Synthesis of novel paclitaxel prodrugs designed for bioreductive activation in hypoxic tumour tissue.

The syntheses and preliminary evaluation of the first potential bioreductive paclitaxel prodrugs are described. These prodrugs were designed as potential candidates in more selective chemotherapy by targeting hypoxic tumour tissue. Aromatic nitro and azide groups were used as the bioreductive trigger. Generation of paclitaxel occurs after reduction and subsequent 1,6-elimination or 1,8-elimination. All prodrugs are stable in buffer and indeed give paclitaxel after chemical reduction of the aromatic nitro or azide functionality. In aerobic cytotoxicity assays several prodrugs exhibit diminished cytotoxicity. These compounds are interesting candidates for further biological evaluation.     

Familial deletion in Becker type muscular dystrophy within the pXJ region

Summary A family of an isolated patient with Becker muscular dystrophy has been investigated by DNA analysis. Southern blotting and hybridization were performed with six probes (C7, pERT87.15, pERT87.1, pXJ1.1, pXJ2.3, 754) mapping in the Xp21 region. A deletion within the pXJ region was demonstrated in the proband, his mother and all three sisters. The segregation pattern for the restriction fragment length polymorphisms (RFLPs) observed with the pXJ probes as well as with pERT87.15, pERT87.1 and 754 probes indicates that the deletion is of grandpaternal origin.     

Translation Initiation Factor-Dependent Extracts from YeastSaccharomyces cerevisiae

Translation initiation factor-dependent extracts are prepared fromSaccharomyces cerevisiaestrains that have no or reduced activity of a translation initiation factor. Elimination of factor activity can be achieved by deletion of the gene encoding the factor if it is not essential for the survival of the strain. If the gene is essential it is placed under the control of the regulatable GAL1 promoter and its expression is shut offin vivo.Alternatively, a temperature-sensitive mutation can be introduced into the gene and the activity of the gene product eliminatedin vitroby preincubation of the extract at the nonpermissive temperature. Factor-dependent extracts can be complementedin vitrowith purified initiation factor preparations isolated fromS. cerevisiaeor fromEscherichia colicells expressing them from plasmid-encoded constructs. To simplify the purification of the factors they may be expressed as fusion proteins with N- or C-terminal tags. Initiation factor-dependent extracts can be used to study initiation factor structure–function relationships and initiation factor requirements for specific mRNA translation.     

Inhibition of 3H-clozapine binding in rat brain after oral administration of neuroleptics

Clozapine, thioridazine, perlapine, clothiapine, chlorpromazine, NT 104–252, loxapine or haloperidol were administered orally, and atropine subcutaneously, to rats. The animals were decapitated, brain tissue was removed and homogenized in tris buffer and incubated with ³H-clozapine. Total and nonspecifically bound ³H-clozapine were measured in each preparation. A dose-dependent inhibition of specific ³H-clozapine binding of more than 50% was observed only after the administration of clozapine or thioridazine. There was no correlation between inhibition of ³H-clozapine binding and that of ³H-haloperidol, a specific ligand for DA-receptors. ³H-Clozapine receptor density was much greater than ³H-haloperidol receptor density, suggesting that the majority of clozapine binding sites are not DA-receptors.     

Variability in rate of human perspiration in european populations

1. 1. In the consideration of ergonomic tasks the attempt is often made to combine the results of physiological research on human perspiration with technical factors such as the transfer of moisture through specific materials.

2. 2. The result of such attempts is often unsatisfactory due to the fact that the percentiles and frequency distribution of perspiration rates are often unknown or not taken into consideration.

3. 3. Further, the interaction between the human user and a particular environmental situation remains unaccounted for.

4. 4. This interaction can produce totally different reactions in both the user and the materials depending upon the specifics of the situation.

5. 5. In response to this deficit we tested 738 persons from various areas in Europe under laboratory conditions to determine perspiration rates and their statistical distribution.

6. 6. Despite the climatic differences existing within Europe, a uniform picture characterized by an extremely skewed distribution resulted.

7. 7. However, it was also shown that these values, including their statistical distribution and percentile ranks, can be strongly influenced by specific external conditions.

8. 8. In the design of human working and living environments it is necessary to examine the situation with research subjects whose perspiration rates are known in order to gain insight into the interactions existing between the human user and the material or technical aspects of the particular environment in question.

Effect of tower base painting on willow ptarmigan collision rates with wind turbines

1. Birds colliding with turbine rotor blades is a well‐known negative consequence of wind‐power plants. However, there has been far less attention to the risk of birds colliding with the turbine towers, and how to mitigate this risk.
2. Based on data from the Smøla wind‐power plant in Central Norway, it seems highly likely that willow ptarmigan (the only gallinaceous species found on the island) is prone to collide with turbine towers. By employing a BACI‐approach, we tested if painting the lower parts of turbine towers black would reduce the collision risk.
3. Overall, there was a 48% reduction in the number of recorded ptarmigan carcasses per search at painted turbines relative to neighboring control (unpainted) ones, with significant variation both within and between years.
4. Using contrast painting to the turbine towers resulted in significantly reduced number of ptarmigan carcasses found, emphasizing the effectiveness of such a relatively simple mitigation measure.

     

Identification and design of a novel series of MGAT2 inhibitors

[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration.     

Transcriptional Profiling of Whole Blood Identifies a Unique 5-Gene Signature for Myelofibrosis and Imminent Myelofibrosis Transformation

Identifying a distinct gene signature for myelofibrosis may yield novel information of the genes, which are responsible for progression of essential thrombocythemia and polycythemia vera towards myelofibrosis. We aimed at identifying a simple gene signature – composed of a few genes - which were selectively and highly deregulated in myelofibrosis patients. Gene expression microarray studies have been performed on whole blood from 69 patients with myeloproliferative neoplasms. Amongst the top-20 of the most upregulated genes in PMF compared to controls, we identified 5 genes (DEFA4, ELA2, OLFM4, CTSG, and AZU1), which were highly significantly deregulated in PMF only. None of these genes were significantly regulated in ET and PV patients. However, hierarchical cluster analysis showed that these genes were also highly expressed in a subset of patients with ET (n = 1) and PV (n = 4) transforming towards myelofibrosis and/or being featured by an aggressive phenotype. We have identified a simple 5-gene signature, which is uniquely and highly significantly deregulated in patients in transitional stages of ET and PV towards myelofibrosis and in patients with PMF only. Some of these genes are considered to be responsible for the derangement of bone marrow stroma in myelofibrosis. Accordingly, this gene-signature may reflect key processes in the pathogenesis and pathophysiology of myelofibrosis development.