CYP2C19 pharmacogenetics in advanced cancer: compromised function independent of genotype

CYP2C19 is a drug-metabolising enzyme involved in the metabolism of a number of chemotherapeutic agents including cyclophosphamide. Variants of the CYP2C19 gene result in a loss of function polymorphism, which affects approximately 3% of the Caucasian population. These individuals are poor metabolisers (PM) of a wide range of medications including omeprazole (OMP). In healthy subjects PM can be identified through homozygous variant genotype. However, a discordance between CYP2C19 genotype and phenotype has been reported previously in a small study of cancer patients. To investigate whether CYP2C19 activity was decreased in patients with advanced cancer, CYP2C19 genotype was determined in 33 advanced cancer patients using PCR-RFLP analysis for the two important allelic variants (*2,681G>A and *3,636G>A) and the activity of the enzyme was evaluated using the CYP2C19 probe drug OMP. The activity of the drug-metabolising enzyme CYP2C19 was severely compromised in advanced cancer patients, resulting in a PM status in 37% of the patients who had normal genotype. This is significantly (P<0.0005) higher than that would be predicted from the genotypic status of these patients. There was no evidence of a correlation between compromised CYP2C19 activity and any of the proinflammatory cytokines or acute phase response proteins studied. However, there was preliminary evidence of an association between PM status and low body mass (P=0.03). There is increasing interest in using pharmacogenetics to ‘individualise medicine', however, the results of this study indicate that in a cancer population genotyping for CYP2C19 would significantly underestimate the number of phenotypic PM of drugs, such as cyclophosphamide, which may be metabolised by this enzyme

Global Discourses and national reconstruction: the impact of globalization on curriculum policy

Globalization has been widely discussed and much contested. It has been claimed that the process of globalization has impacted greatly on the capacity of the nation-state to formulate policy (e.g. Reich, 1992). Moreover, globalization has been accompanied by, or at least runs parallel to, a seemingly endless process of change within education. This process has assumed a worldwide character, as policies have migrated around the world; thus there have existed many similarities in terms of, for instance, curriculum provision, or school governance, between New Zealand, Australia, the United Kingdom and the USA. This article examines the nature and extent of education change in general terms, and the concept of globalization, before analysing the links between globalization and the process of change in one area of education, that is, the development of national frameworks for curriculum and assessment within anglophone nations

Observation and confirmation of six strong-lensing systems in the Dark Energy Survey Science Verification data

We report the observation and confirmation of the first group- and cluster-scale strong gravitational lensing systems found in Dark Energy Survey data. Through visual inspection of data from the Science Verification season, we identified 53 candidate systems. We then obtained spectroscopic follow-up of 21 candidates using the Gemini Multi-object Spectrograph at the Gemini South telescope and the Inamori-Magellan Areal Camera and Spectrograph at the Magellan/Baade telescope. With this follow-up, we confirmed six candidates as gravitational lenses: three of the systems are newly discovered, and the remaining three were previously known. Of the 21 observed candidates, the remaining 15 either were not detected in spectroscopic observations, were observed and did not exhibit continuum emission (or spectral features), or were ruled out as lensing systems. The confirmed sample consists of one group-scale and five galaxy-cluster-scale lenses. The lensed sources range in redshift z ˜ 0.80--3.2 and in i-band surface brightness i SB ˜ 23--25 mag arcsec-2 (2" aperture). For each of the six systems, we estimate the Einstein radius theta E and the enclosed mass M enc, which have ranges theta E ˜ 5"--9" and M enc ˜ 8 × 1012 to 6 × 1013 M &sun;, respectively. This paper includes data gathered with the 6.5 m Magellan Telescopes located at Las Campanas Observatory, Chile

Regulation of cytosolic phospholipase A2 expression by cytokines in human amnion cells

The metabolism of arachidonic acid results in the production of prostaglandins (PGs), which are involved in the initiation of labour at term and preterm. The fetal membranes are a source of pro-inflammatory cytokines which promote increased PG biosynthesis via increased release of arachidonic acid and its conversion to biologically active metabolites such as PGE2and PGF2α. In the amnion, the liberation of arachidonic acid from membrane glycerophospholipid stores can be catalysed by cytosolic phospholipase A2(cPLA2). In amnion-derived WISH cells, the addition of tumour-necrosis factor alpha (TNF-α) (50 ng/ml) provoked a time-dependent increase in the expression of the cPLA2mRNA which was greatest at 8 and 16 h post-treatment (3.62±0.52 and 3.15±0.45-fold of control, N=3). The increase in cPLA2mRNA expression by TNF-α was unaffected by the prior addition of interleukin-4 (IL-4) (10 ng/ml), a known inhibitor of prostaglandin endoperoxide H synthase (PGHS)-2 mRNA and protein expression in WISH cells. TNF-α also increased the level of immunoreactive cPLA2protein in a time-dependent manner with the highest levels evident after 8 and 16 h. As with the mRNA, cPLA2protein levels were unaffected by pre-incubation with IL-4. The inclusion of the cPLA2-specific inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) resulted in a concentration-dependent inhibition of PGE2biosynthesis in WISH cells treated with TNF-α (>95 per cent at 2 μm). We conclude that TNF-α increases the abundance of the cPLA2mRNA and protein in amnion epithelial cells, an effect which plays an important role in amnion PG biosynthesis in the presence of intrauterine infection