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Engineered T Cell Therapies from a Drug Development Viewpoint 预览
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作者 Fang Chen Joseph A. Fraietta +3 位作者 Carl H. June Zhongwei Xu J. Joseph Melenhorst Simon F. Lacey 《工程(英文)》 2019年第1期140-149,共10页
Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike ... Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals. 展开更多
关键词 Engineered T cell THERAPIES CHIMERIC ANTIGEN RECEPTOR Drug development process Biomarkers CD19-specific CHIMERIC ANTIGEN RECEPTOR Anti-CD19 CHIMERIC ANTIGEN RECEPTOR T cells
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Soluble Nogo receptor 1 fusion protein protects neural progenitor cells in rats with ischemic stroke 预览
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作者 Hai-Wei He Yue-Lin Zhang +4 位作者 Bao-Qi Yu Gen Ye Wei You Kwok-fai So Xin Li 《中国神经再生研究:英文版》 SCIE CAS CSCD 2019年第10期1755-1764,共10页
Soluble Nogo66 receptor-Fc protein(sNgR-Fc)enhances axonal regeneration following central nervous system injury.However,the underlying mechanisms remain unclear.In this study,we investigated the effects of sNgR-Fc on ... Soluble Nogo66 receptor-Fc protein(sNgR-Fc)enhances axonal regeneration following central nervous system injury.However,the underlying mechanisms remain unclear.In this study,we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells.The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats.The rats with photothrombotic cortical injury were randomized to receive infusion of 400μg/kg sNgR-Fc(sNgR-Fc group)or an equal volume of phosphate-buffered saline(photothrombotic cortical injury group)into the lateral ventricle for 3 days.The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining.Neurological function was evaluated with the Morris water maze test.To further examine the effects of sNgR-Fc treatment on neural progenitor cells,photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats.The animals were then given an infusion of phosphate-buffered saline(neural progenitor cells group)or sNgR-Fc(sNgR-Fc+neural progenitor cells group)into the lateral ventricle for 3 days.sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo,compared with phosphate-buffered saline,and it also induced the differentiation of neural progenitor cells into neurons.Compared with the photothrombotic cortical injury group,escape latency in the Morris water maze and neurological severity score were greatly reduced,and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group,indicating a substantial improvement in neurological function.Furthermore,compared with phosphate-buffered saline infusion,sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells.Our findings show that 展开更多
关键词 NEURAL REGENERATION Nogo-66 RECEPTOR Nogo66 receptor-Fc protein NEURAL PROGENITOR cells proliferation differentiation stroke photothrombotic cortical injury transplantation NEUROLOGICAL function nerve REGENERATION
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TrkA regulates the regenerative capacity of bone marrow stromal stem cells in nerve grafts 预览
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作者 Mei-Ge Zheng Wen-Yuan Sui +8 位作者 Zhen-Dan He Yan Liu Yu-Lin Huang Shu-Hua Mu Xin-Zhong Xu Ji-Sen Zhang Jun-Le Qu Jian Zhang Dong Wang 《中国神经再生研究:英文版》 SCIE CAS CSCD 2019年第10期1765-1771,共7页
We previously demonstrated that overexpression of tropomyosin receptor kinase A(TrkA)promotes the survival and Schwann celllike differentiation of bone marrow stromal stem cells in nerve grafts,thereby enhancing the r... We previously demonstrated that overexpression of tropomyosin receptor kinase A(TrkA)promotes the survival and Schwann celllike differentiation of bone marrow stromal stem cells in nerve grafts,thereby enhancing the regeneration and functional recovery of the peripheral nerve.In the present study,we investigated the molecular mechanisms underlying the neuroprotective effects of TrkA in bone marrow stromal stem cells seeded into nerve grafts.Bone marrow stromal stem cells from Sprague-Dawley rats were infected with recombinant lentivirus vector expressing rat TrkA,TrkA-shRNA or the respective control.The cells were then seeded into allogeneic rat acellular nerve allografts for bridging a 1-cm right sciatic nerve defect.Then,8 weeks after surgery,hematoxylin and eosin staining showed that compared with the control groups,the cells and fibers in the TrkA overexpressing group were more densely and uniformly arranged,whereas they were relatively sparse and arranged in a disordered manner in the TrkA-shRNA group.Western blot assay showed that compared with the control groups,the TrkA overexpressing group had higher expression of the myelin marker,myelin basic protein and the axonal marker neurofilament 200.The TrkA overexpressing group also had higher levels of various signaling molecules,including TrkA,pTrkA(Tyr490),extracellular signal-regulated kinases 1/2(Erkl/2),pErk1/2(Thr202/Tyr204),and the anti-apoptotic proteins Bcl-2 and Bcl-xL.In contrast,these proteins were downregulated,while the pro-apoptotic factors Bax and Bad were upregulated,in the TrkA-shRNA group.The levels of the TrkA effectors Akt and pAkt(Ser473)were not different among the groups.These results suggest that TrkA enhances the survival and regenerative capacity of bone marrow stromal stem cells through upregulation of the Erk/Bcl-2 pathway.All procedures were approved by the Animal Ethical and Welfare Committee of Shenzhen University,China in December 2014(approval No.AEWC-2014-001219). 展开更多
关键词 NERVE REGENERATION bone marrow stromal stem cells TROPOMYOSIN RECEPTOR kinase A RECEPTOR LENTIVIRAL vector shRNA extracellular SIGNAL-REGULATED protein kinases 1/2 Bcl-2 NERVE grafts peripheral NERVE REGENERATION survival neural REGENERATION
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CB2受体激活对MPP+致SH-SY5Y细胞损伤的保护作用 预览
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作者 万洪丽 马泽刚 《精准医学杂志》 2019年第3期240-244,共5页
目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免... 目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免疫印迹法检测各组细胞CB2受体和酪氨酸羟化酶(TH)蛋白的表达,用流式细胞仪检测细胞线粒体膜电位(ΔΨm)的变化。结果 与C组相比,M组的CB2受体蛋白表达下降( P <0.01);经JWH-133预处理后,CB2受体蛋白表达高于M组( P <0.01),此作用可被AM630所阻断;与C组相比,M组的TH表达降低( P <0.05),经JWH-133预处理后,TH表达高于M组( P <0.05),AM630预处理可抑制此作用;与C组相比,M组细胞的ΔΨm明显下降( P <0.01),经JWH-133预处理后,细胞ΔΨm下降幅度变小( P <0.01),此作用可被AM630所阻断。结论 CB2受体激活可以抑制MPP +对SH-SY5Y细胞的损伤作用。 展开更多
关键词 受体 大麻酚 CB2 大麻素受体激动剂 帕金森病 SH-SY5Y细胞
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TRIP6在胰腺上皮内瘤变及胰腺癌中的表达及临床意义
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作者 叶淳淳 王雯 张晓兰 《中华胰腺病杂志》 CAS 2019年第1期34-37,共4页
目的探讨甲状腺激素受体相互作用蛋白6(TRIP6)在胰腺癌发生过程中的作用。方法采用免疫组织化学SP法检测43例正常胰腺、18例胰腺上皮内瘤变(PanINs)及50例胰腺导管腺癌(PDAC)组织TRIP6蛋白的表达,以免疫组织化学评分(IHCS)表示其表达强... 目的探讨甲状腺激素受体相互作用蛋白6(TRIP6)在胰腺癌发生过程中的作用。方法采用免疫组织化学SP法检测43例正常胰腺、18例胰腺上皮内瘤变(PanINs)及50例胰腺导管腺癌(PDAC)组织TRIP6蛋白的表达,以免疫组织化学评分(IHCS)表示其表达强弱程度,分析胰腺不同组织中TRIP6表达的差异以及PDAC组织TRIP6表达与临床病理特征的关系c结果正常胰腺组织TRIP6阴性表达或仅有极少量表达;PanINs组织TRIP6表达随着组织异型程度增加由弱阳性表达逐渐增强;PDAC组织TRIP6强阳性表达。正常胰腺组织及FanIN-1.PanIN-2 sPanIN-3.PDAC组织TRIP6表达的IHCS分别为(0.010±0.003).(0.029±0.003)、(0.055土0.014)、(0.090±0.025)、(0.094±0.030)分,各组间的差异有统计学意义(PvO.Ol)。组间两两比较结果显示,正常胰腺组TRIP6表达量均显著低于其他4组,PanIN-l组表达量均显著低于除正常胰腺组外的其他3组,PanIN-2组表达量显著低于PanIN-3组和PDAC组,差异均有统计学意义(P值均<0.05);PanIN-3组表达量虽然低于PDAC组,但差异无统计学意义(P=0.13)o PDAC组织TRIP6表达与神经浸润(P<O.Ol)、淋巴结转移(P=0.013)、远处转移(P=0.018)、胰腺癌分化程度(P=0.019)、术前CA19-9水平(P<O.Ol)有关,而与患者性别、年龄及肿瘤大小、肿瘤部位、血管浸润、浸润深度、TNM分期无关。结论TRIP6蛋白表达过强是PDAC发生过程中的早期事件,可能参与了PDAC发生、发展的全过程。 展开更多
关键词 胰腺肿瘤 胰腺上皮内瘤变 受体 甲状腺激素 甲状腺激素受体相互作用蛋白6 免疫组织化学
液态活检方法检测晚期非小细胞肺癌患者EGFR突变及临床分析
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作者 郑晋 张秋蕊 +3 位作者 周灵 戴然然 周敏 丁永杰 《国际呼吸杂志》 2019年第14期1047-1052,共6页
目的探讨在晚期非小细胞肺癌(NSCLC)中表皮生长因子受体(EGFR)突变状态、临床诊疗现状以及表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)的疗效评价。方法回顾性地收集了107例采用液态活检方法进行EGFR基因检测的晚期NSCLC患者,采用统... 目的探讨在晚期非小细胞肺癌(NSCLC)中表皮生长因子受体(EGFR)突变状态、临床诊疗现状以及表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)的疗效评价。方法回顾性地收集了107例采用液态活检方法进行EGFR基因检测的晚期NSCLC患者,采用统计学方法进行分析。结果 107例患者EGFR突变率为58 9%,单个位点突变49例,多个位点突变14例。男性和女性EGFR突变率为48.5%、75.6%,差异具有统计学意义(χ^2=7 685,P =0 006)。EGFR单个位点突变和多位点突变患者肝转移发生率为12. 2%、35. 7%,差异具有统计学意义(χ^2=4. 162,P =0. 041)。EGFR突变型和野生型经药物治疗后总生存期(OS)比较,差异无统计学意义(χ^2=3. 526,P =0 .06),EGFR突变患者无进展生存期(PFS)显著延长(χ^2=5. 927,P =0 .015)。EGFR单个位点突变较多位点突变 OS显著延长(χ^2=3. 951,P =0. 047),但二者PFS比较差异无统计学意义(χ^2=0. 491,P =0. 484)。一线使用或一线联合化疗使用EGFR-TKI治疗EGFR突变型患者较化疗 OS显著延长(χ^2=8. 632,P =0. 003)。结论 EGFR突变更多见于晚期NSCLC中的女性患者,与患者年龄、肿瘤原发灶的部位、影像学分型、远处转移无显著相关性。EGFR-TKI对EGFR突变型晚期NSCLC患者有显著疗效,建议一线使用或早期使用EGFR-TKI治疗。多位点EGFR突变的晚期NSCLC患者更易发生肝转移,预后较单个位点突变差。液态活检可作为肺癌EGFR基因检测的有效手段之一。 展开更多
关键词 受体 表皮生长因子 非小细胞肺 液态活检 表皮生长因子受体-酪氨酸激酶抑制剂
Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor
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作者 Dai Lu Sri Sujana Immadi +1 位作者 Zhixing Wu Debra A.Kendall 《中国药理学报:英文版》 SCIE CAS CSCD 2019年第3期324-335,共12页
The cannabinoid type-1(CB1)receptor,a G-protein-coupled receptor,is an attractive target for drug discovery due to its involvement in many physiological processes.Historically,drug discovery efforts targeting the CB1 ... The cannabinoid type-1(CB1)receptor,a G-protein-coupled receptor,is an attractive target for drug discovery due to its involvement in many physiological processes.Historically,drug discovery efforts targeting the CB1 receptor have focused on thedevelopment of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind.Research performed over the last several decades has revealed substantial difficulties in translating CB1orthosteric ligands into druggable candidates.The dificulty is mainly due to the adverse effects associated with orthosteric CB1 ligands.Recent discoveries of allosteric CB1 modulators provide tremendous opportunities to develop CB1 ligands with novel mechanisms of action;these ligands may potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functionsof the CB1receptor.In this paper,we review and summarize the complex pharmacological profiles of each class of CB1 allosteric modulators,the development of new classes of CB1 allosteric modulators and the results from in vivo assessments of their therapeutic value. 展开更多
关键词 ALLOSTERIC modulator CANNABINOID CB1 RECEPTOR G-protein-coupled RECEPTOR biased signaling functional selectivity therapeutic POTENTIAL drug discovery
Selective dopamine D3 receptor antagonist YQA14 inhibits morphine-induced behavioral sensitization in wild type,but not in dopamine D3 receptor knockout mice
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作者 Yang Lv Rong-rong Hu +5 位作者 Manyi Jing Tai-yun Zhao Ning Wu Rui Song Jin Li Gang Hu 《中国药理学报:英文版》 SCIE CAS CSCD 2019年第5期583-588,共6页
Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental... Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug’s effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25–25mg/kg every day ip) prior to morphine (10mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25-25mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R^-/-) mice in the expression phase. In addition, D3R^-/- mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction. 展开更多
关键词 MORPHINE DOPAMINE D3 RECEPTOR YQA14 behavioral SENSITIZATION DOPAMINE D3 RECEPTOR KNOCKOUT mice
Atypical chemokine receptor CCRL2 is overexpressed in prostate cancer cells 预览
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作者 Niradiz Reyes Ines Benedetti +2 位作者 Juan Rebollo Oscar Correa Jan Geliebter 《生物医学研究杂志:英文版》 CAS CSCD 2019年第1期17-23,共7页
Atypical chemokine receptors have recently emerged as important molecular players in health and diseases;they affect chemokine availability and function and impact a multitude of pathophysiological events,including th... Atypical chemokine receptors have recently emerged as important molecular players in health and diseases;they affect chemokine availability and function and impact a multitude of pathophysiological events,including the tumorigenesis process.This family of atypical receptors comprises five members:ACKR1/DARC,ACKR2/D6,ACKR3/CXCR7,ACKR4/CCRL1,and ACKR5/CCRL2.This work evaluated the differential expression of these receptors in prostate cancer using quantitative PCR.Further evaluation of CCRL2 at the protein level confirmed its overexpression in a metastatic cell line and in malignant prostatic tissues from patients.CCRL2,apresumed member of the atypical chemokine receptor family,plays akey role in lung dendritic cell trafficking to peripherally mphnodes.Recent studies have reported the expression of CCRL2 in different human cancer cell lines and tissues.However,its function and expression in prostate cancer has not been previously addressed. 展开更多
关键词 CHEMOKINE RECEPTOR PROSTATIC NEOPLASMS CCRL2 RECEPTOR real-time POLYMERASE chain reaction tissue array analysis
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Pharmacological Modulation of Vagal Nerve Activity in Cardiovascular Diseases
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作者 Longzhu Liu Ming Zhao +1 位作者 Xiaojiang Yu Weijin Zang 《神经科学通报:英文版》 SCIE CAS CSCD 2019年第1期156-166,共11页
Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal(parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharma... Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal(parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit overexcitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients.Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and b-adrenergic receptors. In addition,vagomimetic drugs(such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed. 展开更多
关键词 Cardiovascular disease CHOLINERGIC DRUGS MUSCARINIC RECEPTOR a7-nACh RECEPTOR VAGUS nerve Vagomimetic DRUGS
Heterogeneity of cannabinoid ligand-induced modulations in intracellular Ca^2+ signals of mouse pancreatic acinar cells in vitro
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作者 Kun-kun Xia Jian-xin Shen +5 位作者 Ze-bing Huang Hui-min Song Ming Gao De-jie Chen Shui-jun Zhang Jie Wu 《中国药理学报:英文版》 SCIE CAS CSCD 2019年第3期410-417,共8页
We recently reported that a CB2R agonist,GW405833(GW),reduced both the ACh-induced Ca^2+ oscillations and the L-arginineinduced Ca2+signal enhancement in mouse pancreatic acinar cells,suggesting that GW-induced inhibi... We recently reported that a CB2R agonist,GW405833(GW),reduced both the ACh-induced Ca^2+ oscillations and the L-arginineinduced Ca2+signal enhancement in mouse pancreatic acinar cells,suggesting that GW-induced inhibition may prevent the pathogenesis of acute pancreatitis.In this study,we aim to evaluate the effects of other cannabinoid ligands on Ca^2+ signaling in acinar cells.Patch-clamp whole-cell recordings were applied to measure ACh-induced intracellular Ca^2+ oscillations in pancreatic acinar cells acutely dissociated from wild-type(WT),CB1R knockout(KO),and CB2R KO mice,and the pharmacological effects of various cannabinoid ligands on the Ca^2+ oscillations were examined.We found that all the 8 CB2R agonists tested inhibited AChinduced Ca^2+ oscillations.Among them,GW,JWH133,and GP1a caused potent inhibition with IC50 values of 5.0,6.7,and 1.2μmol/L,respectively.In CB2R KO mice or in the presence of a CB2R antagonist(AM630),the inhibitory effects of these 3 CB2R agonists were abolished,suggesting that they acted through the CB2Rs.The CB1R agonist ACEA also induced inhibition of Ca^2+ oscillations that existed in CB1R KO mice and in the presence of a CB1R antagonist(AM251),suggesting a non-CB1R effect.In WT,CB1R KO,and CB2R KO mice,a nonselective CBR agonist,WIN55,212-2,inhibited Ca^2+ oscillations,which was not mediated by CB1Rs or CB2Rs.The endogenous cannabinoid substance,2-arachidonoylglycerol(2-AG),did not show an inhibitory effect on Ca^2+ oscillations.In conclusion,CB2R agonists play critical roles in modulating Ca^2+ signals in mouse pancreatic acinar cells,while other cannabinoid ligands modulate Ca^2+ oscillations in a heterogeneous manner through a CB receptor or non-CB-receptor mechanism. 展开更多
关键词 CANNABINOID CB2 RECEPTOR CB1 RECEPTOR ENDOCANNABINOID Ca^2+ oscillations pancreatic acinar cells PATCH-CLAMP
乳酸乳球菌噬菌体与宿主相互作用研究进展 预览
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作者 赵慧莹 李言郡 +3 位作者 陈苏 欧凯 王健 何国庆 《食品工业科技》 CAS 北大核心 2019年第12期331-334,340共5页
发酵乳制品主要依靠乳酸菌对牛奶酸化并形成独特的风味。然而,乳酸菌因易受噬菌体感染而导致乳制品发酵缓慢甚至失败,这对乳制品行业造成巨大的经济损失。乳酸乳球菌是发酵乳制品行业中应用十分广泛的一种乳酸菌,目前其宿主上的受体分... 发酵乳制品主要依靠乳酸菌对牛奶酸化并形成独特的风味。然而,乳酸菌因易受噬菌体感染而导致乳制品发酵缓慢甚至失败,这对乳制品行业造成巨大的经济损失。乳酸乳球菌是发酵乳制品行业中应用十分广泛的一种乳酸菌,目前其宿主上的受体分子和相应噬菌体受体结合蛋白结构分析方面的研究已经取得一定进展。这些乳酸乳球菌模型系统对加深其他乳酸菌噬菌体-宿主相互作用的认识、揭示不同乳酸菌噬菌体-宿主相互作用机制的异同提供理论依据。本文综述了目前所发现的乳酸乳球菌噬菌体及其宿主之间的相互作用,探讨受体主要成分与编码受体结合蛋白基因的研究,为研究其他乳酸菌噬菌体种群及防治措施提供一定的理论基础。 展开更多
关键词 乳酸乳球菌 噬菌体 受体 受体结合蛋白
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非小细胞肺癌的EGFR-TKI治疗
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作者 龙利丽 梁艳玲 +1 位作者 张兴梅 石玉生 《国际肿瘤学杂志》 CAS 2019年第2期105-108,共4页
表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)是治疗晚期非小细胞肺癌的关键,但后期可产生各种耐药突变。第一、二代EGFR-TKI可显著延长EGFR活化突变型肿瘤患者生存期,第三代EGFR-TKI能有效抑制T790M突变型肿瘤的进展,第四代EGFR-TKI对... 表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)是治疗晚期非小细胞肺癌的关键,但后期可产生各种耐药突变。第一、二代EGFR-TKI可显著延长EGFR活化突变型肿瘤患者生存期,第三代EGFR-TKI能有效抑制T790M突变型肿瘤的进展,第四代EGFR-TKI对L858R、T790M突变型和L858R、T790M、C797S突变型肿瘤均有抑制效果。利用循环肿瘤DNA、外泌体RNA能够有效检测EGFR突变类型,可根据突变类型选择EGFR-TKI治疗或联合化疗。 展开更多
关键词 非小细胞肺 受体 表皮生长因子 分子靶向治疗 表皮生长因子受体酪氨酸酶抑制剂 耐药性
Specific activation of mGlu2 induced IGF-1R transactivation in vitro through FAK phosphorylation
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作者 Yong-jian Hu Qian Sun +3 位作者 Wen-hua Zhang Yu-jia Huo Chan-juan Xu Jian-feng Liu 《中国药理学报:英文版》 SCIE CAS CSCD 2019年第4期460-467,共8页
Metabotropic glutamate receptor 2 (mGlu2) belongs to the group-ll metabotropic glutamate (mGlu) receptors and is a neurotransmitter G protein-coupled receptor. The group-ll mGlu receptors are promising antipsychotic t... Metabotropic glutamate receptor 2 (mGlu2) belongs to the group-ll metabotropic glutamate (mGlu) receptors and is a neurotransmitter G protein-coupled receptor. The group-ll mGlu receptors are promising antipsychotic targets, but the specific role of mGlu2 signaling remains unclear. Receptor tyrosine kinases (RTKs) are also believed to participate in brain pathogenesis. To in vestigate whether there is any communicatio n between mGlu2 and RTKs, we gen erated a CH0-mGlu2 cell li ne that stably expresses mGlu2 and showed that activation of mGlu2 by LY379268, a group II mGlu agonist, was able to transactivate insulin-like growth factor 1 receptor (IGF-1R). We further determined that the Gi/O protei n, GpY sub units, phospholipase C, and focal adhesion kinase (FAK) were involved in the IGF-1R transactivation signaling axis, which further induced the phosphorylation of extracellular sign al-regulated kinasei/2 (ERK1/2) and cAMP resp onse eleme nt-binding protei n. In primary mouse cortical neur ons, similar signaling pathways were observed when mGlu2 were stimulated by LY487379, an mGlu2 positive allosteric modulator. Transactivation of IGF-1R through FAK in response to mGlu2 should provide a better understanding of the association of mGlu2 with brain disease. 展开更多
关键词 METABOTROPIC GLUTAMATE RECEPTOR 2 INSULIN-LIKE growth factor 1 RECEPTOR TRANSACTIVATION FAK ERK1/2 LY379268 LY487379 mouse cortical neurons
Impact of taxanes on androgen receptor signaling
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作者 Shanshan Bai Bryan Y Zhang Yan Dong 《亚洲男性学杂志:英文版》 SCIE CAS CSCD 2019年第3期249-252,共4页
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metasta... The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer. 展开更多
关键词 ANDROGEN RECEPTOR ANDROGEN RECEPTOR SPLICE variant CABAZITAXEL docetaxel prostate cancer TAXANE
Uncoupling neurotrophic function from nociception of nerve growth factor:what can be learned from a rare human disease? 预览
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作者 Kijung Sung Wanlin Yang Chengbiao Wu 《中国神经再生研究:英文版》 SCIE CAS CSCD 2019年第4期570-573,共4页
Nerve growth factor(NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors... Nerve growth factor(NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V(HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100th position of mature NGF resulting in a change of residue from arginine to tryptophan(R100W). Although those HSAN V patients associated with the NGFR100W mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGFR100W mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGFR100W provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGFR100W no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGFR100W mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic factor was significantly diminished. The significance of these fin 展开更多
关键词 hereditary sensory and autonomic neuropathy V nerve growth FACTOR NGFR100W mutation pain tyrosine RECEPTOR kinase A p75 NEUROTROPHIC FACTOR RECEPTOR
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Juvenile hormone signaling - a mini review
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作者 Kang Li Qiang-Qiang Jia Sheng Li 《昆虫科学:英文版》 SCIE CAS CSCD 2019年第4期600-606,共7页
Since it was first postulated by Wigglesworth in 1934, juvenile hormone (JH) is considered a status quo hormone in insects because it prevents metamorphosis that is initiated by the molting hormone 20-hydroxyecdysone ... Since it was first postulated by Wigglesworth in 1934, juvenile hormone (JH) is considered a status quo hormone in insects because it prevents metamorphosis that is initiated by the molting hormone 20-hydroxyecdysone (20E). During the last decade, significant advances have been made regarding JH signaling. First, the bHLH-PAS transcription factor Met/Gce was identified as the JH intracellular receptor. In the presence of JH, with the assistance of Hsp83, and through physical association with a bHLH?PAS transcriptional co-activator, Met/Gce enters the nucleus and binds to E-box-like motifs in promoter regions of JH primary?response genes for inducing gene expression. Second, the zinc finger transcription factor Kr-hl was identified as the anti-metamorphic factor which transduces JH signaling. Via Kr-hl binding sites, Kr-hl represses expression of 20E primary?response genes (i.e. Bi\ E93 and E5) to prevent 20E-induced metamorphosis. Third, through the intracellular signaling, JH promotes differ ent aspects of female reproduction. Nevertheless, this action varies greatly from species to species. Last, a hypothetical JH membrane receptor has been predicted to be either a GPCR or a tyrosine kinase receptor. In future, it will be a great challenge to understand how the JH intracellular receptor Met/Gce and the yet unidentified JH membrane receptor coordinate to regulate metamorphosis and reproduction in insects. 展开更多
关键词 INTRACELLULAR RECEPTOR JUVENILE HORMONE (JH) Kr-h 1 membrane RECEPTOR Met/Gce METAMORPHOSIS reproduction
Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy
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作者 Zhao Zhang Jun Jiang +7 位作者 Xiaodong Wu Mengyao Zhang Dan Luo Renyu Zhang Shiyou Li Youwen He Huijie Bian Zhinan Chen 《医学前沿:英文版》 CAS CSCD 2019年第1期57-68,共12页
Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising f... Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvlll) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-γ, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvlll in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery. 展开更多
关键词 CHIMERIC ANTIGEN RECEPTOR T cells epidennal growth factor RECEPTOR lung cancer IMMUNOTHERAPY tumor IMMUNOLOGY
DNMT3A/3B overexpression might be correlated with poor patient survival, hypermethylation and low expression of ESR1/PGR in endometrioid carcinoma: an analysis of The Cancer Genome Atlas
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作者 Dan He Xiao Wang +3 位作者 Yan Zhang Jian Zhao Rui Han Ying Dong 《中华医学杂志:英文版》 SCIE CAS CSCD 2019年第2期161-170,共10页
Background:DNA methylation is involved in numerous biologic events and associates with transcriptional gene silencing, playing an important role in the pathogenesis of endometrial cancer.ESR1/PGR frequently undergoes ... Background:DNA methylation is involved in numerous biologic events and associates with transcriptional gene silencing, playing an important role in the pathogenesis of endometrial cancer.ESR1/PGR frequently undergoes de novo methylation and loss expression in a wide variety of tumors, including breast, colon, lung, and brain tumors.However, the mechanisms underlying estrogen and progesterone receptors (ER/PR) loss in endometrial cancer have not been studied extensively.The aims of this study were to determine the expression of DNA (cytosine-5)-methyltransferase 3A/3B (DNMT3A/3B) in endometrial cancer to investigate whether the methylation catalyzed by DNMT3A/3B contributes to low ER/PR expression.Methods:The clinicopathologic information and RNA-Seq expression data of DNMT3A/3B of 544 endometrial cancers were derived from The Cancer Genome Atlas (TCGA) uterine cancer cohort in May 2018.RNA-Seq level of DNMT3A/3B was compared between these clinicopathologic factors with t-test or one-way analysis of variance.Results:DNMT3A/3B was overexpressed in endometrioid carcinoma (EEC) and was even higher in non-endometrioid carcinoma (NEEC) (DNMT3A, EEC vs.NEEC:37.6% vs.69.9%, t=-7.440, P<0.001;DNMT3B, EEC vs.NEEC:42.4% vs.72.8 %, t=-6.897, P<0.001).In EEC, DNMT3A overexpression was significantly correlated with the hypermethylation and low expression of the ESR1 and PGR (P<0.05).The same trend was observed in the DNMT3B overexpression subgroup.In the ESR1/PGR low-expression subgroups, as much as 83.1% of ESR1 and 59.5% of PGR were hypermethylated, which was significantly greater than the ESR1/PGR high-expression subgroups (31.3% and 11.9%, respectively).However, the above phenomena were absent in NEEC, while DNMT3A/3B overexpression, ESR1/PGR hypermethylation, and low ER/PR expression occurred much more often.In univariate analysis, DNMT3A/3B overexpressions were significantly correlated with worse prognosis.In multivariate analysis, only DNMT3A was an independent predictor of disease-free survival (P<0.05).Conclusions:DNM 展开更多
关键词 DNA (cytosine-5)-methyltransferase 3A/3B ESTROGENS RECEPTOR Progesterone RECEPTOR Endometrial carcinoma The Cancer Genome ATLAS
Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats 预览
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作者 Xiao-Jing Du Yue-Xia Chen +3 位作者 Zun-Cheng Zheng Nan Wang Xiao-Yu Wang Fan-E Kong 《中国神经再生研究:英文版》 SCIE CAS CSCD 2019年第5期876-885,共10页
P2X4 and P2X7 receptors play an important role in neuropathic pain after spinal cord injury.Regulation of P2X4 and P2X7 receptors can obviously reduce pain hypersensitivity after injury.To investigate the role of neur... P2X4 and P2X7 receptors play an important role in neuropathic pain after spinal cord injury.Regulation of P2X4 and P2X7 receptors can obviously reduce pain hypersensitivity after injury.To investigate the role of neural stem cell transplantation on P2X receptor-mediated neuropathic pain and explore related mechanisms,a rat model of spinal cord injury was prepared using the free-falling heavy body method with spinal cord segment 10 as the center.Neural stem cells were injected into the injured spinal cord segment using a micro-syringe.Expression levels of P2X4 and P2X7 receptors,neurofilament protein,and glial fibrillary acidic protein were determined by immunohistochemistry and western blot assay.In addition,sensory function was quantitatively assessed by current perception threshold.The Basso-Beattie-Bresnahan locomotor rating scale was used to assess neuropathological pain.The results showed that 4 weeks after neural stem cell transplantation,expression of neurofilament protein in the injured segment was markedly increased,while expression of glial fibrillary acidic protein and P2X4 and P2X7 receptors was decreased.At this time point,motor and sensory functions of rats were obviously improved,and neuropathic pain was alleviated.These findings demonstrated that neural stem cell transplantation reduced overexpression of P2X4 and P2X7 receptors,activated locomotor and sensory function reconstruction,and played an important role in neuropathic pain regulation after spinal cord injury.Therefore,neural stem cell transplantation is one potential option for relieving neuropathic pain mediated by P2X receptors. 展开更多
关键词 NERVE REGENERATION cell transplantation sensory NERVE FUNCTION GLIAL fibrillary acidic protein NEUROFILAMENT P2X4 RECEPTOR P2X7 RECEPTOR microglial cells perception threshold hind limb FUNCTION GLIAL hyperplasia neural REGENERATION
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