The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In ...The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.展开更多
Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed ...Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.展开更多
目的矽肺是一种以肺纤维化为病理特征的疾病,其发病机制仍不完全清楚,外周血单核细胞表型偏移失衡在肺纤维化病理进展中发挥着重要作用。文中旨在研究石英诱导小鼠矽肺（pneumosilicosis）模型中循环单核细胞亚群在不同病理阶段的变化特...目的矽肺是一种以肺纤维化为病理特征的疾病,其发病机制仍不完全清楚,外周血单核细胞表型偏移失衡在肺纤维化病理进展中发挥着重要作用。文中旨在研究石英诱导小鼠矽肺（pneumosilicosis）模型中循环单核细胞亚群在不同病理阶段的变化特点,探讨其动态变化与肺炎症损伤和纤维化的关系。方法 100只雄性C57BL/6小鼠（18～22 g）随机数字表法分为等渗盐水组和石英组,石英组滴注吸入40 m L石英混悬液（100 mg/kg）,等渗盐水组滴注吸入相同体积无菌等渗盐水。经术后第1、3、7、14和28天应用流式细胞术检测循环单核细胞亚群变化;常规支气管肺泡灌洗术后进行炎症细胞分类计数;HE染色和苦味酸天狼星红染色检测小鼠肺组织炎症评分及胶原容积分数。结果病理染色显示,造模后第7天,小鼠肺组织可见明显的矽结节;与等渗盐水组相比,石英组小鼠肺组织炎症评分、胶原容积分数显著升高[（1.400±0.089）vs（0.920±0.049）、（1.950±0.065）vs（0.525±0.048）,P〈0.01],并持续到第28天[（1.520±0.136）vs（0.800±0.089）,（5.300±0.776）vs（0.850±0.050）,P〈0.01];与相应时间点等渗盐水组比较,石英组BAFL细胞总数于第1天开始升高[（7.693±2.495）vs（2.008±0.901）,P〈0.01],在第3天达到高峰[（13.346±3.563）vs（1.044±0.695）],随后第7、14、28天呈现递减趋势,但仍都高于等渗盐水组（P〈0.01）;石英组BALF巨噬细胞绝对值在第3天时显著高于等渗盐水组（6.821±2.627 vs 0.980±0.663,P〈0.01）,并在第7天维持于高水平状态[（6.697±1.864）vs（1.225±0.601）,P〈0.01],后呈下降趋势,但第14及28天巨噬细胞绝对值仍高于等渗盐水组（P〈0.01）;石英组BALF中性粒细胞绝对值在第1、3、7及14天都显著高于等渗盐水组（P〈0.01）,且呈现出逐渐下降的趋势,在第28天与等渗盐水组差异无统计学意义（P〉0.05）。石英组小鼠Ly6Chi单核细胞亚群占比在所有检测时间点均显著高于等渗盐水组（P〈0.01）,其中第7天达到高峰[（78.300±2.517）vs（58.750±2.386）,P〈0.01];Ly6Clo亚群比例变化与之相反。第7天和第28天的小鼠Ly6Chi单核细胞亚群占比与相应时间点的IS及CVF值呈正相关（P〈0.01）。结论循环Ly6Chi和Ly6Clo单核细胞亚群占比在石英诱导的小鼠矽肺的不同病理时期呈现动态变化,持续性的Ly6Chi单核细胞亚群占比升高可能与矽肺的急慢性炎症及后期的纤维化程度存在密切的联系。展开更多
The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member ...The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uP AR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasivecarcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.展开更多
基金supported by the National Key Research and Development Plan of China(No.2018YFA0107802 to Xiaojian Sun,Nos.2018YFA0107200 and 2018YFA0800203 to Lan Wang)the General Program of the National Natural Science Foundation of China(Nos.81470316 and 81670094 to Xiaojian Sun,No.81972339 to Zhe Bao Wu,Nos.81570122 and 81770205 to Jinyan Huang,Nos.81670122 and 81970150 to Lan Wang)+5 种基金the National Research Center for Translational Medicine(Shanghai)grant(No.NRCTM(SH)-2019-05 to Zhe Bao Wu)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(No.20152506 to Xiaojian Sun)Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01 to Saijuan Chen and Xiaojian Sun)Innovative Research Team of High-level Local Universities in Shanghai(to Weili Zhao and Xiaojian Sun)the Samuel Waxman Cancer Research Foundationthe Shanghai Guangci Translational Medical Research Development Foundation.
文摘The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.
基金supported by the Postdoctoral Research Funds of Hebei Medical University(30705010016-3759)Natural Science Foundation of China(32272328)+4 种基金Natural Science Foundation of Hebei Province(B2022321001)National Key Research Project of Hebei Province(20375502D)Postdoctoral Research Project of Hebei Province(B2022003031)Science and Technology Research Program of Hebei Provincial Colleges(QN2023229)Hebei Provincial Key Laboratory of Nutrition and Health(2023YDYY-KF05)。
文摘Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.
文摘目的矽肺是一种以肺纤维化为病理特征的疾病,其发病机制仍不完全清楚,外周血单核细胞表型偏移失衡在肺纤维化病理进展中发挥着重要作用。文中旨在研究石英诱导小鼠矽肺（pneumosilicosis）模型中循环单核细胞亚群在不同病理阶段的变化特点,探讨其动态变化与肺炎症损伤和纤维化的关系。方法 100只雄性C57BL/6小鼠（18～22 g）随机数字表法分为等渗盐水组和石英组,石英组滴注吸入40 m L石英混悬液（100 mg/kg）,等渗盐水组滴注吸入相同体积无菌等渗盐水。经术后第1、3、7、14和28天应用流式细胞术检测循环单核细胞亚群变化;常规支气管肺泡灌洗术后进行炎症细胞分类计数;HE染色和苦味酸天狼星红染色检测小鼠肺组织炎症评分及胶原容积分数。结果病理染色显示,造模后第7天,小鼠肺组织可见明显的矽结节;与等渗盐水组相比,石英组小鼠肺组织炎症评分、胶原容积分数显著升高[（1.400±0.089）vs（0.920±0.049）、（1.950±0.065）vs（0.525±0.048）,P〈0.01],并持续到第28天[（1.520±0.136）vs（0.800±0.089）,（5.300±0.776）vs（0.850±0.050）,P〈0.01];与相应时间点等渗盐水组比较,石英组BAFL细胞总数于第1天开始升高[（7.693±2.495）vs（2.008±0.901）,P〈0.01],在第3天达到高峰[（13.346±3.563）vs（1.044±0.695）],随后第7、14、28天呈现递减趋势,但仍都高于等渗盐水组（P〈0.01）;石英组BALF巨噬细胞绝对值在第3天时显著高于等渗盐水组（6.821±2.627 vs 0.980±0.663,P〈0.01）,并在第7天维持于高水平状态[（6.697±1.864）vs（1.225±0.601）,P〈0.01],后呈下降趋势,但第14及28天巨噬细胞绝对值仍高于等渗盐水组（P〈0.01）;石英组BALF中性粒细胞绝对值在第1、3、7及14天都显著高于等渗盐水组（P〈0.01）,且呈现出逐渐下降的趋势,在第28天与等渗盐水组差异无统计学意义（P〉0.05）。石英组小鼠Ly6Chi单核细胞亚群占比在所有检测时间点均显著高于等渗盐水组（P〈0.01）,其中第7天达到高峰[（78.300±2.517）vs（58.750±2.386）,P〈0.01];Ly6Clo亚群比例变化与之相反。第7天和第28天的小鼠Ly6Chi单核细胞亚群占比与相应时间点的IS及CVF值呈正相关（P〈0.01）。结论循环Ly6Chi和Ly6Clo单核细胞亚群占比在石英诱导的小鼠矽肺的不同病理时期呈现动态变化,持续性的Ly6Chi单核细胞亚群占比升高可能与矽肺的急慢性炎症及后期的纤维化程度存在密切的联系。
基金Supported by Copenhagen University Hospital(Rigshospitalets Forskningspuljer)The Danish National Research Foundation(Danish-Chinese Centre for Proteases and Cancer)Harboefonden,Torben og Alice Frimodts Fond,Fabrikant Einar Willumsens Mindelegat,Holger Rabitz and hustrus Legat,The Lundbeck Foundation.
文摘The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uP AR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasivecarcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.
