Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substan...Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.展开更多
BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-t...BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-threatening situations.Here,we report a patient with mutations in the uridine 5’-diphospho-glucuronosyltrans-ferase 1A1(UGT1A1)and bile salt export pump(adenosine triphosphate-binding cassette subfamily B member 11,ABCB11)genes who presented multiple intrahe-patic bile duct stones and cholestasis,and the jaundice of the patient increased after partial hepatectomy.CASE SUMMARY A 52-year-old male patient admitted to the hospital on October 23,2021,with a progressive exacerbation of jaundice,was found to have multiple intrahepatic bile duct stones with the diagnoses of obstructive jaundice and acute cholecystitis.Subsequently,the patient underwent left hepatectomy with biliary exploration,stone extraction,T-tube drainage,and cholecystectomy without developing any intraoperative complications.The patient had a dark urine color with worsening jaundice postoperatively and did not respond well to plasma exchange and other symptomatic and supportive treatments.Since the progressive increase in postoperative bilirubin could not be clinically explained with any potential reason,including,if not at all,viral infection,cholangitis,autoimmune liver disease,and other causes,the patient underwent whole-exon screening for any genetic diseases,which surprisingly identified UGT1A1 and ABCB11 gene mutations related to glucuronidation of indirect bilirubin as well as bile acid transport in hepatocytes,respectively.Thus,we hypothesized that postoperative refractory cholestasis might result from UGT1A1 and ABCB11 gene mutations and further recommended liver transplantation to the patient,who eventually declined it and died from liver failure six months later.CONCLUSION Surgery may aggravate cholestasis in patients with multiple intrahepatic bile duct stones and cholestasis associated with UGT1A1 and ABCB11 gene mutations.A liver transplant may be the best option if active medical treatment fails.展开更多
目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB...目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。展开更多
目的研究ATP结合盒亚家族A成员8(ABCA8)在结直肠癌中的作用。方法下载癌症基因组图谱数据库(The Cancer Genome Atlas,TCGA)中的结直肠癌数据,利用limma R包研究ABCA8在TCGA数据集中的表达情况。随即利用结直肠癌的临床生存状态数据研...目的研究ATP结合盒亚家族A成员8(ABCA8)在结直肠癌中的作用。方法下载癌症基因组图谱数据库(The Cancer Genome Atlas,TCGA)中的结直肠癌数据,利用limma R包研究ABCA8在TCGA数据集中的表达情况。随即利用结直肠癌的临床生存状态数据研究该基因是否和结直肠癌的生存预后相关。利用基因相关性分析研究ABCA8在结直肠癌中和其他基因之间是否具有相关性。利用R包estimate包和CIBERSORT R包得到结直肠癌中每个样本的肿瘤微环境打分以及运行肿瘤免疫浸润分析,并且对ABCA8基因表达量高低的两个分组之间进行免疫细胞以及肿瘤微环境的表达进行分析。利用免疫检查点相关基因分析ABCA8和其之间的关联。采用Western Blot验证收集的结直肠癌患者癌、癌旁以及正常组织中的ABCA8的表达情况,并且同时验证人类蛋白图谱数据库(The Human Protein Atlas,HPA)中ABCA8基因在结直肠癌以及正常肠道组织中的表达水平变化。结果通过差异分析发现ABCA8在结直肠癌中低表达。通过相关性分析一共得到了多个与ABCA8密切相关的基因。通过肿瘤微环境评分发现依据ABCA8表达水平不同分成的高、低表达两组中,基质评分,免疫评分和肿瘤微环境评分均有差异。利用生物信息学分析还发现ABCA8基因和免疫细胞以及免疫检查点相关基因之间具有明显的关联。通过Western Blot和HPA数据库中发现正常肠组织中ABCA8的表达水平高于结直肠癌组织。结论ABCA8在结直肠癌和正常肠道组织中具有明显差异,可以作为一种新的诊断生物标志物。展开更多
基金supported by funds from the National Institutes of Health (1R15CA143701)St.John's University Research Seed Grant(579-1110-7002) to Dr.Zhe-Sheng Chen.Drs.Suneet ShuklaSuresh V.Ambudkar were supported by the Intramural Research Program,Center for Cancer Research, National Cancer Institute,National Institutes of Health
文摘Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.
基金Supported by The Science and Technology Planning Projects of Guizhou Province and Zunyi City,No.QKHJCZK[2022]YB642,No.ZSKH·HZ(2022)344,No.gzwjkj2021-071,ZMC·YZ[2018]38,No.ZSKH·HZ[2021]58,and No.ZSKH·HZ[2021]60The General Project of Hubei Province and Jingmen City,No.2021YFYB074.
文摘BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-threatening situations.Here,we report a patient with mutations in the uridine 5’-diphospho-glucuronosyltrans-ferase 1A1(UGT1A1)and bile salt export pump(adenosine triphosphate-binding cassette subfamily B member 11,ABCB11)genes who presented multiple intrahe-patic bile duct stones and cholestasis,and the jaundice of the patient increased after partial hepatectomy.CASE SUMMARY A 52-year-old male patient admitted to the hospital on October 23,2021,with a progressive exacerbation of jaundice,was found to have multiple intrahepatic bile duct stones with the diagnoses of obstructive jaundice and acute cholecystitis.Subsequently,the patient underwent left hepatectomy with biliary exploration,stone extraction,T-tube drainage,and cholecystectomy without developing any intraoperative complications.The patient had a dark urine color with worsening jaundice postoperatively and did not respond well to plasma exchange and other symptomatic and supportive treatments.Since the progressive increase in postoperative bilirubin could not be clinically explained with any potential reason,including,if not at all,viral infection,cholangitis,autoimmune liver disease,and other causes,the patient underwent whole-exon screening for any genetic diseases,which surprisingly identified UGT1A1 and ABCB11 gene mutations related to glucuronidation of indirect bilirubin as well as bile acid transport in hepatocytes,respectively.Thus,we hypothesized that postoperative refractory cholestasis might result from UGT1A1 and ABCB11 gene mutations and further recommended liver transplantation to the patient,who eventually declined it and died from liver failure six months later.CONCLUSION Surgery may aggravate cholestasis in patients with multiple intrahepatic bile duct stones and cholestasis associated with UGT1A1 and ABCB11 gene mutations.A liver transplant may be the best option if active medical treatment fails.
文摘目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。
文摘目的研究ATP结合盒亚家族A成员8(ABCA8)在结直肠癌中的作用。方法下载癌症基因组图谱数据库(The Cancer Genome Atlas,TCGA)中的结直肠癌数据,利用limma R包研究ABCA8在TCGA数据集中的表达情况。随即利用结直肠癌的临床生存状态数据研究该基因是否和结直肠癌的生存预后相关。利用基因相关性分析研究ABCA8在结直肠癌中和其他基因之间是否具有相关性。利用R包estimate包和CIBERSORT R包得到结直肠癌中每个样本的肿瘤微环境打分以及运行肿瘤免疫浸润分析,并且对ABCA8基因表达量高低的两个分组之间进行免疫细胞以及肿瘤微环境的表达进行分析。利用免疫检查点相关基因分析ABCA8和其之间的关联。采用Western Blot验证收集的结直肠癌患者癌、癌旁以及正常组织中的ABCA8的表达情况,并且同时验证人类蛋白图谱数据库(The Human Protein Atlas,HPA)中ABCA8基因在结直肠癌以及正常肠道组织中的表达水平变化。结果通过差异分析发现ABCA8在结直肠癌中低表达。通过相关性分析一共得到了多个与ABCA8密切相关的基因。通过肿瘤微环境评分发现依据ABCA8表达水平不同分成的高、低表达两组中,基质评分,免疫评分和肿瘤微环境评分均有差异。利用生物信息学分析还发现ABCA8基因和免疫细胞以及免疫检查点相关基因之间具有明显的关联。通过Western Blot和HPA数据库中发现正常肠组织中ABCA8的表达水平高于结直肠癌组织。结论ABCA8在结直肠癌和正常肠道组织中具有明显差异,可以作为一种新的诊断生物标志物。
