陕北白绒山羊是我国特色绒肉兼用型山羊品种,其生长性状遗传改良进程相对滞后且表型稳定性不足,亟待筛选与生长性状关联的高效分子标记以加速陕北白绒山羊高效选育。成纤维细胞生长因子受体1(FGFR1)作为调控细胞增殖与分化的关键基因,...陕北白绒山羊是我国特色绒肉兼用型山羊品种,其生长性状遗传改良进程相对滞后且表型稳定性不足,亟待筛选与生长性状关联的高效分子标记以加速陕北白绒山羊高效选育。成纤维细胞生长因子受体1(FGFR1)作为调控细胞增殖与分化的关键基因,其遗传变异可能影响山羊生长性能。因此,本研究旨在探究FGFR1在陕北白绒山羊各组织中的表达水平,分析FGFR1 Indel变异与陕北白绒山羊生长性状的相关性。以1332只成年陕北白绒山羊为对象,采集耳组织与14种组织样本,通过PCR扩增和琼脂糖凝胶电泳检测FGFR1基因InDel分型,利用qRT-PCR分析组织表达谱,并通过一般线性模型分析基因型与生长性状的关联性。结果显示,FGFR1基因在各组织中广泛表达,其中睾丸和大脑表达水平显著高于其它组织(P<0.05);群体遗传变异检测到P5位点存在22 bp InDel多态性,形成纯合插入型(Ⅱ,220 bp)、杂合型(ID,220/198 bp)及纯合缺失型(DD,198 bp)三种基因型,等位基因频率分别为0.822(I)和0.178(D),群体多态信息含量(PIC)为0.25,属中度多态(0.25≤PIC≤0.5);关联分析结果显示,II和ID基因型个体的胸围显著大于DD型(P<0.05),而ID型绒细度显著低于其他基因型(P<0.05)。综上所述,FGFR1基因22 bp InDel变异可作为陕北白绒山羊胸围与绒细度的候选分子标记。本研究为山羊分子标记辅助选择提供了理论依据,对加快绒山羊遗传改良进程具有重要意义。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
文摘陕北白绒山羊是我国特色绒肉兼用型山羊品种,其生长性状遗传改良进程相对滞后且表型稳定性不足,亟待筛选与生长性状关联的高效分子标记以加速陕北白绒山羊高效选育。成纤维细胞生长因子受体1(FGFR1)作为调控细胞增殖与分化的关键基因,其遗传变异可能影响山羊生长性能。因此,本研究旨在探究FGFR1在陕北白绒山羊各组织中的表达水平,分析FGFR1 Indel变异与陕北白绒山羊生长性状的相关性。以1332只成年陕北白绒山羊为对象,采集耳组织与14种组织样本,通过PCR扩增和琼脂糖凝胶电泳检测FGFR1基因InDel分型,利用qRT-PCR分析组织表达谱,并通过一般线性模型分析基因型与生长性状的关联性。结果显示,FGFR1基因在各组织中广泛表达,其中睾丸和大脑表达水平显著高于其它组织(P<0.05);群体遗传变异检测到P5位点存在22 bp InDel多态性,形成纯合插入型(Ⅱ,220 bp)、杂合型(ID,220/198 bp)及纯合缺失型(DD,198 bp)三种基因型,等位基因频率分别为0.822(I)和0.178(D),群体多态信息含量(PIC)为0.25,属中度多态(0.25≤PIC≤0.5);关联分析结果显示,II和ID基因型个体的胸围显著大于DD型(P<0.05),而ID型绒细度显著低于其他基因型(P<0.05)。综上所述,FGFR1基因22 bp InDel变异可作为陕北白绒山羊胸围与绒细度的候选分子标记。本研究为山羊分子标记辅助选择提供了理论依据,对加快绒山羊遗传改良进程具有重要意义。
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.
