛋白复合物或影响其调节功能[1-2]。本团队对1例CdLS患儿及其家系成员进行基因突变检测,发现患儿携带HDAC8基因c.111+3A>T新发突变,既往未见报道,并统计中国目前报道的HDAC8基因突变所致CdLS患者基因型及临床表现,具体报告如下。
文摘目的探讨Cornelia de Lange综合征(CdLS)的临床表型及基因型特点。方法回顾分析1例确诊CdLS患儿的临床资料,并总结分析国内已报道病例的情况。结果女性患儿,1岁2月龄,有特殊外貌,智力及运动发育落后,合并四肢畸形及听力异常。基因检测发现患儿HDAC8基因c.675C>A(p.Y 225X)存在新发杂合无义变异,根据ACMG指南预测为致病性变异,确诊CdLS。通过对万方、维普、中国知网及PubMed数据库搜索,发现国内报道CdLS病例46例。其中26例行基因检查,20例(76.9%)存在NIPBL基因变异,3例(11.5%)HDAC8基因变异,1例(3.8%)SCM1A基因变异,2例未发现与临床吻合的致病性基因变异,表型各异。结论CdLS患儿存在特殊外貌、生长发育迟缓、多器官受累、听力障碍,多数可通过典型临床表型诊断,基因检测有助于非典型患者的早期诊断。
基金supported by grants from the National Natural Science Foundation of China(81872019)the Major Science and Technology Project of Science and Technology Department of Sichuan Province(2017SZ0003)+1 种基金“1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University”“West China Hospital-Jefferson Clinical Cooperation Research Fund”(ZY2017308)
文摘Background: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant primary tumor in the liver, and the rates of incidence and mortality are rapidly increasing globally. Histone deacetylase 8 (HDAC8) is a transcriptional regulator and is associated with tumorigenesis of several tumor types. This study aimed to evaluate the correlation between HDAC8 expression and clinicopathological parameters in ICC patients. Methods: ICC tissues and corresponding nonmalignant bile duct tissues were obtained from 60 patients. HDAC8 and Ki-67 expression were evaluated by immunohistochemistry staining. HDAC8 expression and the clinicopathological features and prognosis of the patients were analyzed. The mRNA level of HDAC8 in ICC was further analyzed using data from The Cancer Genome Atlas (TCGA). Results: The expression of HDAC8 were lower in ICC tissues (39/60, 65%) than in the corresponding nonmalignant bile duct tissues (54/60, 90%)( P = 0.001). Low HDAC8 expression in ICC was significantly associated with lymph node metastases (47.6% vs. 17.9%, P = 0.015). In addition, the positive cells rate of HDAC8 was statistically and negatively correlated with the Ki-67 index in ICC lesions ( r =?0.7660, P < 0.001). Importantly, the overall survival rate and recurrence-free survival rate in ICC patients with low HDAC8 expression were lower than those with high HDAC8 expression ( P = 0.008 and P = 0.011, respectively). Conclusions: Decreased HDAC8 expression in ICC is related to poor prognosis, and HDAC8 may be an independent prognostic indicator of ICC patients after curative resection.
基金supported by the National Natural Science Foundation of China(No.30700882)
文摘Objective： Multiple myeloma is a kind of malignant plasma cell disease that originated from B lymphocyte and secrete great amount of monoclonal immunoglobulin. It is still one of the refractory diseases at present. Numerous studies show that there is an intensive relationship between the disequilibrium of histone acetylation and the occurance of multiple myeloma. Here we investigated the effect of triptolide（TPL） on the proliferation, apoptosis, histone H3 and H4 acetylation and expression of histone deacetylase 8 （HDAC8） in vitro, to explore its anti- myeloma mechanism. Methods： The effect of triptolide on the growth of RPMI8226 was studied by 3-（4,5-Dimethyl-2-thiazolyl） -2,5-diphenyl-2H-tetrazolium（MTT） assay. Apoptosis was detected by Hoechst 33258 staining. The protein expressions of acetyl-histone H3 and H4 were determined by Western blot, and the expression of HDAC8 was assessed by RT-PCR, Western blot and confocal microscopy. Results： Triptolide inhibited the proliferation of RPMI8226 and induced apoptosis in a time- and dosedependent manner. The 36h IC50 value was （105.370 ± 0.189）nmol/L. Triptolide increased the acetylation of histone H3 and H4 greatly. Furthermore, triptolide significantly down-regulated the mRNA and protein expression of HDAC8. Conclusion： Triptolide can inhibit proliferation and induce apoptosis of RPMI8226 significantly. Triptolide reduces the expression of HDAC8 in order to increase the histone H3 and H4 acetylation, which is possibly the anti-myeloma mechanism of triptolide.
文摘目的对1例临床表现为先天发育异常、生后反应差、足月小样儿的新生儿进行临床及遗传学分析。方法对患儿进行临床及实验室检查指标分析。抽取患儿及其父母外周血,提取全基因组DNA,应用二代测序技术进行基因突变检测、生物信息学预测及Sanger测序验证。结果测序结果显示患儿携带X染色体上HDAC8基因(NM_018486.2)的c.556G>A(p.E186K)突变,软件预测该突变为疑似致病性变异。结论患儿为Cornelia de Lange综合征5型,HDAC8基因c.556G>A突变可能导致患儿发病。
基金Talents Introduction Foundation for Universities of Guangdong Province(GD 2011)the Science and Technology Planning Project of Guangzhou(No.2013J4100071)。
文摘HDAC8 is an important target for the treatment of many cancers and other diseases. To develop potent and selective HDAC8 inhibitors, molecular docking and molecular dynamics(MD) simulations were employed for investigation of the mechanism of HDAC8 inhibitions containing hydroxamic acid group. Compound 1 with high activity and compound 2 with low activity were selected for comparative study. Compound 1 formed a stronger chelation with Zn ion and was more stable in the HDAC8 pocket than compound 2. Residues HIS-180, ASP-178, ASP-267, and GLY-140 played a critical role in securing the position of compound 1. Both the head and tail of compound 1 formed strong hydrogen bonds with ASP-178, facilitating the ZBG of compound 1 close to the Zn ion so that they formed permanent chelation during the simulation period. The Cap group of the compounds with branch and long chains was advantageous to form interaction with active pocket opening. What’s more, based on the results of this study, three innovative recommendations for the design of highly active HDAC8 inhibitors were presented, which will be useful for the development of new HDAC8 inhibitors.
文摘目的对3例Cornelia de Lange综合征(CdLS)患儿的临床表型及基因检测结果进行分析,明确其致病原因。方法选取2020年3月12日、8月14日、12月5日于甘肃省妇幼保健院医学遗传中心就诊的3例CdLS患儿为研究对象。收集患儿及其父母的临床资料,采集外周血样进行家系高通量测序分析。结果3例患儿的主要临床表现包括发育迟缓、智力低下、特殊面容和其他伴随症状。根据国际诊断共识标准,3例患儿被拟诊为CdLS。通过家系全外显子组测序及生物信息学分析,确诊CdLS。患儿1携带NIPBL基因c.5567_5569delGAAinsTAT错义变异,患儿2携带SMC1A基因c.607A>G错义变异,患儿3携带HDAC8基因c.628+1G>A剪接变异。3例患儿均为新发变异。结论3例患儿均确诊CdLS,并发现了致病基因变异位点,其中NIPBL基因c.5567_5569delGAAinsTAT及HDAC8基因c.628+1G>A变异位点既往未见报道,丰富了CdLS的变异谱。
文摘Objective To investigate the relationship between the expression of histone acetylation enzyme 2(HDAC2),interleukin-8(IL-8),tumor necrosis factor-α(TNF-α)in lung adenocarcinoma tissues and smoking.Methods A total of 73 cases of lung adenocarcinoma confirmed by pathological examination after surgical
