Stimulation of ornithine decarboxylase activity and inhibition of S-adenosyl-l-methionine decarboxylase activity in leukaemic mice by methylglyoxal bis(guanylhydrazone) (Short Communication)

Administration of methylglyoxal bis(guanylhydrazone) to leukaemic mice results in an early depression followed by a marked elevation of S-adenosyl-l-methionine decarboxylase activity. Further, there is an early prolonged increase in the activity of ornithine decarboxylase, the initial enzyme in the polyamine biosynthetic pathway. Because of the profound effects of methylglyoxal bis(guanylhydrazone) in vivo on the polyamine biosynthetic pathway, the drug can no longer be considered a specific inhibitor of spermidine synthesis.     

Effects of climate change on biodiversity: a review and identification of key research issues

Current knowledge of effects of climate change on biodiversity is briefly reviewed, and results are presented of a survey of biological research groups in the Netherlands, aimed at identifying key research issues in this field. In many areas of the world, biodiversity is being reduced by humankind through changes in land cover and use, pollution, invasions of exotic species and possibly climate change. Assessing the impact of climate change on biodiversity is difficult, because changes occur slowly and effects of climate change interact with other stress factors already imposed on the environment. Research issues identified by Dutch scientists can be grouped into: (i) spatial and temporal distributions of taxa; (ii) migration and dispersal potentials of taxa; (iii) genetic diversity and viability of (meta) populations of species; (iv) physiological tolerance of species; (v) disturbance of functional interactions between species; and (vi) ecosystem processes. Additional research should be done on direct effects of greenhouse gases, and on interactions between effects of climate change and habitat fragmentation. There are still many gaps in our knowledge of effects of climate change on biodiversity. An interdisciplinary research programme could possibly focus only on one or few of the identified research issues, and should generate input data for predictive models based on climate change scenarios.     

Endo‐ and epilithic faunal succession in a Pliocene–Pleistocene cave on Rhodes,Greece: record of a transgression

A fossil cave and associated sediments and fossil fauna located on the Greek island of Rhodes in the eastern Aegean Sea is reported here, and the depositional history discussed. The sediments were deposited during the late Pliocene, in the interstitial space between basement boulders of up to 1500 tons. The depositional history of the cave comprises eight stages. From initial flooding, the basin experienced a continuous transgression with sea‐level rise in excess of 500 m, followed by a rapid, forced regression of similar magnitude. The recognition of a succession of fossil communities illustrates this transgression, with a seemingly abrupt shift from endolithic to epilithic biota dominance late in the transgressive cycle. The communities recording the increasing water depth from 0 to >150 m are: The Gatrochaenolithes torpedo (bivalve boring) and Entobia gonioides (sponge boring) ichnocoenosis, with peak distribution between 0 and 1 m water depth; the E. gonioides – E. magna ichnocoenosis, with 1–5 m depth peak distribution; the exclusive E. magna ichnocoenosis, with 5–40 m depth peak distribution; and the E. gigantea ichnocoenosis, with a peak distribution approaching 150–200 m. Below this depth, an epilithic community without boring organisms takes over, characterized by the calcareous sponge Merlia cf. normani, and the inarticulate brachiopod Novocrania turbinata. Simultaneously with the succession of the endo‐ and epilithic cave wall fossil communities, skeletal calcarenite accumulated on the cave floor; the erosional remnants of this sediment are insufficient to further expand the overall transgression–regression model.     

Receptor-specific targeting with complementary peptide nucleic acids conjugated to peptide analogs and radionuclides

Summary Genomic sequencing makes it possible to identify all the genes of an organism, now includingHomo sapiens. Yet measurement of the expression of each gene of interest still presents a daunting prospect. Northern blots, RNase protection assays, as well as microarrays and related technologies permit measurement of gene expression in total RNA extracted from cultured cells or tissue samples. It would be most valuable, however, to quantitate gene expression noninvasively in living cells and tissues. Unfortunately, no reliable method has been available to measure levels of specific mRNAsin vivo. Peptide nucleic acids (PNAs) display superior ruggedness and hybridization properties as a diagnostic tool for gene expression, and could be used for this purpose. On the down side, they are negligibly internalized by normal or malignant cells in the absence of conjugated ligands. Nevertheless, we have observed that Tc-99m-peptides can delineate tumors, and PNA-peptides designed to bind to IGF-1 receptors on malignant cells are taken up specifically and concentrated in nuclei. We have postulated that antisense Tc-99m-PNA-peptides will be taken up by human cancer cells, will hybridize to complementary mRNA targets, and will permit scintigraphic imaging of oncogene mRNAs in human cancer xenografts in a mouse model. The oncogenes cyclin D1,ERBB2, c-MYC, K-RAS, and tumor suppressor p53 are being probed initially. These experiments provide a proof-of-principle for noninvasive detection of oncogene expression in living cells and tissues. This scintigraphic imaging technique should be applicable to any particular gene of interest in a cell or tissue type with characteristic receptors.     

A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13–1.33, p = 3.02 × 10⁻⁷), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10⁻¹⁴ for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.     

A quantitative approach to catabolite repression in Escherichia coli

A dynamic mathematical model was developed to describe the uptake of various carbohydrates (glucose, lactose, glycerol, sucrose, and galactose) in Escherichia coli. For validation a number of isogenic strains with defined mutations were used. By considering metabolic reactions as well as signal transduction processes influencing the relevant pathways, we were able to describe quantitatively the phenomenon of catabolite repression in E. coli. We verified model predictions by measuring time courses of several extra- and intracellular components such as glycolytic intermediates, EII-ACrr phosphorylation level, both LacZ and PtsG concentrations, and total cAMP concentrations under various growth conditions. The entire data base consists of 18 experiments performed with nine different strains. The model describes the expression of 17 key enzymes, 38 enzymatic reactions, and the dynamic behavior of more than 50 metabolites. The different phenomena affecting the phosphorylation level of EIIACrr, the key regulation molecule for inducer exclusion and catabolite repression in enteric bacteria, can now be explained quantitatively.