Influence of UGT1A9 intronic I399C4T polymorphism on SN-38 glucuronidation in Asian cancer patients

Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.−3140G>A, UGT1A1*28 and UGT1A1*6) and UGT1A9 (g.−118(T)9>10 and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m2 once in every 3 weeks. Genotypic–phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1–1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT10T/GG6GT9C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT10T/GG6GT10C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.

Comparison of three expert elicitation methods for logistic regression on predicting the presence of the threatened brush-tailed rock-wallaby petrogale penicillata

Numerous expert elicitation methods have been suggested for generalised linear models (GLMs). This paper compares three relatively new approaches to eliciting expert knowledge in a form suitable for Bayesian logistic regression. These methods were trialled on two experts in order to model the habitat suitability of the threatened Australian brush-tailed rock-wallaby (Petrogale penicillata). The first elicitation approach is a geographically assisted indirect predictive method with a geographic information system (GIS) interface. The second approach is a predictive indirect method which uses an interactive graphical tool. The third method uses a questionnaire to elicit expert knowledge directly about the impact of a habitat variable on the response. Two variables (slope and aspect) are used to examine prior and posterior distributions of the three methods. The results indicate that there are some similarities and dissimilarities between the expert informed priors of the two experts formulated from the different approaches. The choice of elicitation method depends on the statistical knowledge of the expert, their mapping skills, time constraints, accessibility to experts and funding available. This trial reveals that expert knowledge can be important when modelling rare event data, such as threatened species, because experts can provide additional information that may not be represented in the dataset. However care must be taken with the way in which this information is elicited and formulated.

Effect of selected feed meals and starches on diet digestibility in the mud crab, Scylla serrata

The present study examined the capacity of the mud crab, Scylla serrata to digest experimental diets that contained different animal and plant-based feed meals or different levels or types of starch. The apparent dry matter digestibility (ADMD) coefficients for all feed meals tested in the first part of this study, except meat meal, were similar (78–88%). Crude protein digestibility (ACPD) coefficients for all feed meals were relatively high, with values ranging from 86% to 96%. Cotton seed meal, poultry meal, canola meal, fishmeal, soybean meal and lupin meal had similar gross energy digestibility (AGED) values (P>0.05) ranging from 84% to 89%. In the second part of this study, the impact of selected starches on the digestibility of fishmeal-based formulated diets was assessed. The apparent starch digestibility (ASD) of wheat starch decreased significantly as the inclusion level was increased from 15% to 60%, however, there was no significant effect on ACPD values. At a 30% inclusion level, the ASD of diets containing different starches decreased in the order corn>wheat>potato=rice. Moreover, ACPD values were significantly higher (P<0.05) in the diets containing corn or rice starch than in those containing wheat or potato starches.

Near infrared spectroscopy of stearic acid adsorbed on montmorillonite

The adsorption of stearic acid on both sodium montmorillonites and calcium montmorillonites has been studied by near infrared spectroscopy complimented with infrared spectroscopy. Upon adsorption of stearic acid on Ca-Mt additional near infrared bands are observed at 8236 cm-1 and is assigned to an interaction of stearic acid with the water of hydration. Upon adsorption of the stearic acid on Na-Mt, the NIR bands are now observed at 5671, 5778, 5848 and 5912 cm-1 and are assigned to the overtone and combination bands of the CH fundamentals. Additional bands at 4177, 4250, 4324, 4337, 4689 and 4809 cm-1 are attributed to CH combination bands resulting from the adsorption of the stearic acid. Stearic acid is used as a model molecule for adsorption studies. The application of near infrared spectroscopy to the study of this adsorption proved most useful.

The effect of unlocking RGD-motifs in collagen I on pre-osteoblast adhesion and differentiation

Denaturation of extracellular matrix proteins exposes cryptic binding sites. It is hypothesized that binding of cell adhesion receptors to these cryptic binding sites regulates cellular behaviour during tissue repair and regeneration. To test this hypothesis, we quantify the adhesion of pre-osteoblastic cells to native (Col) and partially-denatured (pdCol) collagen I using single-cell force spectroscopy. During early stages of cell attachment (≤180 s) pre-osteoblasts (MC3T3-E1) adhered significantly stronger to pdCol compared to Col. RGD (Arg-Gly-Asp)-containing peptides suppressed this elevated cell adhesion. We show that the RGD-binding α5β1- and αv-integrins mediated pre-osteoblast adhesion to pdCol, but not to Col. On pdCol pre-osteoblasts had a higher focal adhesion kinase tyrosine-phosphorylation level that correlated with enhanced spreading and motility. Moreover, pre-osteoblasts cultured on pdCol showed a pronounced matrix mineralization activity. Our data suggest that partially-denatured collagen exposes RGD-motifs that trigger binding of α5β1- and αv-integrins. These integrins initiate cellular processes that stimulate osteoblast adhesion, spreading, motility and differentiation. Taken together, these quantitative insights reveal an approach for the development of alternative collagen I- based surfaces for tissue engineering applications.