A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer

The doxorubicin (DOX) prodrug N -[4-doxorubicin- N -carbonyl (oxymethyl) phenyl] O -β-glucuronyl carbamate (DOX-GA3) was synthesised for specific activation by human β-glucuronidase, which is released in necrotic areas of tumour lesions. This novel prodrug was completely activated to the parent drug by human β-glucuronidase with V max= 25.0 μmol min–1mg–1and K m= 1100 μM. The pharmacokinetics and distribution of DOX-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3) were determined and compared with DOX. Administration of DOX at 8 mg kg–1i.v. (maximum tolerated dose, MTD) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 16.4 μM (t = 1 min). A 7.6-times lower peak plasma concentration of DOX was measured after injection of DOX-GA3 at 250 mg kg–1i.v. (50% of MTD). In normal tissues the prodrug showed peak DOX concentrations that were up to 5-fold (heart) lower than those found after DOX administration. DOX-GA3 activation by β-glucuronidase in the tumour yielded an almost 5-fold higher DOX peak concentration of 9.57 nmol g–1(P< 0.05) than the peak concentration of only 2.14 nmol g–1observed after DOX. As a consequence, the area under the curve of DOX calculated in tumour tissue after DOX-GA3 (13.1 μmol min–1g–1) was 10-fold higher than after DOX (1.31 μmol min–1g–1). The anti-tumour effects of DOX-GA3 and DOX were compared at equitoxic doses in OVCAR-3 xenografts at a mean tumour size of 125 mm3. The prodrug given i.v. at 500 mg kg–1weekly × 2 resulted in a maximum tumour growth inhibition of 87%, while the standard treatment with DOX at a dose of 8 mg kg–1i.v. weekly × 2 resulted in a maximum tumour growth inhibition of only 56%. Treatment with DOX-GA3 was also given to mice with larger tumours containing more necrosis. For tumours with a mean size of 400 mm3the specific growth delay by DOX-GA3 increased from 2.7 to 3.9. Our data indicate that DOX-GA3 is more effective than DOX and suggest that the prodrug will be specifically advantageous for treatment of advanced disease. © 2001 Cancer Research Campaign http://www.bjcancer.co

Exposure of bakery and pastry apprentices to airborne flour dust using PM2.5 and PM10 personal samplers

<p>Abstract</p> <p>Background</p> <p>This study describes exposure levels of bakery and pastry apprentices to flour dust, a known risk factor of occupational asthma.</p> <p>Methods</p> <p>Questionnaires on work activity were completed by 286 students. Among them, 34 performed a series of two personal exposure measurements using a PM_2.5and PM₁₀personal sampler during a complete work shift, one during a cold ("winter") period, and the other during a hot ("summer") period.</p> <p>Results</p> <p>Bakery apprentices experience greater average PM_2.5and PM₁₀exposures than pastry apprentices (p < 0.006). Exposure values for both particulate fractions are greater in winter (average PM₁₀values among bakers = 1.10 mg.m^-3[standard deviation: 0.83]) than in summer (0.63 mg.m^-3[0.36]). While complying with current European occupational limit values, these exposures exceed the ACGIH recommendations set to prevent sensitization to flour dust (0.5 mg.m^-3). Over half the facilities had no ventilation system.</p> <p>Conclusion</p> <p>Young bakery apprentices incur substantial exposure to known airways allergens, a situation that might elicit early induction of airways inflammation.</p

Iso-osmotic regulation of nitrate accumulation in lettuce (Lactuca sativa L.)

Concerns about possible health hazards arising from human consumption of lettuce and other edible vegetable crops with high concentrations of nitrate have generated demands for a greater understanding of processes involved in its uptake and accumulation in order to devise more sustainable strategies for its control. This paper evaluates a proposed iso-osmotic mechanism for the regulation of nitrate accumulation in lettuce (Lactuca sativa L.) heads. This mechanism assumes that changes in the concentrations of nitrate and all other endogenous osmotica (including anions, cations and neutral solutes) are continually adjusted in tandem to minimise differences in osmotic potential of the shoot sap during growth, with these changes occurring independently of any variations in external water potential. The hypothesis was tested using data from six new experiments, each with a single unique treatment comprising a separate combination of light intensity, N source (nitrate with or without ammonium) and nitrate concentration carried out hydroponically in a glasshouse using a butterhead lettuce variety. Repeat measurements of plant weights and estimates of all of the main soluble constituents (nitrate, potassium, calcium, magnesium, organic anions, chloride, phosphate, sulphate and soluble carbohydrates) in the shoot sap were made at intervals from about 2 weeks after transplanting until commercial maturity, and the data used to calculate changes in average osmotic potential in the shoot. Results showed that nitrate concentrations in the sap increased when average light levels were reduced by between 30 and 49 % and (to a lesser extent) when nitrate was supplied at a supra-optimal concentration, and declined with partial replacement of nitrate by ammonium in the external nutrient supply. The associated changes in the proportions of other endogenous osmotica, in combination with the adjustment of shoot water content, maintained the total solute concentrations in shoot sap approximately constant and minimised differences in osmotic potential between treatments at each sampling date. There was, however, a gradual increase in osmotic potential (ie a decline in total solute concentration) over time largely caused by increases in shoot water content associated with the physiological and morphological development of the plants. Regression analysis using normalised data (to correct for these time trends) showed that the results were consistent with a 1:1 exchange between the concentrations of nitrate and the sum of all other endogenous osmotica throughout growth, providing evidence that an iso-osmotic mechanism (incorporating both concentration and volume regulation) was involved in controlling nitrate concentrations in the shoot

Compared to conventional, ecological intensive management promotes beneficial proteolytic soil microbial communities for agro-ecosystem functioning under climate change-induced rain regimes

Projected climate change and rainfall variability will affect soil microbial communities, biogeochemical cycling and agriculture. Nitrogen (N) is the most limiting nutrient in agroecosystems and its cycling and availability is highly dependent on microbial driven processes. In agroecosystems, hydrolysis of organic nitrogen (N) is an important step in controlling soil N availability. We analyzed the effect of management (ecological intensive vs. conventional intensive) on N-cycling processes and involved microbial communities under climate change-induced rain regimes. Terrestrial model ecosystems originating from agroecosystems across Europe were subjected to four different rain regimes for 263 days. Using structural equation modelling we identified direct impacts of rain regimes on N-cycling processes, whereas N-related microbial communities were more resistant. In addition to rain regimes, management indirectly affected N-cycling processes via modifications of N-related microbial community composition. Ecological intensive management promoted a beneficial N-related microbial community composition involved in N-cycling processes under climate change-induced rain regimes. Exploratory analyses identified phosphorus-associated litter properties as possible drivers for the observed management effects on N-related microbial community composition. This work provides novel insights into mechanisms controlling agro-ecosystem functioning under climate change

Market Power in Water Markets

Water markets with market power are analysed as multi-market Cournot competition in which the river structure constrains access to local markets and limited resources impose capacity constraints. Conditions for uniqueness are identified. Lerner indices are larger under binding resource constraints. The number of cases explodes in the number of local markets. Under quadratic benefit functions and symmetric constant marginal extraction costs, closed-form solutions for selected cases are derived, and numerical implementation through a single optimization program is available. Upstream locations face less competition than downstream. Observed price patterns in the Goulburn-Murray Irrigation District are consistent with the theoretical results

Enhancement of Late Successional Plants on Ex-Arable Land by Soil Inoculations

Restoration of species-rich grasslands on ex-arable land can help the conservation of biodiversity but faces three big challenges: absence of target plant propagules, high residual soil fertility and restoration of soil communities. Seed additions and top soil removal can solve some of these constraints, but restoring beneficial biotic soil conditions remains a challenge. Here we test the hypotheses that inoculation of soil from late secondary succession grasslands in arable receptor soil enhances performance of late successional plants, especially after top soil removal but pending on the added dose. To test this we grew mixtures of late successional plants in arable top (organic) soil or in underlying mineral soil mixed with donor soil in small or large proportions. Donor soils were collected from different grasslands that had been under restoration for 5 to 41 years, or from semi-natural grassland that has not been used intensively. Donor soil addition, especially when collected from older restoration sites, increased plant community biomass without altering its evenness. In contrast, addition of soil from semi-natural grassland promoted plant community evenness, and hence its diversity, but reduced community biomass. Effects of donor soil additions were stronger in mineral than in organic soil and larger with bigger proportions added. The variation in plant community composition was explained best by the abundances of nematodes, ergosterol concentration and soil pH. We show that in controlled conditions inoculation of soil from secondary succession grassland into ex-arable land can strongly promote target plant species, and that the role of soil biota in promoting target plant species is greatest when added after top soil removal. Together our results point out that transplantation of later secondary succession soil can promote grassland restoration on ex-arable land