目的探讨青少年多形性低级别神经上皮肿瘤(polymorphous low-grade neuroepithelial tumor of the young,PLNTY)的临床病理特征、诊断、鉴别诊断及预后。方法收集7例PLNTY患者临床及影像学资料,采用HE染色进行形态学观察,应用免疫组化En...目的探讨青少年多形性低级别神经上皮肿瘤(polymorphous low-grade neuroepithelial tumor of the young,PLNTY)的临床病理特征、诊断、鉴别诊断及预后。方法收集7例PLNTY患者临床及影像学资料,采用HE染色进行形态学观察,应用免疫组化EnVision法检测CD34、BRAF、IDH1、GFAP、Ki67等蛋白的表达。运用荧光定量PCR检测BRAF基因突变,采用FISH检测CDKN2A/B缺失及1p/19q共缺失,并对部分病例行NGS检测。结果7例患者中男性6例,女性1例,年龄8~29岁,中位年龄22岁,肿瘤位于颞叶5例,左侧岛叶及前颞叶1例,额颞叶1例。其中6例患者临床均有癫痫病史。组织学示7例均存在类似少突胶质细胞瘤的区域,其中2例可见细胞围绕血管呈假菊形团样排列,2例局部出现细胞多形性,所有病例均可见钙化及毛细血管网形成。免疫表型:GFAP及Olig-2阳性,IDH1阴性,均出现特征性CD34弥漫阳性,其中5例BRAF阳性,Ki67增殖指数1%~5%。分子检测:患者均为IDH野生型、无1p/19q共缺失及CDKN2A/B缺失,其中5例为BRAF V600E突变型,2例有FGFR分子改变。随访5~48个月,7例患者均存活,5例无复发,2例肿瘤出现复发。结论PLNTY作为罕见的低级别神经上皮肿瘤,临床及病理医师应掌握其诊断要点与鉴别诊断,以避免误、漏诊。展开更多
Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination str...Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.展开更多
文摘目的探讨青少年多形性低级别神经上皮肿瘤(polymorphous low-grade neuroepithelial tumor of the young,PLNTY)的临床病理特征、诊断、鉴别诊断及预后。方法收集7例PLNTY患者临床及影像学资料,采用HE染色进行形态学观察,应用免疫组化EnVision法检测CD34、BRAF、IDH1、GFAP、Ki67等蛋白的表达。运用荧光定量PCR检测BRAF基因突变,采用FISH检测CDKN2A/B缺失及1p/19q共缺失,并对部分病例行NGS检测。结果7例患者中男性6例,女性1例,年龄8~29岁,中位年龄22岁,肿瘤位于颞叶5例,左侧岛叶及前颞叶1例,额颞叶1例。其中6例患者临床均有癫痫病史。组织学示7例均存在类似少突胶质细胞瘤的区域,其中2例可见细胞围绕血管呈假菊形团样排列,2例局部出现细胞多形性,所有病例均可见钙化及毛细血管网形成。免疫表型:GFAP及Olig-2阳性,IDH1阴性,均出现特征性CD34弥漫阳性,其中5例BRAF阳性,Ki67增殖指数1%~5%。分子检测:患者均为IDH野生型、无1p/19q共缺失及CDKN2A/B缺失,其中5例为BRAF V600E突变型,2例有FGFR分子改变。随访5~48个月,7例患者均存活,5例无复发,2例肿瘤出现复发。结论PLNTY作为罕见的低级别神经上皮肿瘤,临床及病理医师应掌握其诊断要点与鉴别诊断,以避免误、漏诊。
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82172653 and 82472728)the Key Project of Developmental Biology and Breeding from Hunan Province(Grant No.2022XKQ0205)+1 种基金the Research Team for Reproduction Health and Translational Medicine of Hunan Normal University(Grant No.2023JC101)the Natural Science Foundation of Hunan Province(Grant No.2025JJ80150).
文摘Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.
