A multistate model for early decision-making in oncology

The development of oncology drugs progresses through multiple phases, where after each phase, a decision is made about whether to move a molecule forward. Early phase efficacy decisions are often made on the basis of single-arm studies based on a set of rules to define whether the tumor improves (“responds”), remains stable, or progresses (response evaluation criteria in solid tumors [RECIST]). These decision rules are implicitly assuming some form of surrogacy between tumor response and long-term endpoints like progression-free survival (PFS) or overall survival (OS). With the emergence of new therapies, for which the link between RECIST tumor response and long-term endpoints is either not accessible yet, or the link is weaker than with classical chemotherapies, tumor response-based rules may not be optimal. In this paper, we explore the use of a multistate model for decision-making based on single-arm early phase trials. The multistate model allows to account for more information than the simple RECIST response status, namely, the time to get to response, the duration of response, the PFS time, and time to death. We propose to base the decision on efficacy on the OS hazard ratio (HR) comparing historical control to data from the experimental treatment, with the latter predicted from a multistate model based on early phase data with limited survival follow-up. Using two case studies, we illustrate feasibility of the estimation of such an OS HR. We argue that, in the presence of limited follow-up and small sample size, and making realistic assumptions within the multistate model, the OS prediction is acceptable and may lead to better early decisions within the development of a drug.     

分子诊断实验室去除核酸污染的方法学研究

核酸检测因具有良好的灵敏度和特异性而被广泛应用于体外诊断、动植物商品检疫、法医鉴定等领域.然而操作过程中易受到核酸污染导致的假阳性结果,严重影响了检测准确性.因此寻找一种有效的防止和清除核酸污染的方案对于实验室正常运转及保障检测结果的可靠性具有重要意义.文中比较了几种不同清除核酸污染的方法,确认了 84消毒液和PCRg...     

A molecular model for vesicle formation

A molecular model is proposed to explain vesicle formation. The model is based on a balance between elastic and ‘hydrophobic’ forces for various micelle and bilayer geometries in dilute aqueous solutions. It predicts bilayered disc-like transition structures and is in agreement with experimental data.     

A molecular model for the retinol binding protein-transthyretin complex

A three-dimensional model for the complex between human serum retinol binding protein and transthyretin (formerly named prealbumin) is presented. The model was obtained by interactive rigid-body computer graphics docking and the characterization of the molecular surfaces in terms of fractal dimension. Available experimental data, as well as results from molecular dynamics calculations, support the proposed model.     

A laboratory hot tub model for disinfectant efficacy evaluation

This paper describes a novel laboratory hot tub (LHT) apparatus and associated standard operating procedure (SOP) designed to reproduce the key biological, chemical, and engineering parameters associated with recreational and therapeutic hot tubs. Efficacy, as measured quantitatively by log reduction values, was determined against both biofilm and planktonic bacteria. When the LHT was run according to the SOP, with no antimicrobial treatment, a consistent level of bacterial contamination occurred. The means of log10 viable cell densities (+/- the repeatability standard deviation of log densities) were 7.2 (+/-0.31) for the bulk water (density in units of cfu ml-1), 5.3 (+/-0.56) for the coupons (density in units of cfu cm-2), and 6.6 (+/-0.50) for the filters (density in units of cfu cm-2). When control and chlorine treated LHTs were run in parallel, the log reduction increased significantly with chlorine concentration for samples of planktonic bacteria in the bulk water (p=0.016), biofilm bacteria on the coupons (p=0.09) and biofilm bacteria on the filter (p=0.005), indicating that the method was sensitive to chlorine concentration. The method also displayed sensitivity by differentiating between chlorine and bromine treatments; in every case, chlorine produced a greater log reduction than did the same concentration of bromine. The model and SOP were shown to be rugged with respect to slight changes in fluid mixing intensity, water chemistry (saturation index), inoculum size, and organic loading. The LHT and associated SOP provide a reliable second tier in a three-tiered testing process, in which the first tier is a suspension test and the final tier is a field test.     

A molecular model for sporadic human aneuploidy

Aneuploidy is a leading cause of birth defects and a significant contributor to infertility in humans. Maternal age is the only well-established risk factor for gametic aneuploidy in the general population, with the underlying cause(s) yet to be identified. Here we present an extension of the 'two-hit' model for sporadic human aneuploidy. An important implication of this model is that the genetic makeup of an individual will influence the threshold where recombinationally at-risk oocytes (hit-1 events) become sensitive to the effects of advancing age (hit-2 events). Consequently, the age-related risk of gametic aneuploidy in many individuals is likely to differ significantly from the population average, and single nucleotide polymorphisms (SNPs) associated with altered risk should be identifiable.     

Earthquakes and building design: a primer for the laboratory animal professional

Earthquakes can occur in most regions of the United States, so it might be necessary to reinforce vulnerable animal facilities to better protect research animals during these unpredictable events. A risk analysis should include an evaluation of the seismic hazard risk at the proposed building site balanced against the estimated consequences of losses. Risk analysis can help in better justifying and recommending to building owners the costs of incorporating additional seismic reinforcements. The planning team needs to specify the level of post-earthquake building function that is desired in the facility, and then design the facility to it.     

A detailed molecular model for human aromatase

Using a variety of techniques, including sequence alignment, secondary struucture prediction, molecular mechanics and molecular dynamics, we have constructed a model for the three-dimensional structure of P-450_AROM (human aromatase) based on that of P-450_cam, the only cytochrome P-450 enzyme for which crystal structure is known. The predicted structure is found to be in good agreement with current experimental data; both direct, from site-directed mutagenesis studies, and indirect, from the consideration of the structures and activities of known substrates and inhibitors.     

A molecular model for proflavine-DNA intercalation.

A molecular model has been derived for the intercalation of proflavine into the CpG site of the decamer duplex of d(GATACGATAC). The starting geometry of the intercalation site was taken from previous crystallographic studies on the d(CpG)-proflavine complex, and molecular mechanics used to obtain a stereochemically acceptable structure. This has widened grooves compared to standard A- or B- double helices, as well as distinct conformational, roll, twist and tilt features.