Incorporating historical information to improve phase I clinical trials.

Incorporating historical data has a great potential to improve the efficiency of phase I clinical trials and to accelerate drug development. For model-based designs, such as the continuous reassessment method (CRM), this can be conveniently carried out by specifying a "skeleton," that is, the prior estimate of dose limiting toxicity (DLT) probability at each dose. In contrast, little work has been done to incorporate historical data into model-assisted designs, such as the Bayesian optimal interval (BOIN), Keyboard, and modified toxicity probability interval (mTPI) designs. This has led to the misconception that model-assisted designs cannot incorporate prior information. In this paper, we propose a unified framework that allows for incorporating historical data into model-assisted designs. The proposed approach uses the well-established "skeleton" approach, combined with the concept of prior effective sample size, thus it is easy to understand and use. More importantly, our approach maintains the hallmark of model-assisted designs: simplicity-the dose escalation/de-escalation rule can be tabulated prior to the trial conduct. Extensive simulation studies show that the proposed method can effectively incorporate prior information to improve the operating characteristics of model-assisted designs, similarly to model-based designs.

The Study of a New Type of Membrane for Biosensor.

Polyvinyl alcohol (PVA) was selected to develop a new type of membrane for biosensor. The PVA membrane was first activated by cyanogens bromide, followed by coupling with ethyl diamine. After treated by glutaraldehyde, glucose oxidase and lactate oxidase were immobilized onto the membrane respectively. Coupled with oxygen electrode, the enzyme membrane was used to construct glucose and lactate biosensor respectively. The linear range was 5 mg/dl-800 mg/dl for glucose and 1mg/dl-35 mg/dl for lactate, and the response time of these biosensors was 10 seconds.

Multi-center determination of galectin-3 assay performance characteristics: Anatomy of a novel assay for use in heart failure.

BACKGROUND: Galectin-3 is a carbohydrate binding protein that plays many important regulatory roles in inflammation, immunity and cancer. Recent studies indicate that galectin-3 is a mediator of heart failure development and progression. Development of an improved assay for galectin-3 measurement was necessary for appropriate clinical assessment. Key analytical performance characteristics, the reference distribution and association of galectin-3 levels with clinical outcome in heart failure patients are defined. METHODS: A two-site ELISA test was examined for measurement matrix, imprecision, limits of blank, detection, and quantitation, as well as linearity, high-dose hook effect, storage stability, cross-reactivity with nine similar compounds, interference with 22 common medications and icterus, lipemia and hemolysis, all in accordance with CLSI guidance. Also the effects of human anti-mouse antibodies and rheumatoid factor on recovery of galectin-3 were investigated. The reference interval was determined for 1092 ostensibly healthy individuals. The association of galectin-3 concentrations with an outcome of mortality was examined in a preliminary analysis of 129 acute decompensated heart failure patients. RESULTS: Galectin-3 results were equivalent when measured in serum or EDTA plasma. Imprecision studies demonstrated that the total CV was <10% at a low concentration of 6 ng/mL, 7% near the mid-level concentration of 21 ng/mL, and 15% at the high level of 70 ng/mL. The limit of blank was 0.86 ng/mL, the limit of detection was 1.13 ng/mL, and the limit of quantitation was 0.96 ng/mL. The linear measurement range was 0.96-130 ng/mL and there was no high-dose hook at levels up to 500 ng/mL. No cross-reactivity with nine compounds structurally related to galectin-3 and no interference from 22 common medications, icterus or lipemia was found. Hemolysis and presence of human anti-mouse antibodies or rheumatoid factor were found to be potential sources of interference. Samples can be stored for up to 15 days at either 22-28 degrees C or 2-8 degrees C before analysis; measurements are stable after storage at -20 degrees C or -70 degrees C for at least 6 months and through six freeze-thaw cycles. The 90th, 95th and 97.5th percentile of the normal reference interval was 17.6, 20.3 and 22.1 ng/mL, respectively. Galectin-3 in the acute decompensated heart failure patients ranged from 4.0 to 75 ng/mL; using a cutpoint of 22.1 ng/mL in an unadjusted analysis, galectin-3 values were associated with an outcome of death (p=0.035). Galectin-3 is associated with severity of heart failure as indicated by NYHA Class (p-value for trend, 0.017). CONCLUSION: This ELISA for galectin-3 measurement demonstrated acceptable analytical characteristics and was associated with mortality in a preliminary unadjusted analysis.

The complete genome and proteome of Mycoplasma mobile.

Although often considered "minimal" organisms, mycoplasmas show a wide range of diversity with respect to host environment, phenotypic traits, and pathogenicity. Here we report the complete genomic sequence and proteogenomic map for the piscine mycoplasma Mycoplasma mobile, noted for its robust gliding motility. For the first time, proteomic data are used in the primary annotation of a new genome, providing validation of expression for many of the predicted proteins. Several novel features were discovered including a long repeating unit of DNA of approximately 2435 bp present in five complete copies that are shown to code for nearly identical yet uniquely expressed proteins. M. mobile has among the lowest DNA GC contents (24.9%) and most reduced set of tRNAs of any organism yet reported (28). Numerous instances of tandem duplication as well as lateral gene transfer are evident in the genome. The multiple available complete genome sequences for other motile and immotile mycoplasmas enabled us to use comparative genomic and phylogenetic methods to suggest several candidate genes that might be involved in motility. The results of these analyses leave open the possibility that gliding motility might have arisen independently more than once in the mycoplasma lineage.

The genome sequence of the filamentous fungus Neurospora crassa.

Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes--more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes.