At thermal ultra-cold neutron (UCN) sources (neutrons in thermal equilibrium with the moderator) only a very small fraction of neutrons have velocities ~6 m/s. Therefore, the UCN production rate cannot be substantiall...At thermal ultra-cold neutron (UCN) sources (neutrons in thermal equilibrium with the moderator) only a very small fraction of neutrons have velocities ~6 m/s. Therefore, the UCN production rate cannot be substantially increased by simply lowering the temperature of the moderator. The new approach is to use the super-thermal principle, i.e., neutrons not in thermal equilibrium with the converter. We want to investigate scattering kernels for a super-thermal UCN source based on a two-layer arrangement of D2O and solid D2. The solid D2 (sD2) at temperature 8 K is kept in close contact with D2O moderator at room temperature. Using the MCNP code, the fast neutron flux on the spallation target, the thermal flux in the D2O near the sD2, and the cold flux in the sD2 are simulated. For a given cold flux, neutron transport equations are calculated. In order to obtain precise neutron scattering kernels, and consequently UCN flux and density, 330 neutron energy groups have been taken. The coupled energy dependent transport equations have been solved by combining MCNPX code with an analytical approach and using implicit method in MATLAB. We have obtained an optimal dimension for the UCN source. A suitable space step has been taken for the numerical stability.展开更多
UCN-01 (7-Hydroxystaurosporine) is an investigational anticancer agent that is currently being evaluated as targeted therapy in phase II clinical studies. The aims of this work were to describe the population pharmaco...UCN-01 (7-Hydroxystaurosporine) is an investigational anticancer agent that is currently being evaluated as targeted therapy in phase II clinical studies. The aims of this work were to describe the population pharmacokinetics of UCN-01 in patients with advanced solid tumors, and to identify covariates in patients with advanced solid tumors that affected the pharmacokinetic parameters of UCN-01. The utility of performing this research is to provide optimization of treatment and individualized dose therapy for minimization of toxicity. So, in addition to elucidating the population pharmacokinetic parameter estimates from a Phase I trial where UCN-01 was given in combination with carboplatin in patients with advanced solid tumors, and a trial where the drug was given alone as a 72-hour infusion in the same type of population, a covariate analysis was performed in order to identify pharmacokinetic determinants of UCN-01. Using NONMEM to perform nonlinear mixed-effects modeling, a linear two-compartment model was found to provide the best fit for UCN-01 data. A meta-analysis was performed, which included pooled 3-hour and 72-hour infusion data, and provided population pharmacokinetic estimates for CL (0.0157 L/hr [6.1%RSE]), V1 (2.51 L [10.0% RSE]), Q (4.05 L/hr [14.3% RSE]), and V2 (8.39 L [6.6% RSE]). Inter-individual variability was found for each of the main pharmacokinetic parameters to be ETACL (44.9% [20.8% RSE]), ETAV1 (43.9% [39.8% RSE]), ETAQ (6.09% [62.5% RSE]), and ETAV2 (4.17% [30.0% RSE]). Body surface area was found to be a statistically-significant variable from one of the individual study analyses (3-hour infusion). Population PK modeling has contributed to a better understanding of the clinical pharmacology of UCN-01. Dose individualization may improve treatment with UCN-01. Further clinical development may be supported by optimization of combination chemotherapy.展开更多
该研究通过构建携带突变的血小板融合细胞系,探讨12S r RNA 1555A>G和CO1/t RNA^(Ser(UCN))7444G>A突变对线粒体功能的影响。首先,采集携带12S r RNA 1555A>G和CO1/t RNA^(Ser(UCN))7444G>A双突变、单突变及正常对照组患者...该研究通过构建携带突变的血小板融合细胞系,探讨12S r RNA 1555A>G和CO1/t RNA^(Ser(UCN))7444G>A突变对线粒体功能的影响。首先,采集携带12S r RNA 1555A>G和CO1/t RNA^(Ser(UCN))7444G>A双突变、单突变及正常对照组患者外周血,构建血小板融合细胞系。其次,对构建成功的血小板融合细胞系进行一系列功能研究,包括细胞内活性氧类(ROS)生成量、线粒体膜电位水平、蛋白质水平和t RNA稳态水平的分析。通过对各组血小板融合细胞系的线粒体功能的研究,结果与对照组相比发现,细胞内ROS生成量显示,仅携带m.1555A>G单突变组细胞ROS上升66.54%,仅携带m.7444G>A单突变组细胞ROS上升83.09%,而同时携带m.1555A>G和m.7444G>A双突变组细胞ROS上升131.08%;线粒体膜电位水平显示,m.1555A>G单突变组的ΔΨm水平下降32.86%,m.7444G>A单突变组的ΔΨ水平下降0.66%,m.1555A>G和m.7444G>A双突变组的ΔΨm水平下降29.86%;Western blot结果显示,各突变样本的CO1、CO2均有不同程度的下降,仅携带m.1555A>G单突变组中ND4、ND5和ND6差异不明显,而仅携带m.7444G>A单突变组和m.1555A>G和m.7444G>A双突变组中ND4、ND5和ND6均有不同程度的下降;Northern blot结果显示,m.7444G>A对t RNA^(Ser(UCN))稳态水平的改变并不是很明显。提示CO1/t RNA^(Ser(UCN))7444G>A突变可能只是12S r RNA 1555A>G突变的病理效应的修饰因子,但在耳聋的发生过程中,还是12S r RNA 1555A>G突变起主导作用。展开更多
文摘At thermal ultra-cold neutron (UCN) sources (neutrons in thermal equilibrium with the moderator) only a very small fraction of neutrons have velocities ~6 m/s. Therefore, the UCN production rate cannot be substantially increased by simply lowering the temperature of the moderator. The new approach is to use the super-thermal principle, i.e., neutrons not in thermal equilibrium with the converter. We want to investigate scattering kernels for a super-thermal UCN source based on a two-layer arrangement of D2O and solid D2. The solid D2 (sD2) at temperature 8 K is kept in close contact with D2O moderator at room temperature. Using the MCNP code, the fast neutron flux on the spallation target, the thermal flux in the D2O near the sD2, and the cold flux in the sD2 are simulated. For a given cold flux, neutron transport equations are calculated. In order to obtain precise neutron scattering kernels, and consequently UCN flux and density, 330 neutron energy groups have been taken. The coupled energy dependent transport equations have been solved by combining MCNPX code with an analytical approach and using implicit method in MATLAB. We have obtained an optimal dimension for the UCN source. A suitable space step has been taken for the numerical stability.
文摘UCN-01 (7-Hydroxystaurosporine) is an investigational anticancer agent that is currently being evaluated as targeted therapy in phase II clinical studies. The aims of this work were to describe the population pharmacokinetics of UCN-01 in patients with advanced solid tumors, and to identify covariates in patients with advanced solid tumors that affected the pharmacokinetic parameters of UCN-01. The utility of performing this research is to provide optimization of treatment and individualized dose therapy for minimization of toxicity. So, in addition to elucidating the population pharmacokinetic parameter estimates from a Phase I trial where UCN-01 was given in combination with carboplatin in patients with advanced solid tumors, and a trial where the drug was given alone as a 72-hour infusion in the same type of population, a covariate analysis was performed in order to identify pharmacokinetic determinants of UCN-01. Using NONMEM to perform nonlinear mixed-effects modeling, a linear two-compartment model was found to provide the best fit for UCN-01 data. A meta-analysis was performed, which included pooled 3-hour and 72-hour infusion data, and provided population pharmacokinetic estimates for CL (0.0157 L/hr [6.1%RSE]), V1 (2.51 L [10.0% RSE]), Q (4.05 L/hr [14.3% RSE]), and V2 (8.39 L [6.6% RSE]). Inter-individual variability was found for each of the main pharmacokinetic parameters to be ETACL (44.9% [20.8% RSE]), ETAV1 (43.9% [39.8% RSE]), ETAQ (6.09% [62.5% RSE]), and ETAV2 (4.17% [30.0% RSE]). Body surface area was found to be a statistically-significant variable from one of the individual study analyses (3-hour infusion). Population PK modeling has contributed to a better understanding of the clinical pharmacology of UCN-01. Dose individualization may improve treatment with UCN-01. Further clinical development may be supported by optimization of combination chemotherapy.
文摘该研究通过构建携带突变的血小板融合细胞系,探讨12S r RNA 1555A>G和CO1/t RNA^(Ser(UCN))7444G>A突变对线粒体功能的影响。首先,采集携带12S r RNA 1555A>G和CO1/t RNA^(Ser(UCN))7444G>A双突变、单突变及正常对照组患者外周血,构建血小板融合细胞系。其次,对构建成功的血小板融合细胞系进行一系列功能研究,包括细胞内活性氧类(ROS)生成量、线粒体膜电位水平、蛋白质水平和t RNA稳态水平的分析。通过对各组血小板融合细胞系的线粒体功能的研究,结果与对照组相比发现,细胞内ROS生成量显示,仅携带m.1555A>G单突变组细胞ROS上升66.54%,仅携带m.7444G>A单突变组细胞ROS上升83.09%,而同时携带m.1555A>G和m.7444G>A双突变组细胞ROS上升131.08%;线粒体膜电位水平显示,m.1555A>G单突变组的ΔΨm水平下降32.86%,m.7444G>A单突变组的ΔΨ水平下降0.66%,m.1555A>G和m.7444G>A双突变组的ΔΨm水平下降29.86%;Western blot结果显示,各突变样本的CO1、CO2均有不同程度的下降,仅携带m.1555A>G单突变组中ND4、ND5和ND6差异不明显,而仅携带m.7444G>A单突变组和m.1555A>G和m.7444G>A双突变组中ND4、ND5和ND6均有不同程度的下降;Northern blot结果显示,m.7444G>A对t RNA^(Ser(UCN))稳态水平的改变并不是很明显。提示CO1/t RNA^(Ser(UCN))7444G>A突变可能只是12S r RNA 1555A>G突变的病理效应的修饰因子,但在耳聋的发生过程中,还是12S r RNA 1555A>G突变起主导作用。
