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Function,mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4341-4372页

作者： yanyu jiang Shuaishuai Ni Biying Xiao Lijun Jia Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China

Ubiquitin(Ub)and ubiquitin-like(Ubl)pathways are critical post-translational modifications that determine whether functional proteins are degraded or activated/*** date,>600 associated enzymes have been reported that comprise a hierarchical task network(e.g.,E1–E2–E3 cascade enzymatic reaction and deubiquitination)to modulate substrates,including enormous oncoproteins and tumor-suppressive *** strategies,such as classical biochemical approaches,multiomics,and clinical sample analysis,were combined to elucidate the functional relations between these enzymes and *** this regard,the fundamental advances and follow-on drug discoveries have been crucial in providing vital information concerning contemporary translational efforts to tailor individualized treatment by targeting Ub and Ubl ***,emphasizing the current progress of Ub-related pathways as therapeutic targets in cancer is deemed *** the present review,we summarize and discuss the functions,clinical significance,and regulatory mechanisms of Ub and Ubl pathways in tumorigenesis as well as the current progress of small-molecular drug *** particular,multiomics analyses were integrated to delineate the complexity of Ub and Ubl modifications for cancer *** present review will provide a focused and up-to-date overview for the researchers to pursue further studies regarding the Ub and Ubl pathways targeted anticancer strategies.

关键词： Ub and Ubl modifications Ub-activating enzyme Ub-conjugating enzyme Ub ligase Multiomics analyses Drug discovery Small molecule inhibitor Molecular glue

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推拿治疗单纯性肥胖机制研究进展

西部中医药 2024年第3期37卷 77-80页

作者：谢万江晓梅蒋琰瑜唐红珍广西中医药大学广西南宁530023

检索近十年推拿治疗单纯性肥胖的相关文献,从胰岛素抵抗、免疫炎症因子、转录因子家族、激素分泌、肠道菌群作用机制等方面展开综述,指出推拿可能通过调节C/EBP家族因子表达与HPA轴治疗单纯性肥胖。

关键词：单纯性肥胖推拿机制综述

大黄黄连泻心汤联合针刺治疗肥胖2型糖尿病患者的临床研究

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检验医学与临床 2024年第14期21卷 2001-2005,2010页

作者：蒋琰瑜骆雨廖彩云唐红珍李东阳李冬广西中医药大学针灸推拿学院广西南宁530022 广西中医药大学附属瑞康医院广西南宁530011 广西壮族自治区江滨医院物理治疗科广西南宁530011

目的观察大黄黄连泻心汤联合“土郁夺之”针刺法治疗肥胖2型糖尿病患者的临床疗效。方法选择2021年9月至2023年2月于广西壮族自治区江滨医院就诊的肥胖2型糖尿病患者112例,根据随机数字表法分为观察组与对照组,根据纳入排除标准,最终... 详细信息

目的观察大黄黄连泻心汤联合“土郁夺之”针刺法治疗肥胖2型糖尿病患者的临床疗效。方法选择2021年9月至2023年2月于广西壮族自治区江滨医院就诊的肥胖2型糖尿病患者112例,根据随机数字表法分为观察组与对照组,根据纳入排除标准,最终每组54例患者。2组均给予西药常规治疗,对照组给予“土郁夺之”针刺法治疗,观察组在对照组基础上给予大黄黄连泻心汤治疗。观察2组治疗前后临床疗效、中医证候评分、血糖(空腹血糖、餐后2 h血糖、糖化血红蛋白)水平、肥胖指标(体质量指数、内脏脂肪面积、腰臀比)、血脂(总胆固醇、甘油三酯、低密度脂蛋白胆固醇)水平、血清脂肪因子(血清脂联素、血清瘦素、神经肽Y)水平及不良反应发生情况。结果治疗后观察组总有效率为92.59%,显著高于对照组的79.63%(P<0.05)。治疗后2组中医证候评分、血糖、血脂、肥胖指标、血清瘦素、神经肽Y水平均较治疗前降低,且观察组低于对照组,2组治疗后血清脂联素水平较治疗前升高,且观察组高于对照组,差异均有统计学意义(P<0.05)。2组治疗过程中均未出现低血糖等严重不良反应。结论大黄黄连泻心汤联合“土郁夺之”针刺法治疗肥胖2型糖尿病患者临床疗效显著。

关键词：大黄黄连泻心汤土郁夺之针刺肥胖 2型糖尿病脂肪因子

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Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma

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Cancer Biology & Medicine 2022年第4期19卷 504-517页

作者： Jingrong Xian Shiwen Wang yanyu jiang Lihui Li Lili Cai Ping Chen Yue Liu Xiaofei Zeng Guoan Chen Chen Ding Robert MHoffman Lijun Jia Hu Zhao Yanmei Zhang Department of Laboratory Medicine Huadong Hospital Affiliated to Fudan UniversityShanghai 200040China Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Research Center on Aging and Medicine Fudan UniversityShanghai 200040China Shanghai Key Laboratory of Clinical Geriatric Medicine Shanghai 200040China Department of Basic Science of Oncology College of Basic Medical SciencesZhengzhou UniversityCollaborative Innovation Center of Henan Province for Cancer ChemopreventionZhengzhou 450001China School of Medicine Southern University of Science and TechnologyShenzhen 518055China State Key Laboratory of Genetic Engineering Human Phenome InstituteInstitutes of Biomedical SciencesSchool of Life SciencesZhongshan HospitalFudan UniversityShanghai 200032China State Key Laboratory of Cell Differentiation and Regulation Henan International Joint Laboratory of Pulmonary FibrosisHenan Center for Outstanding Overseas Scientists of Pulmonary FibrosisCollege of Life ScienceInstitute of Biomedical ScienceHenan Normal UniversityXinxiang 453007China Department of Surgery University of CaliforniaSan Diego 92101USA Anticancer Inc. San Diego 92101USA

Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer *** aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).Methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue ***8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and *** proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological *** cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in ***:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in *** proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC *** studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in *** experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 ***:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.

关键词： NEDD8 esophageal squamous cell carcinoma cullin-RING E3 ubiquitin ligases apoptosis anticancer target

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山东鲁西北地区馆陶组热储及流体化学特征

中国煤炭地质 2024年第6期36卷 45-51页

作者：孟苗苗计孝飞刘鹏磊马艳粉姜彦玉李晓静杜亚虎冯凯李旭超山东省地矿工程集团有限公司山东济南250000 山东科技大学山东青岛266590

鲁西北地热区热储主要为层状热储,地温相对于其它地热区均匀,具有较高的热流值和富水性较强的含水层,是山东省地热资源开发潜力最大的地区。鲁西北地区的主要热储之一为新近系馆陶组孔隙裂隙热储层组。研究发现其上部地层发育细—中粒... 详细信息

鲁西北地热区热储主要为层状热储,地温相对于其它地热区均匀,具有较高的热流值和富水性较强的含水层,是山东省地热资源开发潜力最大的地区。鲁西北地区的主要热储之一为新近系馆陶组孔隙裂隙热储层组。研究发现其上部地层发育细—中粒砂岩及泥岩与细粒砂岩互层夹粉砂岩;下部地层发育中细粒砂岩、中粒砂岩及砂砾岩夹泥岩;新近系馆陶组热储层具有顶底板埋深自南向北由浅变深、厚度由薄变厚,在凸起区埋藏浅、厚度薄,凹陷区埋藏深、厚度大等变化规律;地热水化学特征在水平方向具有以下分布特征:水化学类型由南部、东南部的SO_(4)·Cl-Na型向北、西北逐渐过渡为Cl·SO_(4)-Na型至Cl-Na。

关键词：馆陶组热储层水化学特征地温分区鲁西北地区

瑞芬太尼在老年高血压患者清醒无痛肠镜中应用的效果分析

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中国校医 2023年第4期37卷 296-298页

作者：姜彦羽徐州医科大学附属医院麻醉科江苏徐州221002

目的分析静脉输注瑞芬太尼在老年高血压患者无痛肠镜检查中的应用效果。方法选取2020年4月—2022年4月在某院消化科接受无痛肠镜检查的ASA分级Ⅰ~Ⅱ级的老年高血压患者66名作为研究对象,采用随机列表法将患者分为对照组和实验组,对照组... 详细信息

目的分析静脉输注瑞芬太尼在老年高血压患者无痛肠镜检查中的应用效果。方法选取2020年4月—2022年4月在某院消化科接受无痛肠镜检查的ASA分级Ⅰ~Ⅱ级的老年高血压患者66名作为研究对象,采用随机列表法将患者分为对照组和实验组,对照组采用静脉输注丙泊酚-瑞芬太尼麻醉处理,实验组采用瑞芬太尼静脉输注处理。结果麻醉肠镜检查过程中肌僵发生率实验组和对照组差异无统计学意义(P>0.05)。实验组低血压、呼吸抑制、体动、低氧血症等发生率分别为9.09%、6.06%、6.06%、3.03%,均低于对照组的60.61%、36.36%、27.27%、24.24%(χ^(2)分别为19.286、9.066、5.345、6.304,P均<0.005);实验组术后苏醒时间为(5.576±0.030)min,短于对照组的(15.121±0.192)min(t=7.32,P<0.05)。结论老年高血压患者在无痛肠镜检查时采用单纯的瑞芬太尼静脉输注,降低了严重低血压及低氧血症的发生率,缩短了患者苏醒及恢复时间,具有较高的应用价值。

关键词：瑞芬太尼老年人高血压无痛肠镜

NEDD8-conjugating enzyme UBC12 as a novel therapeutic target in esophageal squamous cell carcinoma

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1403-1406页

作者： Shiwen Wang Jingrong Xian Lihui Li yanyu jiang Yue Liu Lili Cai Robert M.Hoffman Lijun Jia Hu Zhao Yanmei Zhang Department of Laboratory Medicine Huadong Hospital Affiliated to Fudan UniversityShanghai 200040China Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Research Center on Aging and Medicine Fudan UniversityShanghai 200040China Shanghai Key Laboratory of Clinical Geriatric Medicine Shanghai 200040China Department of Surgery University of CaliforniaSan DiegoCAUSA

Dear Editor,Esophageal squamous cell carcinoma(ESCC)is the major histologic subtype of esophageal cancer with high incidence and mortality.1 However,few achievements have been made in the development of targeted drugs.2 Neddylation,a reversible post-translational modification,attaches ubiquitin-like molecule NEDD8 to substrates in a three-step enzymatic reaction catalyzed by NEDD8-activating enzyme E1(NAE,NAE1 and UBA3 heterodimer),NEDD8-conjugating enzyme E2s(UBE2M/UBC12 or UBE2F)and substrate-specific NEDD8-E3 ligases.3 The best-characterized substrates of neddylation are cullin family proteins,the essential components of multiunit Cullin-RING ubiquitin ligases(CRLs).4 Currently,the inhibition of cullin neddylation by targeting overactivated neddylation pathway has emerged as an attractive approach for anticancer therapy.5,6 Our previous study reported that MLN4924,a specific inhibitor of NAE,significantly inhibited the tumor growth of ESCC by blocking cullin neddylation and inactivating CRLs activity.7 However,recent studies found that MLN4924 treatment-emergent NAE mutations would confer the drug resistance.8,9 Therefore,it is urgent to identify other neddylation enzymes(E2s or E3s)as alternative anticancer targets and develop novel anti-ESCC strategies.

关键词： esophageal NEDD8 squamous

2004―2021年我国居民主要伤害死亡率变化趋势

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中华疾病控制杂志 2024年第3期28卷 249-255页

作者：王素贤蒋帅赵要军段彦然穆子涵王晶汤艳雨郑州大学公共卫生学院社会医学与卫生事业管理学教研室郑州450001 郑州大学第一附属医院运营管理部郑州450052 郑州大学华中阜外医院运营管理部郑州451460 河南省医院管理研究院郑州450052

目的分析2004―2021年我国居民主要伤害死亡率变化趋势,为制定人群伤害防控策略提供参考依据。方法从2004―2021年《中国死因监测数据集》中提取年龄、性别和城乡伤害类别等数据,采用Joinpoint回归模型计算年度变化百分比(annual percen... 详细信息

目的分析2004―2021年我国居民主要伤害死亡率变化趋势,为制定人群伤害防控策略提供参考依据。方法从2004―2021年《中国死因监测数据集》中提取年龄、性别和城乡伤害类别等数据,采用Joinpoint回归模型计算年度变化百分比(annual percent change,APC)和平均年度变化百分比(average annual percent change,AAPC)。结果2004―2021年,伤害标化死亡率总体呈下降趋势(AAPC=-4.43%,P<0.001)。非故意跌落标化死亡率呈上升趋势(AAPC=1.12%,P<0.001),其余4个伤害类型呈下降趋势(AAPC分别为-5.44%、-4.16%、-5.87%和-3.24%,均P<0.001)。从年龄组看,0~<15岁、15~<65岁和≥65岁年龄组首位伤害死因分别是溺水、道路交通事故和非故意跌落;≥65岁非故意跌落死亡率呈上升趋势(AAPC=1.82%,P=0.033)。从人群类型看,男性道路交通事故标化死亡率高于女性;农村伤害标化死亡率每年均高于城市,且农村男性是死亡率最高的群体。结论2004―2021年我国居民伤害死亡率总体呈下降趋势,男性、≥65岁老年人和农村人群是伤害死亡率防控的重点人群。

关键词：伤害死亡率趋势分析 Joinpoint回归

人源化BCMA CAR-T细胞挽救治疗鼠源BCMA CAR-T细胞治疗后再进展的难治多发性骨髓瘤二例

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中华血液学杂志 2021年第6期42卷 502-507页

作者：崔蕊李平李青穆娟蒋怡丽江嫣雨邓琦天津市第一中心医院血液科南开大学医学院300192 德州市人民医院血液科 253000

目的探讨人源化B细胞成熟抗原(BCMA)嵌合抗原受体T细胞(CAR-T细胞)治疗鼠源BCMA CAR-T后疾病再进展的难治性多发性骨髓瘤(RRMM)患者临床疗效及安全性。方法采集两例患者自体外周血单个核细胞,制备BCMA CAR-T细胞,FC方案(氟达拉滨+环磷酰... 详细信息

目的探讨人源化B细胞成熟抗原(BCMA)嵌合抗原受体T细胞(CAR-T细胞)治疗鼠源BCMA CAR-T后疾病再进展的难治性多发性骨髓瘤(RRMM)患者临床疗效及安全性。方法采集两例患者自体外周血单个核细胞,制备BCMA CAR-T细胞,FC方案(氟达拉滨+环磷酰胺)预处理后分别予鼠源/人源化BCMA CAR-T细胞输注。输注后监测CAR-T细胞扩增、细胞因子变化及不良反应。体外试验检测鼠源/人源化BCMA CAR-T转染效率、对MM细胞株的杀伤活力及炎症细胞因子释放水平。结果例1及例2输注鼠源CAR-T后3个月分别为完全缓解(CR)及疾病稳定(SD)。16个月及18个月后出现疾病再进展,且例1出现髓外病变,输注人源化BCMA CAR-T细胞挽救治疗后,分别达到部分缓解(PR)及非常好的部分缓解(VGPR)的疗效,例1髓外病变4个月消失。两例患者在人源化BCMA CAR-T细胞治疗期间,CAR-T细胞体内扩增峰值、体内持续时间均较鼠源输注期间水平升高。人源化BCMA CAR-T治疗期间IL-6、IL-8、IFN-γ、IL-10及TNF-α峰值高于鼠源CAR-T峰值。两例患者输注鼠源CAR-T期间细胞因子释放综合征(CRS)均为1级,无神经系统毒性(ICANS);人源化CAR-T治疗例1 CRS为3级,ICANS为2级,支持对症治疗后好转,例2 CRS 2级,无ICANS发生。体外试验证实48 h效靶比为1∶1时,人源化BCMA CAR-T、鼠源CAR-T细胞分别与例1、例2患者共培养,BCMA+肿瘤细胞残余比例分别为(17.38±5.18)%对(28.27±4.58)%、(13.25±1.62)%对(22.77±1.77)%,人源化BCMA-CAR-T对原代MM的细胞毒作用优于鼠源CAR-T细胞(P<0.001),且IFN-γ、TNF-α及IL-6释放水平均高于鼠源CAR-T细胞(P值均<0.001)。结论鼠源BCMA CAR-T治疗后复发进展的RRMM患者再次输注人源BCMA CAR-T可能有效且安全性可控。

关键词：多发性骨髓瘤人源化嵌合抗原受体T细胞安全性疗效