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Systematic screening for potential therapeutic targets in osteosarcoma through a kinome-wide CRISPR-Cas9 library

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Cancer Biology & Medicine 2020年第3期17卷 782-794页

作者： Yuanzhong Wu Liwen Zhou Zifeng Wang Xin Wang Ruhua Zhang Lisi Zheng Tiebang Kang Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China

Objective:Osteosarcoma is the most common primary malignant bone tumor.However,the survival of patients with osteosarcoma has remained unchanged during the past 30 years,owing to a lack of efficient therapeutic targets.Methods:We constructed a kinome-targeting CRISPR-Cas9 library containing 507 kinases and 100 nontargeting controls and screened the potential kinase targets in osteosarcoma.The CRISPR screening sequencing data were analyzed with the Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout(MAGeCK)Python package.The functional data were applied in the 143B cell line through lenti-CRISPR-mediated gene knockout.The clinical significance of kinases in the survival of patients with osteosarcoma was analyzed in the R2:Genomics Analysis and Visualization Platform.Results:We identified 53 potential kinase targets in osteosarcoma.Among these targets,we analyzed 3 kinases,TRRAP,PKMYT1,and TP53RK,to validate their oncogenic functions in osteosarcoma.PKMYT1 and TP53RK showed higher expression in osteosarcoma than in normal bone tissue,whereas TRRAP showed no significant difference.High expression of all 3 kinases was associated with relatively poor prognosis in patients with osteosarcoma.Conclusions:Our results not only offer potential therapeutic kinase targets in osteosarcoma but also provide a paradigm for functional genetic screening by using a CRISPR-Cas9 library,including target design,library construction,screening workflow,data analysis,and functional validation.This method may also be useful in potentially accelerating drug discovery for other cancer types.

关键词： Osteosarcoma kinase CRISPR-Cas9 library TRRAP PKMYT1 TP53RK

RMI2 plays crucial roles in growth and metastasis of lung cancer

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Signal Transduction and Targeted Therapy 2020年第1期5卷 907-909页

作者： Weixiang Zhan Yina Liu Ying Gao Run Gong Wen Wang Ruhua Zhang Yuanzhong Wu Tiebang Kang Denghui Wei State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer Center510060 GuangzhouChina The Sixth Affiliated Hospital Sun Yat-sen University510000 GuangzhouChina Department of Abdominal Oncology The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University519000 ZhuhaiGuangdongChina

Dear Editor,Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death in the world,but its therapeutic targets are still being explored.Genome instability as a key hallmark of cancer not only contributes to cancer initiation and progression,1 but also creates vulnerabilities that are relatively specific to cancer cells,which may be potential therapeutic targets for cancer patients.During DNA Double-Strand Breaks(DSBs)repair,BTR(BLM-Topo IIIα-RMI1/RMI2)complex promotes the dissolution of double Holliday junctions to form non-crossover products and is often considered as a tumor suppressor.2 However,the function of each individual component of this BTR complex in cancer remains largely unknown.

关键词： cancer metastasis Lung

SUMOylation stabilizes hSSB1 and enhances the recruitment of NBS1 to DNA damage sites

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1516-1527页

作者： Liwen Zhou Lisi Zheng Kaishun Hu Xin Wang Ruhua Zhang Yezi Zou Li Zhong Shang Wang Yuanzhong Wu Tiebang Kang Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research CenterSun Yat-sen Memorial HospitalSun Yat‐sen UniversityGuangzhouChina

Human single-stranded DNA-binding protein 1(hSSB1)is required for the efficient recruitment of the MRN complex to DNA doublestrand breaks and is essential for the maintenance of genome integrity.However,the mechanism by which hSSB1 recruits NBS1 remains elusive.Here,we determined that hSSB1 undergoes SUMOylation at both K79 and K94 under normal conditions and that this modification is dramatically enhanced in response to DNA damage.SUMOylation of hSSB1,which is specifically fine-tuned by PIAS2α,and SENP2,not only stabilizes the protein but also enhances the recruitment of NBS1 to DNA damage sites.Cells with defective hSSB1 SUMOylation are sensitive to ionizing radiation,and global inhibition of SUMOylation by either knocking out UBC9 or adding SUMOylation inhibitors significantly enhances the sensitivity of cancer cells to etoposide.Our findings reveal that SUMOylation,as a novel posttranslational modification of hSSB1,is critical for the functions of this protein,indicating that the use of SUMOylation inhibitors(e.g.,2-D08 and ML-792)may be a new strategy that would benefit cancer patients being treated with chemo-or radiotherapy.

关键词： SSB1 damage NBS1

Mechanisms of Traditional Chinese Medicine Bushenantai granules(补肾安胎颗粒) in promoting angiogenesis at the maternal-fetal interface of recurrent spontaneous abortion mice

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Journal of Traditional Chinese Medicine 2021年第4期41卷 556-563页

作者： LI Yuanqi LI Weili YU Xinhui wu Hua WANG yuanzhong JIN Ya HAO Lele LIU Mingmin SONG Xiaoge Nanjing University of Chinese Medicine Nanjing 230023China Department of Obstetrics and Gynecology The First Affiliated Hospital of Anhui University of Traditional Chinese MedicineHefei 230000China Anhui University of Chinese Medicine Hefei 230000China

OBJECTIVE:To assess the effects of Bushenantai(BSAT)granule(补肾安胎颗粒)on angiogenesis-related factors[E2,P,and vascular endothelial growth factor(VEGF)]at the maternal-fetal interface of recurrent spontaneous abortion(RSA)mice,and to evaluate the role of BSAT in promoting angiogenesis at the maternal-fetal interface by influencing the expression of sex hormones,and VEGF.METHODS:A mouse model with normal pregnancy and another with Clark’s classic RSA were established.The RSA mice were randomly assigned to six groups:normal,model,progesterone,high-doseBSAT granule(BSAT-H),medium-dose-BSAT granule(BSAT-M),and low-dose-BSAT granule(BSAT-L)(n=10 for each group).The embryo loss rate and the histopathological changes in the decidual tissues were measured.Serum levels of estrogen(E2),progesterone(P),and VEGF were detected by enzyme-linked immunosorbent assay.The m RNA and protein expressions of estradiol receptor(ER),progesterone receptor(PR),VEGF,and vascular endothelial growth factor receptor 2(VEGFR2)in the decidual tissues were identified by immunohistochemistry,Western blotting,and quantitative reverse transcription polymerase chain reaction.RESULTS:The embryo loss rate in all groups that received BSAT treatment was reduced,while the number of blood vessels at decidual tissues was increased.The serum levels of E2,P and VEGF were elevated,and the m RNA and protein expressions of ER,PR,VEGF,and VEGFR2 in the decidual tissues were enhanced.CONCLUSION:BSAT can improve angiogenesis at the maternal-fetal interface and reduce the embryo loss rate,which may be associated with its ability to increase the serum levels of estrogen,progesterone,and VEGF,in addition to up-regulation of m RNA and protein expression of ER,PR,VEGF,and VEGFR2 in the decidual tissues.

关键词： abortion spontaneous progesterone vascular endothelial growth factor angiogenesis maternal-fetal interface Bushenantai granule

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X射线荧光光谱法测定镍烧结矿中10种组分

冶金分析 2023年第4期43卷 64-71页

作者：陈树伟宋元仲吴秀清广东广青金属科技有限公司

在高炉冶炼过程中，通过测定镍烧结矿的化学组分可以直观反馈炉况和产出铁水的质量。对镍烧结矿的化学组分进行测定时，由于缺少匹配的标准物质和合适的X射线荧光光谱法(XRF),目前行业内仍主要采用传统化学湿法进行测定，操作较为繁琐... 详细信息

在高炉冶炼过程中，通过测定镍烧结矿的化学组分可以直观反馈炉况和产出铁水的质量。对镍烧结矿的化学组分进行测定时，由于缺少匹配的标准物质和合适的X射线荧光光谱法(XRF),目前行业内仍主要采用传统化学湿法进行测定，操作较为繁琐且测定周期长。实验采用熔融制样-X射线荧光光谱法测定镍烧结矿中的10种组分(Ni、TFe、Cr、Mn、SiO2、CaO、MgO、Al2O3、P、TiO2)含量，探讨了熔剂、稀释比、脱模剂、熔融温度以及熔融时间对样品熔解和测定结果的影响。结果表明：在以无水四硼酸锂-碳酸锂(质量比为6∶1)作为熔剂、熔剂与样品的稀释比为20∶1、160 mg碘化铵试剂作为脱模剂、熔融温度为1 050℃的条件下熔制15 min,能够制成均匀、透明、无杂质的玻璃状样片。以普通烧结矿标准样品为主体，按一定比例添加镍标准溶液和高纯三氧化二铬试剂，配制11个具有一定含量梯度的校准样品用于建立校准曲线，能有效避免基体效应的干扰，所建立的各组分校准曲线的相关系数为0.999 6～1.000 0。方法用于镍烧结矿各组分的测定，结果的相对标准偏差(RSD,n=10)在0.07%～3.2%之间。对镍烧结矿标准样品和实际生产样品进行测定，测定结果与认定值、传统湿法测定值基本一致。采用实验方法测定镍烧结矿，对高炉冶炼工艺的提升具有较好的促进作用。

关键词：镍烧结矿 X射线荧光光谱法(XRF) 熔融制样基体效应镍铬主次组分

CRISPR/Cas9 screening identifies a kinetochore-microtubule dependent mechanism for Aurora-A inhibitor resistance in breast cancer

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Cancer Communications 2021年第2期41卷 121-139页

作者： Ailin Chen Shijun Wen Fang Liu Zijian Zhang Meiling Liu Yuanzhong Wu Bin He Min Yan Tiebang Kang Eric W-F Lam Zifeng Wang Quentin Liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060P.R.China Institute of Cancer Stem Cell Dalian Medical UniversityDalianLiaoning 116044P.R.China Department of Surgery and Cancer Imperial College LondonW120NNLondonUK

Background:Overexpression of Aurora-A(AURKA)is a feature of breast cancer and associates with adverse prognosis.The selective Aurora-A inhibitor alisertib(MLN8237)has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of patients.Thus,identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic outcome.Methods:Here,we conducted a systematic synthetic lethality CRISPR/Cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with MLN8237.Then,we performed competitive growth assays,colony formation assays,cell viability assays,apoptosis assays,and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin(GSG2)depletion or inhibition with MLN8237.For mechanistic studies,immunofluorescence was used to detect the state of microtubules and the localization of Aurora-B and mitotic centromere-associated kinesin(MCAK).Results:Among the hits,we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of MLN8237.Mechanistic studies showed that co-treatment with Aurora-A and Haspin inhibitors abolished the recruitment of Aurora-B and mitotic centromere-associated kinesin(MCAK)to centromeres which were associated with excessive microtubule depolymerization,kinetochore-microtubule(KT-MT)attachment failure,and severe mitotic catastrophe.We further showed that the combination of MLN8237 and the Haspin inhibitor CHR-6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor growth.Conclusions:These findings establish Haspin as a synthetic lethal target and demonstrate CHR-6494 as a potential combin

关键词： alisertib Aurora-A breast cancer CHR-6494 CRISPR/Cas9 screening haspin kinetochoremicrotubule mitotic centromere-associated kinesin synthetic lethal xenograft

Human KIAA1018/FAN1 nuclease is a new mitotic substrate of APC/C^(Cdh1)

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Chinese Journal of Cancer 2012年第9期31卷 440-448页

作者： Fenju Lai Kaishun Hu Yuanzhong Wu Jianjun Tang Yi Sang Jingying Cao Tiebang Kang State Key Laboratory of Oncology in South China Department of Experimental Research Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China

A recently identified protein, FAN1 (FANCD2-associated nuclease 1, previously known as KIAA1018), is a novel nuclease associated with monoubiquitinated FANCD2 that is required for cellular resistance against DNA interstrand crosslinking (ICL) agents. The mechanisms of FAN1 regulation have not yet been explored. Here, we provide evidence that FAN1 is degraded during mitotic exit, suggesting that FAN1 may be a mitotic substrate of the anaphase-promoting cyclosome complex (APC/C). Indeed, Cdh1, but not Cdc20, was capable of regulating the protein level of FAN1 through the KEN box and the D-box. Moreover, the up-and down-regulation of FAN1 affected the progression to mitotic exit. Collectively, these data suggest that FAN1 may be a new mitotic substrate of APC/C Cdh1 that plays a key role during mitotic exit.

关键词：有丝分裂过程核酸酶基板蛋白质含量人力 DNA链 ICL 泛素化

Recent trends of machine learning applied to multi-source data of medicinal plants

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Journal of Pharmaceutical Analysis 2023年第12期13卷 1388-1407页

作者： Yanying Zhang yuanzhong Wang Medicinal Plants Research Institute Yunnan Academy of Agricultural SciencesKunming650200China College of Traditional Chinese Medicine Yunnan University of Chinese MedicineKunming650500China

In traditional medicine and ethnomedicine,medicinal plants have long been recognized as the basis for materials in therapeutic applications worldwide.In particular,the remarkable curative effect of traditional Chinese medicine during corona virus disease 2019(COVID-19)pandemic has attracted extensive attention globally.Medicinal plants have,therefore,become increasingly popular among the public.However,with increasing demand for and profit with medicinal plants,commercial fraudulent events such as adulteration or counterfeits sometimes occur,which poses a serious threat to the clinical outcomes and interests of consumers.With rapid advances in artificial intelligence,machine learning can be used to mine information on various medicinal plants to establish an ideal resource database.We herein present a review that mainly introduces common machine learning algorithms and discusses their application in multi-source data analysis of medicinal plants.The combination of machine learning algorithms and multi-source data analysis facilitates a comprehensive analysis and aids in the effective evaluation of the quality of medicinal plants.The findings of this review provide new possibilities for promoting the development and utilization of medicinal plants.

关键词： Machine learning Medicinal plant Multi-source data Data fusion Application

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房产测量中房屋分层分户平面图的自动化生产

城市勘测 2011年第3期 138-140页

作者：吴远忠福建省八闽测绘院福建厦门361012

结合晋江市房产测量中的实际情况,介绍了房产测量成果中房屋分层分户平面图的自动化生产程序,该程序可以满足不同县市房产部门对房屋分层分户平面图的多样化需求。

关键词：房产测量分层分户平面图 LISP