Radiation-activated prodrugs as hypoxia-selective cytotoxins: model studies with nitroarylmethyl quaternary salts

Bioreductive drugs are designed to be activated by enzymatic reduction in hypoxic regions of tumours, but activation of these drugs is not always fully suppressed by oxygen in normal tissues. A further limitation is that bioreductive drug activation depends on suitable reductases being expressed in the hypoxic zone. This essay proposes an alternative approach in which prodrugs are reduced, and thereby activated, in hypoxic regions by ionizing radiation rather than by enzymes. This strategy is theoretically attractive, but design requirements for such radiation-activated cytotoxins are challenging. In particular, the reducing capacity of radiation at clinically relevant doses is small, which necessitates the development of prodrugs capable of releasing very potent cytotoxins efficiently in hypoxic tissue. It is shown that nitroarylmethyl quaternary (NMQ) salts possess many of the features required of a radiation-activated prodrug. In some heterocyclic NMQ compounds the cytotoxicity of the latent cytotoxic amine effector is suppressed by > 100-fold in the prodrug form, and the effector is released rapidly by fragmentation following reduction by a single electron. Appreciable cytotoxic activation of NMQ prodrugs can be achieved by irradiation at clinically relevant doses in anoxic plasma. Some of the further drug design challenges required to develop a clinical agent based on this approach are outlined.     

CFD modelling for a TiO2-coated glass-bead photoreactor irradiated by optical fibres: Photocatalytic degradation of oxalic acid

Computational fluid dynamics coupled with the radiant transport equation was used to simulate oxalic acid photodegradation in a TiO₂-coated glass-bead photoreactor irradiated by end-emitting optical fibre (EEOF) or side-emitting optical fibre (SEOF) bundles. Light irradiance distributions in the photoreactor were modelled for specular, partially specular and diffusive reactor wall reflectivities with specularly reflective reactor walls best representing the experimental data. The light irradiance distribution for the SEOF bundle was found to be more uniform along the fibre length than for the EEOF bundle. Under the experimental radiant power input (108 mW) the EEOF and SEOF bundles exhibited similar oxalic acid photodegradation rates. However, the developed model demonstrated that at incident radiant power more than ten times greater than the experimental power used, a uniform light distribution gave faster oxalic acid photodegradation with the relative improvement of the SEOF bundle over the EEOF bundle increasing with increasing radiant power. This was attributed to increased electron-hole recombination in photocatalytic surfaces close to the EEOF tip, induced by the increased light irradiance in this region. The model also demonstrated a constant light irradiance profile along the length of a SEOF bundle giving an improved photocatalytic performance when compared to linear or exponentially decaying light profiles.     

The impact of increased interconnection on electricity systems with large penetrations of wind generation: A case study of Ireland and Great Britain

Increased interconnection has been highlighted as potentially facilitating the integration of wind generation in power systems by increasing the flexibility to balance the variable wind output. This paper utilizes a stochastic unit commitment model to simulate the impacts of increased interconnection for the island of Ireland with large penetrations of wind generation. The results suggest that increased interconnection should reduce average prices in Ireland, and the variability of those prices. The simulations also suggest that while increased interconnection may reduce carbon dioxide emissions in Ireland, Great Britain would experience an increase in emissions, resulting in total emissions remaining almost unchanged. The studies suggest that increased interconnection would not reduce excess wind generation. This is because under unit commitment techniques which incorporate wind power forecasts in the scheduling decisions, wind curtailment is minimal even with low levels of interconnection. As would be expected an increase in interconnection should improve system adequacy considerably with a significant reduction in the number of hours when the load and reserve constraints are not met.     

Channelled optical fibre photoreactor for improved air quality control

An optical fibre reactor with 30 hexagonal-shaped channels distributed within the optical fibre structure was investigated as a gas-phase photocatalytic reactor. TiO₂ photocatalyst, with SiO₂ sol acting as a binder, was coated on the channel walls at a thickness of 1.5 μm. Effective light propagation lengths of 3.4 and 4.9 cm were observed for incidental angles of 81.5° and 87.1°, respectively. The TiO₂-coated channelled optical fibre reactor (COFR) was assessed for the photocatalytic degradation of gas-phase ethylene. The photocatalytic reaction rate of ethylene degradation was linear with respect to the incident photons. The reaction rate order for the incident photons was determined to be 0.93. Despite a longer effective light propagation length for an incidental angle of 87.1°, the quantum yield was independent of the incidental angle. The independence of the quantum yield on the incident photons and the angle of light incidence was attributed to the COFR design, where the propagating light was wholly confined within the reactor and, in turn, more effectively utilised by the TiO₂.     

Irrelevant speech, serial rehearsal, and temporal distinctiveness: A new approach to the irrelevant speech effect.

D. C. LeCompte (see record 1995-04375-001) showed that the irrelevant speech effect—that is, the impairment of performance by the presentation of irrelevant background speech—extends to free recall, recognition, and cued recall. The present experiments extended the irrelevant speech effect to the missing-item task (Experiments 1 and 2), thereby contradicting a key prediction of the changing state hypothesis, which states that tasks that do not involve serial rehearsal should not be affected by the presence of irrelevant speech. Temporal distinctiveness theory provides an alternative explanation of the irrelevant speech effect. Experiment 3 tested and confirmed a unique prediction of this theory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exploiting tumor hypoxia through bioreductive release of diffusible cytotoxins: the cobalt(III)-nitrogen mustard complex SN 24771

PURPOSE: To assess the oxygen dependence of a novel cobalt-nitrogen mustard complex, SN 24771, designed to release a diffusible cytotoxic metabolite in hypoxic tumor microenvironments. METHODS AND MATERIALS: Oxygen dependence of cell killing was assessing in well-stirred single cell suspensions obtained by enzymatic dissociation of EMT6 spheroids, using a sensitive oxygen electrode to measure oxygen concentrations in solution. Cell killing in intact EMT6 spheroids was also compared with that in single cell suspensions. RESULTS: Cytotoxicity of SN 24771 in single cell suspensions was inhibited by very low concentrations of oxygen. The C50 value (O2 required for 50% inhibition of log cell kill) was ca. 0.02% O2 at 1 h, and the K value (O2 required to give a cytotoxic potency equal to the average of that at zero and infinite O2) was of a similar order. However, intact spheroids were much more sensitive to SN 24771 than could be accounted for by the K curve for single cell suspensions, this estimate being based on published data for the oxygen concentration profile in these spheroids. CONCLUSION: The cytotoxicity of SN 24771 is inhibited appreciably at oxygen concentrations which are too low to provide radiosensitization. In this respect, SN 24771 resembles organic bioreductive drugs such as quinones and nitroaromatic compounds. However, the extensive killing observed in multicellular spheroids is consistent with release of a diffusible nitrogen mustard on reduction. Bioreductive drugs with a low K value for activation, but which release a diffusible cytotoxin, may have desirable properties as tumor radiosensitizers.     

Child care history and kindergarten adjustment.

Parents gave histories of 589 children just before kindergarten. Children were later assessed with teacher, peer, and observer measures of social adjustment in school. Children with higher day-care amounts in each of 3 eras (0–4, and 4–5 yrs) scored higher on the composite negative adjustment and lower on positive adjustment (however, they also scored lower on teacher-rated internalizing problems). Day care predicted even after statistical control for measures representing alternative explanations, such as family stress and socioeconomic status, accounting for 2.7% of variance in negative adjustment and 2.9% of positive adjustment. Interactions between day care and other variables did not add to predictions of the molar adjustment composites. Extensive infancy care did not in itself predict adjustment, according to planned contrasts that controlled for total amount of day care received across the 3 eras of the child's life. (PsycINFO Database Record (c) 2010 APA, all rights reserved)