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VPS33B suppresses lung adenocarcinoma metastasis and chemoresistance to cisplatin

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Genes & Diseases 2021年第3期8卷 307-319页

作者： Zhen Liu Jiahao Liu Yang Li Hao Wang Zixi Liang xiaojie deng Qiaofen Fu Weiyi Fang Ping Xu Affiliated Cancer Hospital&Institute of Guangzhou Medical University Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and DegradationState Key Laboratory of Respiratory DiseaseSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhouGuangdong Province510095PR China Cancer Center Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouGuangdong Province510310PR China Cancer Institute School of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong Province510515PR China Respiratory Department Peking University Shenzhen HospitalShenzhenGuangdong Province518034PR China

The presence of VPS33B in tumors has rarely been *** VPS33B protein expression is an unfavorable factor that promotes the pathogenesis of lung adenocar-cinoma(LUAD).Overexpressed VPS33B was shown to reduce the migration,invasion,metas-tasis,and chemoresistance of LUAD cells to cisplatin(DDP)in vivo and in *** analyses have indicated that VPS33B first suppresses epidermal growth factor receptor(EGFR)Ras/ERK signaling,which further reduces the expression of the oncogenic factor ***-regulated c-Myc expression reduces the rate at which it binds the p53 promoter and weakens its transcription inhibition;therefore,decreased C-Myc stimulates p53 expression,leading to decreased epithelial-to-mesenchymal transition(EMT)***1 has been shown to be an unfavorable indicator of non-small-cell lung cancer(NSCLC).Here,NESG1 Was identified as an interactive protein of *** addition,NESG1 was found to exhibit mutual stimulation with VPS33B via reduced RAS/ERK/c-Jun-mediated transcription *** of NESG1 activated EGFR/Ras/ERK/c-Myc signaling and further downregulated p53 expression,which thus activated EMT signaling and promoted LUAD migration and ***,we observed that nicotine suppressed VPS33B expression by inducing PI3K/AKT/c-Jun-mediated transcription *** study demonstrates that VPS33B as a tumor suppressor is signif-icantly involved in the pathogenesis of LUAD.

关键词： Chemoresistance Lung adenocarcinoma Metastasis Nicotine VPS33B

Enzyme-linked immunosorbent assays for quantification of MMAE-conjugated ADCs and total antibodies in cynomolgus monkey sera

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Journal of Pharmaceutical Analysis 2022年第4期12卷 645-652页

作者： Min Pei Tingting Liu Lu Ouyang Jianhua Sun xiaojie deng Xiaomin Sun Wei Wu Peng Huang Yi-Li Chen Xiaorong Tan Xiaoyue Liu Peng Zhu Yongzhen Liu Deheng Wang Junliang Wu Qi Wang Guifeng Wang Likun Gong Qiuping Qin Chunhe Wang Biotherapeutics Discovery Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Pharmacy University of Chinese Academy of SciencesBeijing100049China Center for Drug Safety Evaluation and Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China Research and Development Center Dartsbio Pharmaceuticals Ltd.ZhongshanGuangdong528400China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdong528400China School of Pharmacy Shanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghai201203China

Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical *** this study,we report the generation of a monoclonal antibody against monomethyl auristatin E(MMAE)and the development,validation,and application of sensitive and high-throughput enzyme-linked immunosorbent assays(ELISA)to measure the concentrations of MMAE-conjugated ADCs and total antibodies(tAb,antibodies in ADC plus unconjugated antibodies)in cynomolgus monkey *** assays were successfully applied to in vitro plasma stability and pharmacokinetic(PK)studies of SMADC001,an MMAE-conjugated ADC against trophoblast cell surface antigen 2(TROP-2).The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit,Lys(m-dPEG24)-Cit,and Val-Cit *** developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD450 values,with R2 at 1.000,and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL,respectively;the intra-and inter-assay accuracy bias%ranged from -12.2% to -5.2%,precision ranged from -12.4% to -1.4%,and the relative standard deviation(RSD)was less than 6.6% and 8.7%,*** total error was less than 20.4%.The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters,which suggested that these can be applied to quantify MMAE-conjugated ADCs,as well as in PK ***,these assays can be easily adopted for development of other similar immunoassays.

关键词： Monomethyl auristatin E Antibody-drug conjugates Pharmacokinetics Trophoblast cell surface antigen 2

Development and validation of a bridging electrochemiluminescent assay for the detection of antibodies against a chimeric therapeutic antibody in human serum

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Development and validation of a bridging electrochemilumines...

Development and validation of a competitive electrochemiluminescent assay for the detection of neutralizing antibodies against a therapeutic antibody in human serum

中国毒理学会药物毒理与安全性评价学术大会（2019年）暨粤港澳大湾区生物医药产业第一届高峰论坛

作者： Tingting Liu Wenjing Fang xiaojie deng Likun Gong Jin Ren Qiuping Qin Department of Immunoassay and Immunochemistry Center for Drug Safety Evaluation and Research(CDSER)State Key Laboratory of New Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences

Background All therapeutic antibodies have the potential to elicit anti-drug antibody(ADA)responses in *** can affect pharmacokinetics(PK),pharmacodynamics(PD),efficacy,safety,and bioanalytical assay *** aimed to develop and validate a bridging electrochemiluminescent assay(Bridging ECLA) coupled with affinity capture elution(ACE) for the detection of antibodies against a chimeric therapeutic antibody in human *** We raised antisera from cynomolgus monkeys by immunizing the animals with the drug through a subcutaneous *** obtained positive polyclonal antibodies served as a source of standards and quality controls applied in the assay development and *** Bridging ECLA was constructed with self-made biotinylated and ruthenium-labeled forms of the therapeutic *** was used to reduce drug interference in the *** ACE treatment,anti-drug antibodies were first captured in solution by a combination of biotinylated and ruthenium-labeled drug molecules,and then bound to solid-phased streptavidin via a Meso Scale Discovery(MSD) plate and detected by *** development,the method was further validated in the forms of a screening assay,a confirmation assay and a titration *** screening assay was used to identify samples with the ratio of ECL signal/background signal(SB) no less than the screening cut point(SCP).The screening assay positive samples were then submitted to the confirmation assay for specificity of antibodies for the therapeutic *** with percent of inhibition rate values(IR%) higher than the confirmation cut point(CCP) were subjected to the titration assay for *** method validation parameters included the determination of SCP,CCP and TCP,assay sensitivity and precision,drug tolerance,selectivity,specificity,ranges of assay quality controls,assessment of Hook effect as well as sample *** No matrix effect was observed with the use of 5-fol

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Development and validation of a competitive electrochemilumi...

黔东北石阡香树园剖面志留系香树园组生屑滩微相

中国毒理学会药物毒理与安全性评价学术大会（2019年）暨粤港澳大湾区生物医药产业第一届高峰论坛

Background Therapeutic antibodies are large molecules able to elicit anti-drug antibody(ADA)*** responses may result in the loss of therapeutic efficacy due to the formation of neutralization antibody(NAbs).Therefore,NAb detection is important for interpretation of efficacy and safety data of therapeutic antibodies in *** aimed to develop and validate a competitive electrochemiluminescent assay by using Meso Scale Discovery(MSD) platform for the detection of neutralizing antibodies against a therapeutic antibody in human *** The positive antibody of a neutralizing property was obtained from our sponsor and served as a source of quality controls applied in the assay development and validation *** chemiluminescent method was made by utilizing self-made ruthenium-labeled therapeutic antibody and *** dissociation was conducted to reduce possible drug interference in serum *** the samples did not have Nabs,the ruthenium-labeled drug bound to the EGFR coated a MSD *** the samples contained NAb,it competed with the ruthenium-labeled antibody to bind to the *** electrochemiluminescence values were measured at 620 *** development,the method was validated extensively,including the neutralization cut point(NCP),assay sensitivity,precision,drug tolerance,analogue interference,ranges of assay quality controls as well as sample *** No matrix effect was observed with the use of 5-fold diluted human *** NCP was 9.3%(IR%).Intra-and inter-assay coefficients of variation of low,medium,and high quality controls were no more than 19.1%.Inter-assay accuracy of the low,medium,and high quality controls was good as the IR% values of the controls were all within the established target *** tolerance at 10μg/mL and 5 μg/mL of the tested positive antibody was>100 μg/mL and> 1.563 μg/mL of the drug,*** positive antibody in human serum was stable after 5 freeze/thaw cycles,at RT or at 2-8℃fo

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微体古生物学报 2016年第1期33卷 94-104页

作者：倪超李越邓小杰中国科学院资源地层学与古地理学重点实验室中国科学院南京地质古生物研究所南京210008 中国科学院大学北京100049 贵州省地质调查研究院贵阳550004

奥陶纪末赫南特冰期和生物大灭绝事件结束后,扬子陆表海区志留纪兰多维列世早期的海进序列伴随着生物逐渐复苏的过程。在黔中古陆北缘石阡一带鲁丹晚期至晚埃隆早期的香树园组属近岸浅水带灰岩—碎屑岩沉积区。石阡县城北香树园剖面的... 详细信息

奥陶纪末赫南特冰期和生物大灭绝事件结束后,扬子陆表海区志留纪兰多维列世早期的海进序列伴随着生物逐渐复苏的过程。在黔中古陆北缘石阡一带鲁丹晚期至晚埃隆早期的香树园组属近岸浅水带灰岩—碎屑岩沉积区。石阡县城北香树园剖面的香树园组以灰岩为主,夹含少量粉砂质、泥质陆源碎屑岩,频繁出现含丰富壳相后生动物化石碎片形成的薄层滩相单元。与大颗粒壳相化石为主形成的各类生物层状礁类似,生屑滩多为动荡流水改造的后生动物碎片近源沉积。滩相具有较高的生物多样性和化石丰度,是奥陶纪末生物礁复苏前浅海暖水区广泛分布的生态单元。此地香树园组缺少粗砂级以上的陆源碎屑颗粒,也无岩屑颗粒,指示沉积物具有较高的成熟度。推测黔中古陆靠近石阡的部位已经夷平,黔东北浅海区在香树园组灰岩沉积期具有偏低的海水浑浊度和碎屑岩沉积速率,生屑滩相灰岩单元是在正常盐度和高清洁度的环境下堆积的,附近有粉砂-泥级颗粒注入,但无大型河流输入丰富的淡水和陆源粗碎屑。

关键词：生物滩香树园组兰多维列阶志留系石阡黔东北

黔东北石阡香树园剖面“龙马溪组”灰岩中的生物多样性

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微体古生物学报 2015年第1期32卷 105-113页

作者：倪超李越邓小杰中国科学院南京地质古生物研究所南京210008 中国科学院大学北京100049 贵州省地质调查研究院贵阳550004

黔东北石阡香树园剖面志留系底部的"龙马溪组"沉积于上扬子区黔中古陆近岸浅海带,与其它远岸相的龙马溪组下部的黑色笔石页岩差异很大,厚度仅3.3m,为黄色、黄绿色含粉砂质页岩夹6个灰岩薄层或透镜体。从灰岩中识别出叠层石、海绵、床板... 详细信息

黔东北石阡香树园剖面志留系底部的"龙马溪组"沉积于上扬子区黔中古陆近岸浅海带,与其它远岸相的龙马溪组下部的黑色笔石页岩差异很大,厚度仅3.3m,为黄色、黄绿色含粉砂质页岩夹6个灰岩薄层或透镜体。从灰岩中识别出叠层石、海绵、床板珊瑚、四射珊瑚、三叶虫、介形类、腕足类和棘皮类等化石碎片类型,指示了奥陶纪末赫南特冰期结束后,适宜于各类底栖生物生长的生态条件在近岸区最早出现。

关键词：生物多样性 “龙马溪组” 志留系底部石阡黔东北

miR-1254 as a negative regulator of nicotine induced by NESG1 suppresses nasopharyngeal carcinoma metastasis through inactivating a HDGF/DDX5/β-catenin/TCF4/ZEB1/cMyc feedback loop

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miR-1254 as a negative regulator of nicotine induced by NESG...

过表达丝裂原诱导基因6通过抑制内质网应激减少棕榈酸诱导的肝细胞脂质蓄积

2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青年科学家论坛

作者： xiaojie deng Zhen Liu Qiaofen Fu Yuantong deng Chao Cheng Yiyu Chen Xian Lin Yiyi Liu Zixi Liang Weiyi Fang Cancer Center Integrated Hospital of Traditional Chinese MedicineSouthern Medical University Key Laboratory of Protein Modification and Degradation School of Basic Medical Sciences Department of Cancer Biotherapy Center Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province) Pediatric Center of Zhujiang Hospital Southern Medical University

Here we report that miR-1254 suppresses nasopharyngeal carcinoma(NPC) cell migration,invasion, and metastasis. Mechanistic studies demonstrate that miR-1254 directly targets the oncogenic protein hepatoma derived growth factor(HDGF) and further suppresses DEAD-box helicase 5(DDX5), an oncogenic protein is identified to interact with HDGF. Subsequently, reduced DDX5 downregulates β-catenin/TCF4/ZEB1 signaling, which thus blocks epithelial–mesenchymal transition(EMT) signal. Interestingly, we also observe that ZEB1 interacts with HDGF and directly induces its expression by combining the promoter region of HDGF and thus forms a feedback loop of HDGF/DDX5/β-catenin/TCF4/ZEB1. Furthermore, we find that tumor suppressor NESG1 was observed to be suppressed by nicotine via activating PI3 K/Akt/C-Jun and thus suppresses HDGF/DDX5/β-catenin/TCF4/ZEB1 signal by inactivating PI3 K/AKT/c-Myc-mediated transcription suppression of miR-1254. Further, miR-1254 expression was also reduce by nicotine. In clinical samples, reduced miR-1254 as an unfavorable prognosis factor is inversely correlated with the expression of HDGF. These results provide a novel mechanism by which miR-1254 induced by NESG1 directly targets HDGF/DDX5/β-catenin/TCF4/ZEB1 feedback loop ultimately inhibiting EMT signaling-induced NPC metastasis.

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中国病理生理杂志 2024年第7期40卷 1213-1221页

作者：王甜邓小杰蔡梦茵梁华中山大学附属第三医院广东广州510630 南方医科大学顺德医院(佛山市顺德区第一人民医院) 广东佛山528300

目的:探讨过表达丝裂原诱导基因6(MIG6)通过调节肝细胞内质网应激影响棕榈酸(PA)诱导的肝细胞脂肪变性的作用及其机制。方法:通过使用高脂饲料喂养20只C57BL/6J小鼠26周构建小鼠非酒精性脂肪性肝炎模型,将小鼠随机分为2组:普通饮食对照... 详细信息

目的:探讨过表达丝裂原诱导基因6(MIG6)通过调节肝细胞内质网应激影响棕榈酸(PA)诱导的肝细胞脂肪变性的作用及其机制。方法:通过使用高脂饲料喂养20只C57BL/6J小鼠26周构建小鼠非酒精性脂肪性肝炎模型,将小鼠随机分为2组:普通饮食对照组和高脂饮食组,每组10只,留取其肝脏进行后续实验。使用PA诱导HepG2细胞和AML12细胞的脂质蓄积,将细胞分为2组:BSA(10%BSA)组和PA(500μmol/L)组。通过给HepG2细胞和AML12细胞分别转染人和小鼠MIG6过表达质粒诱导肝细胞MIG6过表达,根据不同的干预条件分为4组:阴性对照质粒+10%BSA(negative+BSA)组、MIG6过表达质粒+10%BSA(MIG6+BSA)组、阴性对照质粒+PA(negative+PA)组和MIG6过表达质粒+PA(MIG6+PA)组,每组每次干预至少设3个生物学复孔。使用油红O染色评估肝细胞脂质蓄积情况;通过RT-qPCR检测肝组织MIG6的mRNA表达水平,Western blot检测肝细胞MIG6、脂肪酸合酶(FASN)和胆固醇调节元件结合蛋白1(SREBP1)等脂质合成相关分子及内质网应激标志物葡萄糖调节蛋白78(GRP78)和C/EBP同源蛋白(CHOP)的蛋白水平。结果:高脂饮食组小鼠肝组织甘油三酯含量增加,肝组织脂肪变性显著,MIG6的mRNA表达水平显著下调(P<0.01);PA干预促使肝细胞FASN、SREBP1、GRP78和CHOP蛋白水平升高,但是降低MIG6蛋白水平(P<0.01)。转染MIG6过表达质粒显著增加肝细胞MIG6蛋白水平,并抑制GRP78和CHOP的表达(P<0.01),显著减轻PA诱导的肝细胞脂质蓄积并抑制FASN和SREBP1的表达(P<0.01)。以上结果表明过表达MIG6可抑制PA诱导的肝细胞内质网应激并减少其脂质蓄积。结论:过表达MIG6具有抑制内质网应激进而抑制肝细胞脂质蓄积的作用。

关键词：丝裂原诱导基因6 内质网应激非酒精性脂肪性肝病脂质蓄积

哮喘患者外周血Rho激酶及CD4^+ CD25^+调节性T细胞测定

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中南大学学报（医学版） 2014年第6期39卷 577-581页

作者：邓晓杰朱洪志吴尚洁中南大学湘雅二医院呼吸科长沙410011

目的:比较不同研究对象外周血Rho激酶及CD4+CD25+调节性T细胞的表达规律,探讨Rho激酶和CD4+CD25+调节性T细胞在哮喘患者中的变化和相关性。方法:选取中、重度哮喘患者16例,健康对照组14例,通过年龄、性别配对,ELISA测定所有研究对象血清... 详细信息

目的:比较不同研究对象外周血Rho激酶及CD4+CD25+调节性T细胞的表达规律,探讨Rho激酶和CD4+CD25+调节性T细胞在哮喘患者中的变化和相关性。方法:选取中、重度哮喘患者16例,健康对照组14例,通过年龄、性别配对,ELISA测定所有研究对象血清Rho激酶水平,流式细胞仪测定CD4+CD25+调节性T细胞水平,所有研究对象经肺功能仪测定肺功能。结果:哮喘组外周血Rho激酶表达水平高于对照组(P0.05);两组外周血CD4+CD25+调节性T细胞水平与肺功能FEV1%呈轻度正相关关系(r=0.380,P=0.038);两组外周血Rho激酶与CD4+CD25+调节性T细胞水平无相关关系(r=-0.438,P>0.05)。结论:哮喘患者外周血Rho激酶水平升高,CD4+CD25+调节性T细胞水平降低,可能在哮喘发病过程中起一定的作用。

关键词：哮喘 Rho激酶 CD4+CD25+调节性T细胞第1秒用力呼气容积