Bayesian enrichment strategies for randomized discontinuation trials

We propose optimal choice of the design parameters for random discontinuation designs (RDD) using a Bayesian decision-theoretic approach. We consider applications of RDDs to oncology phase II studies evaluating activity of cytostatic agents. The design consists of two stages. The preliminary open-label stage treats all patients with the new agent and identifies a possibly sensitive subpopulation. The subsequent second stage randomizes, treats, follows, and compares outcomes among patients in the identified subgroup, with randomization to either the new or a control treatment. Several tuning parameters characterize the design: the number of patients in the trial, the duration of the preliminary stage, and the duration of follow-up after randomization. We define a probability model for tumor growth, specify a suitable utility function, and develop a computational procedure for selecting the optimal tuning parameters.     

Synergistic effects in the designs of neuraminidase ligands: Analysis from docking and molecular dynamics studies

Docking and molecular dynamics were used to study the nine ligands (see Scheme 1) at the neuraminidase (NA) active sites. Their binding modes are structurally and energetically different, with details given in the text. Compared with 1A (oseltamivir carboxylate), the changes of core template or/and functional groups in the other ligands cause the reductions of interaction energies and numbers of H-bonds with the NA proteins. Nonetheless, all these ligands occupy the proximity space at the NA active sites and share some commonness in their binding modes. The fragment approach was then used to analyze and understand the binding specificities of the nine ligands. The contributions of each core template and functional group were evaluated. It was found that the core templates rather than functional groups play a larger role during the binding processes; in addition, the binding qualities are determined by the synergistic effects of the core templates and functional groups. Among the nine ligands, 1A (oseltamivir carboxylate) has the largest synergistic energy and its functional groups fit perfectly with the NA active site, consistent with the largest interaction energy, numerous H-bonds with the NA active-site residues as well as experimentally lowest IC₅₀ value. Owing to the poorer metabolizability than oseltamivir, large contribution of the benzene core template and fine synergistic effects of the functional groups, the 4-(N-acetylamino)-5-guanidino-3-(3-pentyloxy)benzoic acid should be an ideal lead compound for optimizing NA drugs.     

广藿香FPPS基因原核表达及茉莉酸甲酯对FPPS表达量的影响

法尼基焦磷酸合酶(farnesyl diphosphate synthase,FPPS)是广藿香甲羟戊酸途径中萜类物质生物合成的关键酶,其催化异戊二烯焦磷酸(IPP)和二甲基烯丙基焦磷酸(DMAPP)合成萜类物质前体法尼基焦磷酸。为了进一步研究广藿香萜类合成途径的分子机制,该文通过逆转录聚合酶链式反应获得FPPS基因的cDNA序列,利用生物信息学软件预测FPPS编码蛋白的理化性质、结构和功能。结果表明:(1)该序列的开放阅读框全长1 050 bp,编码349个氨基酸,预测分子量为40 KD,等电点为5.43,存在一个结构域,参与异戊二烯化合物的合成,不存在信号肽,亚细胞定位于细胞质;系统发育分析结果显示,广藿香FPPS氨基酸序列和丹参(Salvia miltiorrhiza)、撒尔维亚(S. officinalis)的氨基酸序列亲缘关系最近。(2)使用无缝克隆技术构建pET-32b-FPPS原核表达载体,并导入菌株BL21(DE3)中,考察不同浓度异丙基-β-D-硫代半乳糖苷(IPTG)对诱导融合蛋白的表达量的影响。结果发现融合表达蛋白以包涵体形式存在沉淀中,4个浓度的IPTG诱导蛋白表达效果差异不明显。(3)采用荧光定量技术分析0.10、0.25 mmol·L-1MeJA对FPPS基因表达水平的影响,发现0.10 mmol·L~(-1)MeJA诱导后FPPS基因的表达量趋势是先升高后降低再升高再降低; 0.25 mmol·L~(-1)MeJA诱导后FPPS基因的表达量趋势是先降低后升高再降低。因此,推测植物体内MeJA浓度的变化能影响FPPS基因的表达,高浓度具抑制作用,低浓度具促进作用。本研究为广藿香萜类合成途径的研究奠定基础,以及为后续基因功能验证提供理论参考。     

STATISTICAL OPTIMIZATION OF A NOVEL LOW-COST MEDIUM BASED ON REGIONAL AGRO-INDUSTRIAL BY-PRODUCTS FOR THE PRODUCTION OF PROTEOLYTIC ENZYMES BY Bacillus cereus

Bacillus sp. are specific producers of peptidase amongst bacteria and peptidase enzymes and are of significant ones due to their multifarious applications. Advances in industrial biotechnology offer potential opportunities for economic utilization of agro-industrial by-products for many biochemical reactions. Due to their rich organic nature, they can serve as an ideal substrate for the production of different value added products like peptidases. In the present work, an attempt was made to optimize different variables by Taguchi methodology for the production of peptidase using agro-industrial by-products hydrolyzed by a Bacillus cereus strain, resulting in brewer's spent grain (BSG) being the optimal organic substrate. Subsequently, operative variables for the BSG were investigated using Taguchi methodology in order to maximize the enzyme production. Additionally, the main medium components were optimized using a mixture design. Finally, the production of peptidase by B. cereus was investigated; also the possible interaction with other proteolytic microbial strains was evaluated. A notorious synergistic effect was observed when B. cereus was inoculated with Pseudomonas sp. These brought a triple benefit, first, opening the possibility to produce technical enzymes at low cost, second, giving greater value to a food industry by-product, and third, reducing the environmental impact caused by the product removal directly into the environment.     

The placebo response in clinical trials: more questions than answers

Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This 'additive model' is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in 'comparator' studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.     

Sex-biased genetic component distribution among populations: additive genetic and maternal contributions to phenotypic differences among populations of Chinook salmon

An approach frequently used to demonstrate a genetic basis for population-level phenotypic differences is to employ common garden rearing designs, where observed differences are assumed to be attributable to primarily additive genetic effects. Here, in two common garden experiments, we employed factorial breeding designs between wild and domestic, and among wild populations of Chinook salmon (Oncorhynchus tshawytscha). We measured the contribution of additive (V(A)) and maternal (V(M)) effects to the observed population differences for 17 life history and fitness-related traits. Our results show that, in general, maternal effects contribute more to phenotypic differences among populations than additive genetic effects. These results suggest that maternal effects are important in population phenotypic differentiation and also signify that the inclusion of the maternal source of variation is critical when employing models to test population differences in salmon, such as in local adaptation studies.     

Osteochondral tissue engineering: scaffolds, stem cells and applications

Osteochondral tissue engineering has shown an increasing development to provide suitable strategies for the regeneration of damaged cartilage and underlying subchondral bone tissue. For reasons of the limitation in the capacity of articular cartilage to self-repair, it is essential to develop approaches based on suitable scaffolds made of appropriate engineered biomaterials. The combination of biodegradable polymers and bioactive ceramics in a variety of composite structures is promising in this area, whereby the fabrication methods, associated cells and signalling factors determine the success of the strategies. The objective of this review is to present and discuss approaches being proposed in osteochondral tissue engineering, which are focused on the application of various materials forming bilayered composite scaffolds, including polymers and ceramics, discussing the variety of scaffold designs and fabrication methods being developed. Additionally, cell sources and biological protein incorporation methods are discussed, addressing their interaction with scaffolds and highlighting the potential for creating a new generation of bilayered composite scaffolds that can mimic the native interfacial tissue properties, and are able to adapt to the biological environment.     

Non-Iterative Least Squares Estimation of Missing Values in Replicated Latin Square Designs

In this paper an attempt has been made to estimate several missing values in replicated latin square designs. The explicit computable expressions for the non-iterative least squares estimates of the missing values are presented for particular patterns of missing values.