Topoisomerase II and the etiology of chromosomal translocations

Acute leukemias with balanced chromosomal translocations, protean morphologic and immunophenotypic presentations but generally shorter latency and absence of myelodysplasia are recognized as a complication of anti-cancer drugs that behave as topoisomerase II poisons. Translocations affecting the breakpoint cluster region of the MLL gene at chromosome band 11q23 are the most common molecular genetic aberrations in leukemias associated with the topoisomerase II poisons. These agents perturb the cleavage-religation equilibrium of topoisomerase II and increase cleavage complexes. One model suggests that this damages the DNA directly and leads to chromosomal breakage, which may result in untoward DNA recombination in the form of translocations. This review will summarize the evidence for topoisomerase II involvement in the genesis of translocations and extension of the model to acute leukemia in infants characterized by similar MLL translocations.     

Relative and absolute quantitative expression profiling of cytochromes P450 using isotope-coded affinity tags

The development of a novel method for absolute quantification of proteins based on isotope-coded affinity tagging using ICAT reagents is described. The method exploits synthetic peptide standards to determine protein content at the femtomole level in biological samples. The approach is generally applicable to any subset of proteins, but is particularly appropriate for quantitative analysis of multiple, closely related isoforms, and for hydrophobic proteins that are poorly represented in 2-D gels. Relative and absolute quantification techniques are applied to an important group of microsomal metabolic enzymes, the cytochromes P450 (P450), which are critical in determining the disposition, safety and efficacy of drugs in man. Measurement of the P450 induction profile in response to chemicals is a fundamental aspect of drug safety evaluation and is currently achieved by low-throughput methods employing poorly discriminatory antibodies or substrates. Tagging technology is shown to supersede conventional methods for P450 profiling in terms of discriminatory power and throughput, exemplified by the simultaneous detection of distinct induction profiles for cyp2c subfamily members in response to phenobarbitone: cyp2c29 expression, but not cyp2c40 or cyp2c50, was induced threefold by treatment. This technology should abbreviate the drug development pathway, and provide a widely applicable, rapid means of quantifying proteins.     

The biosynthesis and regulation of bacterial prodiginines

The red-pigmented prodiginines are bioactive secondary metabolites produced by both Gram-negative and Gram-positive bacteria. Recently, these tripyrrole molecules have received renewed attention owing to reported immunosuppressive and anticancer properties. The enzymes involved in the biosynthetic pathways for the production of two of these molecules, prodigiosin and undecylprodigiosin, are now known. However, the biochemistry of some of the reactions is still poorly understood. The physiology and regulation of prodiginine production in Serratia and Streptomyces are now well understood, although the biological role of these pigments in the producer organisms remains unclear. However, research into the biology of pigment production will stimulate interest in the bioengineering of strains to synthesize useful prodiginine derivatives.     

LitMiner: integration of library services within a bio-informatics application

Background

This paper examines how the adoption of a subject-specific library service has changed the way in which its users interact with a digital library. The LitMiner text-analysis application was developed to enable biologists to explore gene relationships in the published literature. The application features a suite of interfaces that enable users to search PubMed as well as local databases, to view document abstracts, to filter terms, to select gene name aliases, and to visualize the co-occurrences of genes in the literature. At each of these stages, LitMiner offers the functionality of a digital library. Documents that are accessible online are identified by an icon. Users can also order documents from their institution's library collection from within the application. In so doing, LitMiner aims to integrate digital library services into the research process of its users.

Methods

Case study

Results

This integration of digital library services into the research process of biologists results in increased access to the published literature.

Conclusion

In order to make better use of their collections, digital libraries should customize their services to suit the research needs of their patrons.

     

Toxicity of diclofenac to Gyps vultures

Three endemic vulture species Gyps bengalensis, Gyps indicus and Gyps tenuirostris are critically endangered following dramatic declines in South Asia resulting from exposure to diclofenac, a veterinary drug present in the livestock carcasses that they scavenge. Diclofenac is widely used globally and could present a risk to Gyps species from other regions. In this study, we test the toxicity of diclofenac to a Eurasian (Gyps fulvus) and an African (Gyps africanus) species, neither of which is threatened. A dose of 0.8 mg kg(-1) of diclofenac was highly toxic to both species, indicating that they are at least as sensitive to diclofenac as G. bengalensis, for which we estimate an LD50 of 0.1-0.2 mg kg(-1). We suggest that diclofenac is likely to be toxic to all eight Gyps species, and that G. africanus, which is phylogenetically close to G. bengalensis, would be a suitable surrogate for the safety testing of alternative drugs to diclofenac.     

Sex allocation theory aids species conservation

Supplementary feeding is often a key tool in the intensive management of captive and threatened species. Although it can increase such parameters as breeding frequency and individual survival, supplementary feeding may produce undesirable side effects that increase overall extinction risk. Recent attempts to increase breeding frequency and success in the kakapo Strigops habroptilus using supplementary feeding inadvertently resulted in highly male-biased chick sex ratios. Here, we describe how the inclusion of sex allocation theory has remedied this conservation dilemma. Our study is the first to manipulate chick sex ratios in an endangered species by altering maternal condition and highlights the importance of incorporating evolutionary theory into modern conservation practice.     

Single-strand conformation polymorphism (SSCP) for the analysis of genetic variation

The accurate analysis of genetic variation has major implications in many areas of biomedical research, including the identification of infectious agents (such as parasites), the diagnosis of infections, and the detection of unknown or known disease-causing mutations. Mutation scanning methods, including PCR-coupled single-strand conformation polymorphism (SSCP), have significant advantages over many other nucleic acid techniques for the accurate analysis of allelic and mutational sequence variation. The present protocol describes the SSCP method of analysis, including all steps from the small-scale isolation of genomic DNA and PCR amplification of target sequences, through to the gel-based separation of amplicons and scanning for mutations by SSCP (either by the analysis of radiolabeled amplicons in mutation detection enhancement (MDE) gels or by non-isotopic SSCP using precast GMA gels). The subsequent sequence analysis of polymorphic bands isolated from gels is also detailed. The SSCP protocol can readily detect point mutations for amplicon sizes of up to 450-500 bp, and usually takes 1-2 days to carry out. This user-friendly, low-cost, potentially high-throughput platform has demonstrated the utility to study a wide range of pathogens and diseases, and has the potential to be applied to any gene of any organism.     

Should symptomatic menopausal women be offered hormone therapy?

Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.     

Improved parameterized complexity of the maximum agreement subtree and maximum compatible tree problems

Given a set of evolutionary trees on a same set of taxa, the maximum agreement subtree problem (MAST), respectively, maximum compatible tree problem (MCT), consists of finding a largest subset of taxa such that all input trees restricted to these taxa are isomorphic, respectively compatible. These problems have several applications in phylogenetics such as the computation of a consensus of phylogenies obtained from different data sets, the identification of species subjected to horizontal gene transfers and, more recently, the inference of supertrees, e.g., Trees Of Life. We provide two linear time algorithms to check the isomorphism, respectively, compatibility, of a set of trees or otherwise identify a conflict between the trees with respect to the relative location of a small subset of taxa. Then, we use these algorithms as subroutines to solve MAST and MCT on rooted or unrooted trees of unbounded degree. More precisely, we give exact fixed-parameter tractable algorithms, whose running time is uniformly polynomial when the number of taxa on which the trees disagree is bounded. The improves on a known result for MAST and proves fixed-parameter tractability for MCT.