BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants signif...BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.展开更多
目的 探讨老年终末期肾病(end-stage renal disease,ESRD)血液透析患者中血清葡萄糖调节蛋白78(glucose regulatory protein 78,GRP78)、血管性血友病因子裂解蛋白酶(a disintegrin like and metalloproteinase with thrombospondin typ...目的 探讨老年终末期肾病(end-stage renal disease,ESRD)血液透析患者中血清葡萄糖调节蛋白78(glucose regulatory protein 78,GRP78)、血管性血友病因子裂解蛋白酶(a disintegrin like and metalloproteinase with thrombospondin type 1 motifs 13,ADAMTS13)表达对心脏瓣膜钙化的预测价值。方法 选取2022年5月至2024年2月在蒙城县中医院(亳州市第二中医院)接受血液透析治疗的老年ESRD患者86例,心脏超声仪检查确定其中36例发生心脏瓣膜钙化(钙化组)、50例未发生心脏瓣膜钙化(无钙化组)。采用酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)对血清GRP78、ADAMTS13水平进行检测;采用多因素Logistic回归分析不同临床资料与老年ESRD血液透析患者心脏瓣膜钙化的关系;采用受试者工作特征曲线分析血清GRP78、ADAMTS13单独及联合预测老年ESRD血液透析患者心脏瓣膜钙化的价值。结果 钙化组老年ESRD血液透析患者血清GRP78水平[(4.59±1.12)μg/L比(2.91±0.73)μg/L]、透析龄[(72.86±12.73)个月比(60.40±15.75)个月]、钙镁比(2.47±0.42比2.16±0.40)高于无钙化组,ADAMTS13水平[(522.58±129.05)μg/L比(864.52±221.13)μg/L]低于无钙化组(P<0.05)。血清GRP78、ADAMTS13与老年ESRD血液透析患者心脏瓣膜钙化独立相关(P<0.05)。血清GRP78、ADAMTS13单独及联合预测老年ESRD血液透析患者心脏瓣膜钙化的曲线下面积(area under the curve,AUC)分别为0.861、0.833、0.939,联合预测的AUC高于单独预测的AUC(Z=2.206、2.998,P<0.05)。结论 发生心脏瓣膜钙化的老年ESRD血液透析患者中血清GRP78高表达,ADAMTS13低表达,二者联合可有效提升心脏瓣膜钙化的预测效能。展开更多
目的:急性肾损伤(acute kidney injury,AKI)是临床上常见的危重症,目前仍缺乏早期、精准且无创的诊断和治疗手段,亟需深入探讨AKI发生和发展的潜在机制,寻找更精准可靠的靶点。本研究探讨缺血/再灌注(ischemia/reperfusion,I/R)、顺铂(c...目的:急性肾损伤(acute kidney injury,AKI)是临床上常见的危重症,目前仍缺乏早期、精准且无创的诊断和治疗手段,亟需深入探讨AKI发生和发展的潜在机制,寻找更精准可靠的靶点。本研究探讨缺血/再灌注(ischemia/reperfusion,I/R)、顺铂(cisplatin,Cis)、叶酸(folic acid,FA)诱导的3种AKI小鼠模型中整合素样金属蛋白酶结构域含血小板反应蛋白I型基序样3(adisintegrin-like and metalloprotease domain with thrombospondin type I motifslike-3,ADAMTSL3)的表达水平与分布情况。方法:将24只雄性C57BL/6小鼠随机分为对照组(Sham)、I/R组、Cis组和FA组4组,每组6只。造模后检测血肌酐(serum creatinine,SCr)和血尿素氮(blood urea nitrogen,BUN)水平。取各组小鼠的肾脏组织进行制片,并进行苏木精-伊红(hematoxylin and eosin,HE)染色、过碘酸希夫(periodic acid Schiff,PAS)染色、马松三色(Masson’s trichrome,Masson)染色、原位末端转移酶标记(terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling,TUNEL)染色、免疫荧光染色及蛋白质印迹法(Western blotting,WB)观察肾脏的损伤情况及ADAMTSL3的表达水平。结果:与Sham组相比,I/R、Cis和FA组的SCr、BUN均显著升高(均P<0.05),肾小管损伤程度均更严重,胶原纤维化、糖原沉积及细胞凋亡均增加,ADAMTSL3蛋白的表达水平均显著升高(均P<0.05),且主要定位于肾小管和间质;同时,Cis与FA组中ADAMTSL3蛋白的表达水平均高于I/R组(均P<0.05)。结论:3种AKI小鼠模型均成功建立,各组AKI小鼠肾脏中ADAMTSL3蛋白的表达水平均显著升高,可能为损伤性表达,可以作为肾实质损伤的潜在定位标志。ADAMTSL3可能在AKI发生和发展的机制中发挥重要作用,靶向ADAMTSL3可能可以帮助开发早期、无创、精准的新型AKI诊断标志物和靶点药物。展开更多
Proteases are essential for homeostasis,and their primary function is proteolytic in extracellular and intracellular compartments.The deregulation of expression,abundance,and activity of proteases has been related to ...Proteases are essential for homeostasis,and their primary function is proteolytic in extracellular and intracellular compartments.The deregulation of expression,abundance,and activity of proteases has been related to several pathologies,including cancer.This deregulation contributes to their pro-tumorigenic activity since they participate in the degradation of extracellular matrix components and adhesion molecules,and the activation of growth factors.However,some proteases,such as ADAM metallopeptidase with thrombospondin type 1 motif 8 and kallikrein-related peptidases 5 and 10,have emerged as tumor suppressors due to their antitumoral actions in specific cancer contexts.In this article,we discuss the antitumoral effects of ADAM metallopeptidase with thrombospondin type 1 motif 8,kallikrein-related peptidases 5 and 10 that have been described to date,suggesting their potential use as novel biomarkers and therapeutic targets in cancer.展开更多
基金Supported by the National Natural Science Foundation of China,No.81573507,No.81473283,No.81173131,and No.81320108027Guangdong Provincial Key Laboratory Construction Foundation,No.2017B030314030+1 种基金The National Key Research and Development Program,No.2016YFC0905003the 111 Project,No.B16047
文摘BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.
文摘目的 探讨老年终末期肾病(end-stage renal disease,ESRD)血液透析患者中血清葡萄糖调节蛋白78(glucose regulatory protein 78,GRP78)、血管性血友病因子裂解蛋白酶(a disintegrin like and metalloproteinase with thrombospondin type 1 motifs 13,ADAMTS13)表达对心脏瓣膜钙化的预测价值。方法 选取2022年5月至2024年2月在蒙城县中医院(亳州市第二中医院)接受血液透析治疗的老年ESRD患者86例,心脏超声仪检查确定其中36例发生心脏瓣膜钙化(钙化组)、50例未发生心脏瓣膜钙化(无钙化组)。采用酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)对血清GRP78、ADAMTS13水平进行检测;采用多因素Logistic回归分析不同临床资料与老年ESRD血液透析患者心脏瓣膜钙化的关系;采用受试者工作特征曲线分析血清GRP78、ADAMTS13单独及联合预测老年ESRD血液透析患者心脏瓣膜钙化的价值。结果 钙化组老年ESRD血液透析患者血清GRP78水平[(4.59±1.12)μg/L比(2.91±0.73)μg/L]、透析龄[(72.86±12.73)个月比(60.40±15.75)个月]、钙镁比(2.47±0.42比2.16±0.40)高于无钙化组,ADAMTS13水平[(522.58±129.05)μg/L比(864.52±221.13)μg/L]低于无钙化组(P<0.05)。血清GRP78、ADAMTS13与老年ESRD血液透析患者心脏瓣膜钙化独立相关(P<0.05)。血清GRP78、ADAMTS13单独及联合预测老年ESRD血液透析患者心脏瓣膜钙化的曲线下面积(area under the curve,AUC)分别为0.861、0.833、0.939,联合预测的AUC高于单独预测的AUC(Z=2.206、2.998,P<0.05)。结论 发生心脏瓣膜钙化的老年ESRD血液透析患者中血清GRP78高表达,ADAMTS13低表达,二者联合可有效提升心脏瓣膜钙化的预测效能。
文摘目的:急性肾损伤(acute kidney injury,AKI)是临床上常见的危重症,目前仍缺乏早期、精准且无创的诊断和治疗手段,亟需深入探讨AKI发生和发展的潜在机制,寻找更精准可靠的靶点。本研究探讨缺血/再灌注(ischemia/reperfusion,I/R)、顺铂(cisplatin,Cis)、叶酸(folic acid,FA)诱导的3种AKI小鼠模型中整合素样金属蛋白酶结构域含血小板反应蛋白I型基序样3(adisintegrin-like and metalloprotease domain with thrombospondin type I motifslike-3,ADAMTSL3)的表达水平与分布情况。方法:将24只雄性C57BL/6小鼠随机分为对照组(Sham)、I/R组、Cis组和FA组4组,每组6只。造模后检测血肌酐(serum creatinine,SCr)和血尿素氮(blood urea nitrogen,BUN)水平。取各组小鼠的肾脏组织进行制片,并进行苏木精-伊红(hematoxylin and eosin,HE)染色、过碘酸希夫(periodic acid Schiff,PAS)染色、马松三色(Masson’s trichrome,Masson)染色、原位末端转移酶标记(terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling,TUNEL)染色、免疫荧光染色及蛋白质印迹法(Western blotting,WB)观察肾脏的损伤情况及ADAMTSL3的表达水平。结果:与Sham组相比,I/R、Cis和FA组的SCr、BUN均显著升高(均P<0.05),肾小管损伤程度均更严重,胶原纤维化、糖原沉积及细胞凋亡均增加,ADAMTSL3蛋白的表达水平均显著升高(均P<0.05),且主要定位于肾小管和间质;同时,Cis与FA组中ADAMTSL3蛋白的表达水平均高于I/R组(均P<0.05)。结论:3种AKI小鼠模型均成功建立,各组AKI小鼠肾脏中ADAMTSL3蛋白的表达水平均显著升高,可能为损伤性表达,可以作为肾实质损伤的潜在定位标志。ADAMTSL3可能在AKI发生和发展的机制中发挥重要作用,靶向ADAMTSL3可能可以帮助开发早期、无创、精准的新型AKI诊断标志物和靶点药物。
基金Supported by Colegio de Ciencia y Tecnologia de la Universidad Autónoma de la Ciudad de México,No.UACM-CCyT-2025-CON-11.
文摘Proteases are essential for homeostasis,and their primary function is proteolytic in extracellular and intracellular compartments.The deregulation of expression,abundance,and activity of proteases has been related to several pathologies,including cancer.This deregulation contributes to their pro-tumorigenic activity since they participate in the degradation of extracellular matrix components and adhesion molecules,and the activation of growth factors.However,some proteases,such as ADAM metallopeptidase with thrombospondin type 1 motif 8 and kallikrein-related peptidases 5 and 10,have emerged as tumor suppressors due to their antitumoral actions in specific cancer contexts.In this article,we discuss the antitumoral effects of ADAM metallopeptidase with thrombospondin type 1 motif 8,kallikrein-related peptidases 5 and 10 that have been described to date,suggesting their potential use as novel biomarkers and therapeutic targets in cancer.
