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
BACKGROUND Gastrointestinal stromal tumors(GISTs)are generally characterized by driver mutations in KIT or PDGFRA.However,the molecular landscape of wild-type GISTs remains complex,posing significant therapeutic chall...BACKGROUND Gastrointestinal stromal tumors(GISTs)are generally characterized by driver mutations in KIT or PDGFRA.However,the molecular landscape of wild-type GISTs remains complex,posing significant therapeutic challenges.Recent evidence has indicated alterations in FGFR2 as potential oncogenic drivers in patients with various cancers.However,the role of these drivers in GIST pathogenesis remains underexplored.CASE SUMMARY We retrospectively evaluated two patients with GIST,diagnosed between August 2021 and July 2022,harboring FGFR2 mutations through hybrid capture-based next-generation sequencing(NGS).We analyzed their clinicopathological characteristics,treatment response,and long-term follow-up data.Both patients,a 47-year-old man(case 1)and a 43-year-old woman(case 2),underwent successful surgical resection and received adjuvant imatinib therapy.They achieved sustained remission with a median follow-up of 28 months.Notably,the NGS revealed novel FGFR2 rearrangements,an FGFR2-CIT/intergenic-FGFR2 fusion in case 1 and FGFR2-CAMK2G/FGFR2-VCL fusions in case 2 without canonical KIT or PDGFRA mutations.Both patients exhibited a favorable response to standard imatinib treatment.CONCLUSION Our findings provided preliminary evidence that novel FGFR2 fusions might act as primary oncogenic drivers in a rare subset of KIT/PDGFRA wild-type GISTs.These cases highlight the importance for comprehensive genomic profiling and suggest that fibroblast growth factor receptor-targeted inhibitors could be a potential therapeutic strategy for advanced or imatinib-resistant diseases,warranting further investigation in larger cohorts.展开更多
Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult t...Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.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.
文摘BACKGROUND Gastrointestinal stromal tumors(GISTs)are generally characterized by driver mutations in KIT or PDGFRA.However,the molecular landscape of wild-type GISTs remains complex,posing significant therapeutic challenges.Recent evidence has indicated alterations in FGFR2 as potential oncogenic drivers in patients with various cancers.However,the role of these drivers in GIST pathogenesis remains underexplored.CASE SUMMARY We retrospectively evaluated two patients with GIST,diagnosed between August 2021 and July 2022,harboring FGFR2 mutations through hybrid capture-based next-generation sequencing(NGS).We analyzed their clinicopathological characteristics,treatment response,and long-term follow-up data.Both patients,a 47-year-old man(case 1)and a 43-year-old woman(case 2),underwent successful surgical resection and received adjuvant imatinib therapy.They achieved sustained remission with a median follow-up of 28 months.Notably,the NGS revealed novel FGFR2 rearrangements,an FGFR2-CIT/intergenic-FGFR2 fusion in case 1 and FGFR2-CAMK2G/FGFR2-VCL fusions in case 2 without canonical KIT or PDGFRA mutations.Both patients exhibited a favorable response to standard imatinib treatment.CONCLUSION Our findings provided preliminary evidence that novel FGFR2 fusions might act as primary oncogenic drivers in a rare subset of KIT/PDGFRA wild-type GISTs.These cases highlight the importance for comprehensive genomic profiling and suggest that fibroblast growth factor receptor-targeted inhibitors could be a potential therapeutic strategy for advanced or imatinib-resistant diseases,warranting further investigation in larger cohorts.
基金supported by the National Key R&D Program of China(2023YFC3603400)the National Natural Science Foundation of China(82072506,92268115)+2 种基金the Hunan Provincial Science Fund for Distinguished Young Scholars(2024JJ2089)the Science and Technology Innovation Program of Hunan Province(2021RC3025)the National Clinical Research Center for Geriatric Disorders(Xiangya Hospital,2021KF02).
文摘Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.
