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Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152):a novel triple angiokinase inhibitor for cancer therapy

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1453-1475页

作者： Yuqin Yao zhuowei liu Manyu Zhao Zhengxia Chen Peng Li Yang Zhang Yuxi Wang Chengjian Zhao Chaofeng Long Xiaoxin Chen Jinliang Yang State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China School of Public Health and West China Fourth HospitalSichuan UniversityChengdu 610041China Guangdong Zhongsheng Pharmaceutical Co. Ltd.Dongguan 523325China West China School of Public Health and West China Fourth Hospital Healthy Food Evaluation Research CenterSichuan UniversityChengdu 610041China Guangdong Raynovent Biotech Co. Ltd.Dongguan 523325China WuXi AppTec Ltd.Shanghai 200131 China

Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and *** conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.

关键词： inhibited clinical synthesis

经皮肾穿刺微造瘘引流术对输尿管结石引起脓毒症患者的效果

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中外医学研究 2024年第9期22卷 123-127页

作者：包华宇劳景茂刘卓伟叶贻俊廖志广钦州市第一人民医院广西钦州535000

目的:探究经皮肾穿刺微造瘘引流术对输尿管结石引起脓毒症患者的效果。方法:选取2020年3月—2022年2月钦州市第一人民医院收治的输尿管结石引起脓毒症的患者73例,依据随机数表法将患者分为对照组(n=36)和观察组(n=37),对照组采用常规碎... 详细信息

目的:探究经皮肾穿刺微造瘘引流术对输尿管结石引起脓毒症患者的效果。方法:选取2020年3月—2022年2月钦州市第一人民医院收治的输尿管结石引起脓毒症的患者73例,依据随机数表法将患者分为对照组(n=36)和观察组(n=37),对照组采用常规碎石引流方法治疗,观察组采用经皮肾穿刺微造瘘引流术。比较两组患者临床指标、治疗前后肾功能、肾积水程度、炎症水平,术后复发脓毒症率和术后并发症发生率。结果:观察组引流成功率高于对照组,手术时间、脓毒症好转时间、住院时间、术后复发脓毒症率和并发症总发生率均优于对照组,差异有统计学意义(P<0.05)。治疗后,观察组肾功能、肾积水程度及炎症水平低于对照组,差异有统计学意义(P<0.05)。结论:在输尿管结石引起脓毒症患者应用经皮肾穿刺微造瘘引流术,可改善患者肾功能并降低炎症因子水平,有助于患者后续恢复。

关键词：输尿管结石脓毒症经皮肾穿刺微造瘘引流术

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Efficacy of radical cystectomy plus adjuvant intraarterial chemotherapy with gemcitabine and cisplatin on locally advanced bladder cancer

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Chinese Medical Journal 2014年第7期127卷 1249-1254页

作者： Jiang Lijuan Zhang Zhiling Dong Pei Li Yonghong Yao Kai liu zhuowei Han Hui Qin Zike Yao Min Zhou Fangjian State Key Laboratory of Oncology in South China GuangzhouGuangdong Department of Urology Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 China Department of Surgery Boston University School of Medicine andBoston Medical Center Boston MA 02118 USA

Background Bladder cancer is the ninth most common cancer in the world; fewer than 15％ of transitional-cell carcinoma patients survive 2 years if left *** radical cystectomy is the standard treatment of choice,much of them relapse and the necessity of adjuvant chemotherapy is still under *** aim of the study was to evaluate the efficacy of adjuvant intraarterial chemotherapy （IAC） with gemcitabine and cisplatin （GC） on locally advanced bladder *** This is a retrospective study on 60 patients with locally advanced bladder carcinoma who underwent radical cystectomy between May 2000 and June *** were studied in two groups based on IAC and followed up for up to 5 *** Among 60 patients,there were 25 patients who underwent IAC （GC） after radical cystectomy （the IAC group） and 35 patients who underwent radical cystectomy alone （the control group）.Although not significant,the relapse rates were slightly reduced in the IAC group than in the control *** with IAC had a reduction in mortality compared with patients without IAC over 5 ***,IAC significantly reduced about 82％ of mortality within the first year （hazard ratio=0.18,95％ Cl 0.03-0.97,P=-0.04）.Additionally,IAC was well tolerated and *** most common adverse effect was transient myelosuppression （10/25,40％）,which was resolved by various medical *** Compared with radical cystectomy alone,radical cystectomy in combination with adjuvant IAC moderately but significantly reduces 1-year *** preliminary data showed only marginal benefit for the early ***,a randomized clinical study is needed to determine the long-term survival benefit.

关键词： adjuvant intraarterial chemotherapy adjuvant chemotherapy, bladder cancer radical cystectomy

An improved ileal conduit surgery for bladder cancer with fewer complications

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Cancer Communications 2019年第1期39卷 178-187页

作者： Zhiyong Li zhuowei liu Kai Yao Zike Qin Hui Han Yonghong Li Pei Dong Yunlin Ye Yanjun Wang Zhiming Wu Zhiling Zhang Fangjian Zhou Department of Urology State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterNo.651 Dongfeng Road EastGuangzhou 510060GuangdongP.R.China

Background:Radical cystectomy and urinary diversion remains the standard surgical treatment for patients with muscle-invasive or high-risk or recurrent non-muscle-invasive bladder *** this approach prolongs patient survival remarkably,there are postoperative complications associated with urinary *** study aimed to assess the efficacy of modified ileal conduit surgery for reducing early and late stoma-and ureteroileal anastomo-sis-related complications,as compared with conventional ileal conduit urinary ***:We retrospectively evaluated the clinical data of bladder cancer patients treated with radical cystectomy and ileal conduit urinary diversion at Sun Yat-sen University Cancer Center between January 1,2000 and June 30,*** conduit was created by the conventional or a modified *** clinicopathologic features of the conventional and the modified ileal conduit groups were compared using the t test and the Chi square ***-able logistic regression analysis and multivariable Cox regression analysis were performed to determine the odds of developing stoma-and ureteroileal anastomosis-related complications in the two ***:145 and 100 patients underwent the modified and conventional ileal conduit surgery,*** two groups were comparable with regard to clinicopathologic *** rate of stoma-related complications was significantly lower in the modified ileal conduit group than in the conventional ileal conduit group(0.7%vs.17.0%,P<0.001).No late stoma-related complications were seen in the modified ileal conduit group,but were seen in 13(13.0%)patients in the conventional ileal conduit *** rate of ureteroileal anastomosis-related complications was significantly lower in the modified ileal conduit group than in the conventional ileal conduit group(4.8%vs.15.0%,P=0.001).In multivariable analyses,the modified ileal conduit group was significantly less likely to develop stoma-(odds rati

关键词： Bladder cancer Cystectomy Urinary diversion Ileal conduit Complication Surgical technique

免气腹单孔后腹腔镜肾上腺肿瘤切除术初步探讨

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中华腔镜泌尿外科杂志(电子版) 2024年第1期18卷 25-30页

作者：马楠杨振宇林旭曼刘振华陈贤达郭胜杰韩辉周芳坚刘卓炜尧凯华南恶性肿瘤防治全国重点实验室/广东省恶性肿瘤临床医学研究中心/中山大学肿瘤防治中心泌尿外科

目的总结分析免气腹单孔后腹腔镜肾上腺肿瘤切除术的方法和围手术期资料，探讨免气腹单孔后腹腔镜肾上腺肿瘤切除术的安全性和可行性。方法回顾性收集2020年10月至2022年3月中山大学肿瘤防治中心由同一术者完成的65例单孔后腹腔镜肾... 详细信息

目的总结分析免气腹单孔后腹腔镜肾上腺肿瘤切除术的方法和围手术期资料，探讨免气腹单孔后腹腔镜肾上腺肿瘤切除术的安全性和可行性。方法回顾性收集2020年10月至2022年3月中山大学肿瘤防治中心由同一术者完成的65例单孔后腹腔镜肾上腺肿瘤切除术患者的临床资料，其中免气腹单孔腹腔镜23例，有气腹单孔腹腔镜42例。结果 65例单孔腹腔镜手术均成功完成，无中转开放或者改多孔操作。免气腹单孔腹腔镜组和有气腹单孔腹腔镜组在手术时间、术中出血量、术后住院时间、术后止痛药物使用时间、引流管留置时间差异均无统计学意义（P>0.05）；免气腹组住院平均费用低于气腹组[（32 072±2 667 vs 34 972±2 783）元，P<0.001]。结论免气腹单孔后腹腔镜肾上腺肿瘤切除术安全可行，能避免气腹并发症，减少患者住院费用，是一种微创，美容和经济的术式。

关键词：免气腹单孔,腹腔镜肾上腺肿瘤

昂拉地韦潜在基因毒性杂质的合成、表征和检测

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合成化学 2024年第1期32卷 53-58页

作者：李波刘呈武刘卓伟黎志豪广东众生睿创生物科技有限公司工艺开发部广东广州510700

为了对流感I类新药昂拉地韦的潜在基因毒性杂质进行研究,合成了昂拉地韦原料药中潜在基因毒性杂质3-叠氮基-5-氟-1-(四氢-2 H-吡喃-2-基)-^(1)H-吡唑并[3,4-b]吡啶(SMI-H),其结构通过核磁共振氢谱、碳谱、质谱进行表征。采用自行开发并... 详细信息

为了对流感I类新药昂拉地韦的潜在基因毒性杂质进行研究,合成了昂拉地韦原料药中潜在基因毒性杂质3-叠氮基-5-氟-1-(四氢-2 H-吡喃-2-基)-^(1)H-吡唑并[3,4-b]吡啶(SMI-H),其结构通过核磁共振氢谱、碳谱、质谱进行表征。采用自行开发并验证的液相色谱-质谱法(LC-MS)对昂拉地韦原料药和关键起始物料3-溴-5-氟-1-(四氢-2 H-吡喃-2-基)-^(1)H-吡唑并[3,4-b]吡啶(SMI)进行杂质的检测。结果表明:在昂拉地韦中未检出该杂质,而在SMI中有检出(0.1%~0.2%),但杂质含量低于标准限度(≤0.3%),因此昂拉地韦的安全风险是可控的。

关键词：昂拉地韦 SMI-H 流感合成结构表征基因毒性

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基于单光子计数激光雷达的恒虚警检测研究

中国激光 2023年第5期50卷 176-184页

作者：刘卓伟李自芹苏志刚中国民航大学电子信息与自动化学院天津300300 新疆农垦科学院新疆石河子832000 中国民航大学中欧航空工程师学院天津300300

本文围绕光子计数激光雷达在噪声背景下的目标检测问题,利用其回波雷达信号的特点,设计了一种降噪预处理方法,继而提出了一种改进的恒虚警检测方法。该方法能在目标回波较弱时自适应地对不同宽度的回波进行检测,同时能够保持较高的检测... 详细信息

本文围绕光子计数激光雷达在噪声背景下的目标检测问题,利用其回波雷达信号的特点,设计了一种降噪预处理方法,继而提出了一种改进的恒虚警检测方法。该方法能在目标回波较弱时自适应地对不同宽度的回波进行检测,同时能够保持较高的检测概率。仿真结果显示:相比传统的信号检测方法,本文所提方法的检测性能更优。实验结果表明,在噪声较强或回波信号较弱的情况下,所提检测方法依然可以以较高的检测概率检测到目标。相比当前的检测方法,在相同信噪比环境下,所提检测方法可使目标的平均检测概率提高40%。

关键词：量子光学激光雷达单光子计数目标检测恒虚警检测

战场威胁约束下的纯方位探测单观测站轨迹优化

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国防科技大学学报 2018年第5期40卷 133-137页

作者：吴昊陈树新刘卓崴空军工程大学信息与导航学院陕西西安710077

为保证战场环境下单站纯方位无源探测的精度和观测站的战场生存能力,提出一种战场威胁约束下的单观测站轨迹优化方法。对典型战场威胁进行分析,建立战场威胁和单观测站运动轨迹的数学模型。在此基础上综合考虑单观测站探测精度和所受威... 详细信息

为保证战场环境下单站纯方位无源探测的精度和观测站的战场生存能力,提出一种战场威胁约束下的单观测站轨迹优化方法。对典型战场威胁进行分析,建立战场威胁和单观测站运动轨迹的数学模型。在此基础上综合考虑单观测站探测精度和所受威胁程度,分别构建精度打分函数和威胁打分函数,得到单观测站的路径选择函数,并对观测站不同轨迹进行评价。仿真结果表明,所提方法能够有效规避战场威胁并提高定位精度,保证战场环境下单站纯方位探测的准确性和可靠性。

关键词：战场威胁单站无源探测轨迹优化

A nomogram for individualized estimation of survival among adult patients with adrenocortical carcinoma after surgery:a retrospective analysis and multicenter validation study

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Cancer Communications 2019年第1期39卷 683-695页

作者： Jianqiu Kong Junjiong Zheng Jinhua Cai Shaoxu Wu Xiayao Diao Weibin Xie Xiong Chen Chenyi Liao Hao Yu Xinxiang Fan Chaowen Huang zhuowei liu Wei Chen Qiang Lv Haide Qin Jian Huang Tianxin Lin Department of Urology Sun Yat-Sen Memorial HospitalSun Yat-Sen University107 Yan Jiang West RoadGuangzhou 510120GuangdongP.R.China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhou 510120GuangdongP.R.China Department of Neurology Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhou 510120GuangdongP.R.China Department of Obstetrics and Gynecology Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630GuangdongP.R.China Department of Urology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Urology First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080GuangdongP.R.China Department of Urology The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029JiangsuP.R.China State Key Laboratory of Oncology in South China Guangzhou 510120GuangdongP.R.China

Background:Clinical outcome of adrenocortical carcinoma(ACC)varies because of its heterogeneous nature and reliable prognostic prediction model for adult ACC patients is *** objective of this study was to develop and externally validate a nomogram for overall survival(OS)prediction in adult patients with ACC after ***:Based on the data from the Surveillance Epidemiology,and End Results(SEER)database,adults patients diagnosed with ACC between January 1988 and December 2015 were identified and classified into a training set,comprised of 404 patients diagnosed between January 2007 and December 2015,and an internal validation set,com-prised of 318 patients diagnosed between January 1988 and December *** endpoint of this study was *** nomogram was developed using a multivariate Cox proportional hazards regression algorithm in the training set and its performance was evaluated in terms of its discriminative ability,calibration,and clinical *** nomogram was then validated using the internal SEER validation,also externally validated using the Cancer Genome Atlas set(TCGA,82 patients diagnosed between 1998 and 2012)and a Chinese multicenter cohort dataset(82 patients diag-nosed between December 2002 and May 2018),***:Age at diagnosis,T stage,N stage,and M stage were identified as independent predictors for OS.A nomo-gram incorporating these four predictors was constructed using the training set and demonstrated good calibration and discrimination(C-index 95%confidence interval[CI],0.715[0.679-0.751]),which was validated in the internal validation set(C-index[95%CI],0.672[0.637-0.707]),the TCGA set(C-index[95%CI],0.810[0.732-0.888])and the Chi-nese multicenter set(C-index[95%CI],0.726[0.633-0.819]),***,the nomogram was able to successfully distinguished patients with a high-risk of mortality in all enrolled patients and in the subgroup *** curve analysis indicated that the nomogram wa

关键词： Adrenocortical carcinoma Adult patients Overall survival Nomogram Validation Decision curve analysis Surveillance Epidemiology and End Results(SEER) The Cancer Genome Atlas(TCGA) Multicenter