Niclosamide,an oral antihelminthic drug,has been used to treat tapeworm infection for about 50 years.Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs.Recently,several ...Niclosamide,an oral antihelminthic drug,has been used to treat tapeworm infection for about 50 years.Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs.Recently,several groups have independently discovered that niclosamide is also active against cancer cells,but its precise mechanism of antitumor action is not fully understood.Evidence supports that niclosamide targets multiple signaling pathways (NF-κB,Wnt/β-catenin,Notch,ROS,mTORC1,and Stat3),most of which are closely involved with cancer stem cells.The exciting advances in elucidating the antitumor activity and the molecular targets of this drug will be discussed.A method for synthesizing a phosphate pro-drug of niclosamide is provided.Given its potential antitumor activity,clinical trials for niclosamide and its derivatives are warranted for cancer treatment.展开更多
Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation.Unfortunately,once metastatic,no available therapy is curative.The vast majority will die despite a...Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation.Unfortunately,once metastatic,no available therapy is curative.The vast majority will die despite aggressive systemic combinational androgenablation therapies.Thus,there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer(mCRPC).To accomplish this goal,advantage can be taken of the unique biology of mCRPC cells.Like their normal cell of origin,mCRPCs retain expression of the prostate-specific differentiation protein,prostate-specific antigen(PSA),which they abundantly secrete into their extracellular fluid(ECF).This unique,and essentially universal,secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as“molecular grenades”covalently linked to cysteine-34 of human serum albumin(HSA)via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis(i.e.,“detonation”)releases the grenades restrictively within the ECF of mCRPC.This approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days(i.e.,pharmacokinetic effect)and increasing the tissue concentration of the maleimide coupled albumin delivery(MAD)in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites(i.e.,enhanced permeability and retention effect).This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic form.Only within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently“pull the pin”on the grenades releasing their lipophilic cellpenetrant toxins from HSA.Thus,if a sufficient level of“detonation”occurs,this will kill mCRPC cells,and sterilize the entire PSA-rich metastatic sites via a bystander effect.In this review,two examples of such MAD-PSA detonated molecular grenades are presenteddone based upon thapsigagin and the other on niclosamide.展开更多
The turbulence characteristics of plasmas with internal transport barriers in the HL-2A tokamak are analyzed by means of linear gyrokinetic simulations. It is found that turbulence is dominated by the ion temperature ...The turbulence characteristics of plasmas with internal transport barriers in the HL-2A tokamak are analyzed by means of linear gyrokinetic simulations. It is found that turbulence is dominated by the ion temperature gradient(ITG)mode together with large-scale modes characterized by high-frequency electromagnetic fluctuation, which are destabilized by the steep ion temperature gradient in the weak magnetic shear regime. Comparison with solutions of analytical dispersion relations shows that their linear features match well with the beta-induced Alfvén eigenmode branch of the shear Alfvénic spectrum. It is further clarified that the large population of fast ions in these plasmas plays a stabilization role through the dilution mechanism in high-n ITG mode regimes.展开更多
电力变压器匝间故障将导致绝缘击穿,甚至造成整个电网事故的发生,为此,应用在线频率响应分析法检测变压器绕组变形。通过安装于变压器套管表面的非侵入式电容传感器（NICS）将测试信号通过高压套管注入变压器绕组从而实现了绕组变形的...电力变压器匝间故障将导致绝缘击穿,甚至造成整个电网事故的发生,为此,应用在线频率响应分析法检测变压器绕组变形。通过安装于变压器套管表面的非侵入式电容传感器（NICS）将测试信号通过高压套管注入变压器绕组从而实现了绕组变形的在线监测。开发了基于脉冲信号注入法的变压器绕组变形在线监测系统。着重阐述了测试信号的选择,在线信号的注入,保护电路的设计。分析了信号源和采样频率对频响特性测试结果的影响。对一台型号为35 k VA/10 k V/400 V的配电变压器进行测试,并与安捷伦频谱网络分析仪4395A的测试结果进行对比发现,在0~5 MHz频率范围内,两条频响曲线的相关系数为0.955 3。结果表明,该系统能在在线状态下准确、快速地获取变压器绕组数10 MHz内的频响特性。监测系统具有较高的灵敏度和重复性,能有效检测变压器绕组变形。展开更多
基金supported in part by grants from National Natural Science Foundation of China for Distinguished Young Scholars(81025021)the National Basic Research Program of China(973Program grant2009CB825506)+2 种基金the Major Research Plan of the National Natural Science Foundation of China(90713036)the National High Technology Research and Development Program of China(863Program grant2008AA02Z420)the Fundamental Research Foundation for the Central Universities to Jing-Xuan Pan
文摘Niclosamide,an oral antihelminthic drug,has been used to treat tapeworm infection for about 50 years.Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs.Recently,several groups have independently discovered that niclosamide is also active against cancer cells,but its precise mechanism of antitumor action is not fully understood.Evidence supports that niclosamide targets multiple signaling pathways (NF-κB,Wnt/β-catenin,Notch,ROS,mTORC1,and Stat3),most of which are closely involved with cancer stem cells.The exciting advances in elucidating the antitumor activity and the molecular targets of this drug will be discussed.A method for synthesizing a phosphate pro-drug of niclosamide is provided.Given its potential antitumor activity,clinical trials for niclosamide and its derivatives are warranted for cancer treatment.
基金We would like to acknowledge the Prostate Cancer Foundation,Department of Defense Prostate Cancer Research Program(W81XWH-16-1-0410)NIH Prostate SPORE(P50 CA058236)Patrick C.Walsh Prostate Cancer Research Fund,and the Hopkins-Allegheny Health Network Cancer Research Fund。
文摘Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation.Unfortunately,once metastatic,no available therapy is curative.The vast majority will die despite aggressive systemic combinational androgenablation therapies.Thus,there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer(mCRPC).To accomplish this goal,advantage can be taken of the unique biology of mCRPC cells.Like their normal cell of origin,mCRPCs retain expression of the prostate-specific differentiation protein,prostate-specific antigen(PSA),which they abundantly secrete into their extracellular fluid(ECF).This unique,and essentially universal,secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as“molecular grenades”covalently linked to cysteine-34 of human serum albumin(HSA)via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis(i.e.,“detonation”)releases the grenades restrictively within the ECF of mCRPC.This approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days(i.e.,pharmacokinetic effect)and increasing the tissue concentration of the maleimide coupled albumin delivery(MAD)in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites(i.e.,enhanced permeability and retention effect).This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic form.Only within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently“pull the pin”on the grenades releasing their lipophilic cellpenetrant toxins from HSA.Thus,if a sufficient level of“detonation”occurs,this will kill mCRPC cells,and sterilize the entire PSA-rich metastatic sites via a bystander effect.In this review,two examples of such MAD-PSA detonated molecular grenades are presenteddone based upon thapsigagin and the other on niclosamide.
基金supported by the National Key Research and Development Program of China (Grant No. 2017YFE0301201)partially by the National Natural Science Foundation of China (Grant Nos. U1967206 and 11775069)。
文摘The turbulence characteristics of plasmas with internal transport barriers in the HL-2A tokamak are analyzed by means of linear gyrokinetic simulations. It is found that turbulence is dominated by the ion temperature gradient(ITG)mode together with large-scale modes characterized by high-frequency electromagnetic fluctuation, which are destabilized by the steep ion temperature gradient in the weak magnetic shear regime. Comparison with solutions of analytical dispersion relations shows that their linear features match well with the beta-induced Alfvén eigenmode branch of the shear Alfvénic spectrum. It is further clarified that the large population of fast ions in these plasmas plays a stabilization role through the dilution mechanism in high-n ITG mode regimes.
文摘电力变压器匝间故障将导致绝缘击穿,甚至造成整个电网事故的发生,为此,应用在线频率响应分析法检测变压器绕组变形。通过安装于变压器套管表面的非侵入式电容传感器（NICS）将测试信号通过高压套管注入变压器绕组从而实现了绕组变形的在线监测。开发了基于脉冲信号注入法的变压器绕组变形在线监测系统。着重阐述了测试信号的选择,在线信号的注入,保护电路的设计。分析了信号源和采样频率对频响特性测试结果的影响。对一台型号为35 k VA/10 k V/400 V的配电变压器进行测试,并与安捷伦频谱网络分析仪4395A的测试结果进行对比发现,在0~5 MHz频率范围内,两条频响曲线的相关系数为0.955 3。结果表明,该系统能在在线状态下准确、快速地获取变压器绕组数10 MHz内的频响特性。监测系统具有较高的灵敏度和重复性,能有效检测变压器绕组变形。
