Premature regression of the leg apical ectodermal ridge in the Japanese chick wingless mutant

The autosomal dominant Japanese wingless mutant has varying degrees of wing and leg truncations. The wing defects range from complete loss to negligible defects, whereas leg abnormalities are usually restricted to loss of the phalanges. Further analyses of the mutant focusing on the leg, which has been relatively uncharacterized, were performed. The expression pattern of Fgf8, a marker gene for the apical ectodermal ridge (AER) that controls outgrowth of the limbs, revealed premature regression at stage 28. Electron microscopy study showed abnormalities in the basement membrane all through the AER in the same stage. In the mutant, cell death was observed in the mesenchyme underlying AER between stages 31 and 32, although in the wild-type leg, AER regression and cell death occurred almost simultaneously at stages 33–34. To know if the cell death and cessation of the outgrowth are common mechanisms of wild-type and the mutant, we removed the AER in wild-type embryos at stage 28 and followed the fate of the limb. This also resulted in premature cell death 48 h after AER removal (equivalent to stage 32) and limb truncations similar to those observed in mutant limbs. To confirm whether either AER or underlying mesenchyme is responsible for the truncation, transplantation of the AER between the wild-type and the mutant was performed. This revealed that AER is the defective tissue in this mutant.     

Methods for assessing whether change depends on initial value

Statistical analysis of whether the change in a variable depends on its initial value, in clinical trials and other studies, is complicated by the phenomenon of regression to the mean. We review this problem and examine some approaches for handling it. MacGregor's log-log plot fails to correct for the regression effect, while Oldham's method of plotting the change against the average of initial and final values is shown to give misleading results when the effect of treatment varies between subjects, or when subjects are selected for study if their initial observations fall above or below a specified cut-off point. These results are illustrated by computer simulations. We prefer the use of Blomqvist's method of correcting the association between change and initial value to allow for the regression effect.     

Modeling Sustained Treatment Effects in Tumor Xenograft Experiments

In cancer drug development, demonstrated efficacy in tumor xenograft models is an important step toward bringing a promising compound to human use. A key outcome variable is tumor volume measured over a period of time, while mice are treated with certain treatment regimens. A constrained parametric model has been proposed to account for special features, such as intrinsic tumor growth, or tumor volume truncations due to tumor size being either too large or too small to detect. However, since the drug concentration in the blood of a mouse or its tissues may be stabilized at a certain level and maintained during a period of time, the treatment may have sustained effects. This article extends the constrained parametric model to account for the sustained drug effects. The ECM algorithm for incomplete data is applied to estimating the dose-response relationship in the proposed model. The model selection based on likelihood functions is given and a simulation study is conducted to investigate the performance of the proposed estimator. A real xenograft study on the antitumor agent temozolomide combined with irinotecan against the rhabdomyosarcoma is analyzed using the proposed methods.     

截短型乙型肝炎病毒表面抗原中蛋白反式激活作用的初步研究

目的 探讨乙型肝炎病毒（HBV）表面抗原中蛋白羧基末端缺失突变体（MHBs^t)的反式激活功能。方法 用聚合酶链反应（PCR）扩增截短的HBV表面抗原中蛋白（MHBs^t167)基因,克隆 至真核表达载体pcDNA3.1(-) 中,转染COS－7细胞,酶联免疫吸附法（ELISA）检测细胞MHBs^t167蛋白的瞬时表达;与报告质粒pSV-lacZ共转染COS－7细胞,检测β－半乳糖苷酶的活性。结果 构建成含有红500bp基因的质粒pcDNA3.1(-)-Mt,在COS－7细胞表达出相应蛋白,对pSV-lacZ的表达具有反式激活作用。结论 构建的表达载体能在哺乳 动物细胞中表达, 并具有反式激活功能。     

徐力运用“截断疗法”治疗宫颈人乳头瘤病毒感染经验撷菁

宫颈人乳头瘤病毒(HPV)感染是宫颈癌发生的必要条件,徐力教授善用“截断疗法”治疗HPV感染并阻截其向宫颈癌发展的进程。徐力教授认为运用“截断疗法”治疗HPV感染关键在于掌握其病因病机及发展规律从而先证而治,同时须从阻截显证及预截潜证两方面着手打击病邪,以求彻底歼灭病邪。徐力教授认为宫颈HPV感染主要因湿邪为患,加之脾气虚弱,水液内停,肝失疏泄,肝肾失养,肝脾肾脏腑功能失调,以致冲任受损、带脉失约,发而为病。故而以四妙散为基本方加减化裁,并联合对症用药及疏肝养肝、健脾补肾、解毒抗癌之品以“先安未受邪之地”,每获良效。     

整合素β3胞浆段尾部序列对αvβ3介导的细胞行为的影响

目的:探讨在与整合素αv复合的模式下,整合素β3亚基胞浆段序列在肿瘤细胞的黏附、伸展和迁移中所起的作用,从而为寻找干扰肿瘤进展的分子靶点提供思路。方法:利用中国仓鼠卵巢(CHO)细胞模型,建立共表达整合素αv与整合素β3全长及其T758、Y759位截短体的稳定细胞株,检测各稳定细胞株在固相化的αvβ3配体玻璃黏连蛋白上的黏附、伸展功能,运用transwell观察各细胞株的迁移能力。结果:稳定表达整合素αvβ3全长的CHO细胞具有在固相化玻璃黏连蛋白上的黏附、伸展和迁移能力。相较于CHO-αvβ3全长细胞株,CHO-αvβ3△758截短体细胞株的黏附、伸展以及迁移能力均明显受损;而CHO-αvβ3△759截短体细胞株仍保留着黏附能力,但伸展能力减弱,并且迁移能力受损明显。结论:整合素β3胞浆尾端YRGT和RGT氨基酸序列在αvβ3介导的细胞黏附和迁移方面发挥不同的作用,提示β3亚基胞内段参与调控肿瘤细胞的重要细胞行为,是潜在的肿瘤治疗靶点。     

Hierarchical Models for Tumor Xenograft Experiments in Drug Development

Abstract

In cancer drug development, demonstrated anticancer activity in animal models is an important step to bring a promising compound to clinic. Proper design and analysis of experiments using laboratory animals have received increasing attention recently. These experiments involve informatively censored longitudinal data with small samples. The problem is further complicated because of order constraints due to the intrinsic growth of control tumors without treatment. This article proposes a Bayesian hierarchical model to analyze informatively censored longitudinal data while accounting for the parameter constraints and providing valid small sample inference. We adopt a noniterative sampling approach, the inverse Bayes formulae (IBF) sampler, to generate independent posterior samples, which avoids convergence problems associated with Markov chain Monte-Carlo methods. To effectively deal with the restricted parameter problem, we use a linear transformation to simplify the constraints and exploit the IBF method to generate random samples from truncated multivariate normal distributions. Because diffuse priors are used, the posterior modes approximate the maximum likelihood estimates well, and the hierarchical model can be considered as an extended mixed-effects model. A real xenograft experiment on a new treatment is analyzed by using the proposed method.     

磁共振截断频谱图像的层析法边缘检测技术

本文提出一种适合于含有截断伪影磁共振图像的边缘检测新算法。按奇异函数分析理论 ,把任何有截断伪影的信号表示为以奇异点为参量的截断奇异函数的加权和 ,奇异点和加权系数由该信号决定。层析边缘检测的关键在于一层层地剥去奇异点上的加权截断奇异函数 ,从而一层层地检测出奇异点。这些奇异点可以构成图像的边缘。本方法可以有效地剔除由截断伪影而引入的虚假边缘。实际和仿真结果都表明这种方法效果高于现有方法     

Extreme Rank Selections for Linkage Analysis of Quantitative Trait Loci Using Selected Sib-Pairs

It is well known that linkage analysis using simple random sib-pairs has relatively low power for detecting quantitative trait loci with small genetic effects. The power can be substantially increased by using samples selected based on their trait values. Usually, samples that are obtained by truncation selection consist of random samples from a truncated trait distribution. In this article we propose an alternative method using extreme ranks for linkage analysis with selected sib-pairs. This approach approximates the truncation selection. With similar screening sizes and the same sample size of selected sib-pairs, the extreme rank selection and truncation method have similar power performance, both of which are substantially more powerful than when using random sib-pairs. Simulation results on the comparison of powers between the truncation selection and the extreme rank selection and/or random selection for linkage analysis are reported.