Content and quality of currently published phase II cancer trials. (17/647)

PURPOSE: A number of statistical methods have been proposed for the design and analysis of phase II studies based on dichotomous outcomes. To investigate to what extent such methods are in current use, we conducted a survey of published studies. MATERIALS AND METHODS: We identified studies by conducting a computerized literature search of MEDLINE. We considered trials on systemic antineoplastic treatments described as phase II or pilot. The search was limited to articles written in English and published in 1997. RESULTS: Three hundred eight trials were identified. The majority, ie, 295 (95.8%), had been conducted as single-arm studies, with objective tumor response as the primary efficacy end point. An identifiable statistical design was reported for only 58 (19.7%) of these trials. The quality in reporting the statistical design and compliance with the design in carrying out the study or results interpretation were frequently poor. The frequency of reporting the statistical design was not shown to increase over the years of study start and was not associated with sample size or study duration. Instead, a significant association was found with trial results (which were less frequently positive among studies with a statistical design) and with the impact factor of the publishing journal. CONCLUSION: This survey shows that the quality of the statistical component of published phase II cancer trials is generally poor and raises suspicion that low quality is likely to bias study findings. Journals might improve the methodologic standard of published articles through a more vigilant reviewing policy.  (+info)

Selective activation of pre-replication complexes in vitro at specific sites in mammalian nuclei. (18/647)

As the first step in determining whether or not pre-replication complexes are assembled at specific sites along mammalian chromosomes, nuclei from G(1)-phase hamster cells were incubated briefly in Xenopus egg extract in order to initiate DNA replication. Most of the nascent DNA consisted of RNA-primed DNA chains 0.5 to 2 kb in length, and its origins in the DHFR gene region were mapped using both the early labeled fragment assay and the nascent strand abundance assay. The results revealed three important features of mammalian replication origins. First, Xenopus egg extract can selectively activate the same origins of bi-directional replication (e.g. ori-beta) and (beta') that are used by hamster cells in vivo. Previous reports of a broad peak of nascent DNA centered at ori-(beta/(beta)' appeared to result from the use of aphidicolin to synchronize nuclei and from prolonged exposure of nuclei to egg extracts. Second, these sites were not present until late G(1)-phase of the cell division cycle, and their appearance did not depend on the presence of Xenopus Orc proteins. Therefore, hamster pre-replication complexes appear to be assembled at specific chromosomal sites during G(1)-phase. Third, selective activation of ori-(beta) in late G(1)-nuclei depended on the ratio of Xenopus egg extract to nuclei, revealing that epigenetic parameters such as the ratio of initiation factors to DNA substrate could determine the number of origins activated.  (+info)

High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. (19/647)

We have developed an accurate, yet inexpensive and high-throughput, method for determining the allele frequency of biallelic polymorphisms in pools of DNA samples. The assay combines kinetic (real-time quantitative) PCR with allele-specific amplification and requires no post-PCR processing. The relative amounts of each allele in a sample are quantified. This is performed by dividing equal aliquots of the pooled DNA between two separate PCR reactions, each of which contains a primer pair specific to one or the other allelic SNP variant. For pools with equal amounts of the two alleles, the two amplifications should reach a detectable level of fluorescence at the same cycle number. For pools that contain unequal ratios of the two alleles, the difference in cycle number between the two amplification reactions can be used to calculate the relative allele amounts. We demonstrate the accuracy and reliability of the assay on samples with known predetermined SNP allele frequencies from 5% to 95%, including pools of both human and mouse DNAs using eight different SNPs altogether. The accuracy of measuring known allele frequencies is very high, with the strength of correlation between measured and known frequencies having an r(2) = 0.997. The loss of sensitivity as a result of measurement error is typically minimal, compared with that due to sampling error alone, for population samples up to 1000. We believe that by providing a means for SNP genotyping up to thousands of samples simultaneously, inexpensively, and reproducibly, this method is a powerful strategy for detecting meaningful polymorphic differences in candidate gene association studies and genome-wide linkage disequilibrium scans.  (+info)

Scrapie transmission in Britain: a recipe for a mathematical model. (20/647)

Responses to an anonymous postal survey concerning scrapie are analysed. Risk factors associated with farms that have had scrapie are identified as size, geographical region, lambing practices and holding of certain breeds. Further analysis of farms that have scrapie only in bought-in animals reveals that such farms tend to breed a smaller proportion of their replacement animals than farms without scrapie. Farms that have had scrapie in home-bred animals have attributes associated with breeding many animals: large numbers of rams bought, few ewes bought, and many animals that are home-bred. The demography of British sheep farms as described by size, breeds, purchasing behaviour, age structure and proportion of animals that are home-bred is summarized. British farms with scrapie reveal certain special features: they have more sheep that are found dead, more elderly ewes and more cases of scab.  (+info)

The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin. (21/647)

The androgen receptor (AR) gene, located on the X-chromosome at Xq11-12, contains in exon 1 a polymorphic CAG repeat which codes for a polyglutamine tract. Contractions of the CAG repeat are said to be related to prostate cancer. In contrast, sizeable expansion of the CAG repeat can cause spinal and bulbar muscular atrophy (SBMA). In infertile patients of Chinese origin and in a Melbourne multinational population impaired sperm production has been postulated to be related to moderate expansions of the polyglutamine tract. In a study of a Swedish population of infertile patients these findings could not be corroborated. The aim of our investigation was to examine the correlation between the length of the CAG repeat and impaired sperm production in an infertile Caucasoid patient sample of German ethnic origin. We found no statistically significant relationship between the size of the CAG repeat or polyglutamine tract and idiopathic impaired sperm production in the population studied. The variability of the results by various investigators may be attributed to different ethnic origins and hence different genetic modifiers of the populations studied and/or to the high probability that these infertile males may represent a heterogeneous group with respect to the causes of defective spermatogenesis.  (+info)

SEGMENT: identifying compositional domains in DNA sequences. (22/647)

MOTIVATION: DNA sequences are formed by patches or domains of different nucleotide composition. In a few simple sequences, domains can simply be identified by eye; however, most DNA sequences show a complex compositional heterogeneity (fractal structure), which cannot be properly detected by current methods. Recently, a computationally efficient segmentation method to analyse such nonstationary sequence structures, based on the Jensen-Shannon entropic divergence, has been described. Specific algorithms implementing this method are now needed. RESULTS: Here we describe a heuristic segmentation algorithm for DNA sequences, which was implemented on a Windows program (SEGMENT). The program divides a DNA sequence into compositionally homogeneous domains by iterating a local optimization procedure at a given statistical significance. Once a sequence is partitioned into domains, a global measure of sequence compositional complexity (SCC), accounting for both the sizes and compositional biases of all the domains in the sequence, is derived. SEGMENT computes SCC as a function of the significance level, which provides a multiscale view of sequence complexity.  (+info)

The oxalate/sulfate antiporter in lobster hepatopancreas: internal and external binding constants. (23/647)

Utilizing a purified basolateral plasma membrane vesicle (BLMV) preparation containing a sulfate/oxalate antiporter, it was demonstrated that sulfate exhibited similar binding characteristics to the transporter whether bound internally or externally. It was also demonstrated that oxalate had similar binding characteristics to the antiporter whether it was bound internally or externally. Oxalate had a greater affinity to the transporter than did sulfate. Several organic anions affected binding and, therefore, overall transport by the antiporter. Most notably, sulfate was the only anion that stimulated oxalate uptake into BLMVs, which suggests a conservative binding specificity for the antiporter. 4-Acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) and/or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited the transport rate, confirming the existence of oxalate/sulfate exchange by the transporter. These results suggest that oxalate, not sulfate, regulates the transport rate because of its greater affinity to the transporter.  (+info)

Understanding the overdispersed molecular clock. (24/647)

Rates of molecular evolution at some protein-encoding loci are more irregular than expected under a simple neutral model of molecular evolution. This pattern of excessive irregularity in protein substitutions is often called the "overdispersed molecular clock" and is characterized by an index of dispersion, R(T) > 1. Assuming infinite sites, no recombination model of the gene R(T) is given for a general stationary model of molecular evolution. R(T) is shown to be affected by only three things: fluctuations that occur on a very slow time scale, advantageous or deleterious mutations, and interactions between mutations. In the absence of interactions, advantageous mutations are shown to lower R(T); deleterious mutations are shown to raise it. Previously described models for the overdispersed molecular clock are analyzed in terms of this work as are a few very simple new models. A model of deleterious mutations is shown to be sufficient to explain the observed values of R(T). Our current best estimates of R(T) suggest that either most mutations are deleterious or some key population parameter changes on a very slow time scale. No other interpretations seem plausible. Finally, a comment is made on how R(T) might be used to distinguish selective sweeps from background selection.  (+info)