The T genotype of the MGMT C>T (rs16906252) enhancer single-nucleotide polymorphism (SNP) is associated with promoter methylation and longer survival in glioblastoma patients.

Clinical studies in patients with newly diagnosed glioblastoma treated with temozolomide have shown that the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is both predictive and prognostic of outcome. Methylation of the promoter region of MGMT is the most clinically relevant measure of MGMT expression and its assessment has become integral in current and planned clinical trials in glioblastoma. Our study confirmed that MGMT methylation, assessed by pyrosequencing, is associated with a significant survival benefit in glioblastoma patients treated with temozolomide (either concurrently with radiotherapy or sequential treatment). More interestingly, our study demonstrated that a promoter variant, the c.-56C>T (rs16906252) single nucleotide polymorphism (SNP) located within a cis-acting enhancer element at the proximal end of MGMT, is associated with the presence of MGMT promoter methylation in de novo glioblastoma. Furthermore, we show that the overall survival of patients carrying both the SNP and MGMT methylation showed a strong survival benefit when compared to either molecular event on their own. Promoter reporter experiments in MGMT methylated glioblastoma cell lines showed the T allele conferred a ∼30% reduction in normalised MGMT promoter activity compared to the wild-type haplotype. This might account for the propensity of the T allele to undergo promoter methylation, and in turn, the improved survival observed in carriers of the T allele. An independent validation on larger cohorts is required to confirm the prognostic and predictive value of individuals carrying the T allele.

LOV (light, oxygen, or voltage) domains of the blue-light photoreceptor phototropin (nph1): binding sites for the chromophore flavin mononucleotide.

Phototropism, the bending response of plant organs to or away from a directional light source, is one of the best studied blue light responses in plants. Although phototropism has been studied for more than a century, recent advances have improved our understanding of the underlying signaling mechanisms involved. The NPH1 gene of Arabidopsis thaliana encodes a blue light-dependent autophosphorylating protein kinase with the properties of a photoreceptor for phototropism. NPH1 apoprotein noncovalently binds FMN to form the holoprotein nph1. The N-terminal region of the protein contains two LOV (light, oxygen, or voltage) domains that share homology with sensor proteins from a diverse group of organisms. These include the bacterial proteins NIFL and AER, both of which bind FAD, and the phy3 photoreceptor from Adiantium capillus-veneris. The LOV domain has therefore been proposed to reflect a flavin-binding site, regulating nph1 kinase activity in response to blue light-induced redox changes. Herein we demonstrate that the LOV domains of two nph1 proteins and phy3 bind stoichiometric amounts of FMN when expressed in Escherichia coli. The spectral properties of the chromopeptides are similar to the action spectrum for phototropism, implying that the LOV domain binds FMN to function as a light sensor. Thus, our findings support the earlier model that nph1 is a dual-chromophoric flavoprotein photoreceptor regulating phototropic responses in higher plants. We therefore propose the name phototropin to designate the nph1 holoprotein.

A phytochrome from the fern Adiantum with features of the putative photoreceptor NPH1.

In plant photomorphogenesis, it is well accepted that the perception of red/far-red and blue light is mediated by distinct photoreceptor families, i.e., the phytochromes and blue-light photoreceptors, respectively. Here we describe the discovery of a photoreceptor gene from the fern Adiantum that encodes a protein with features of both phytochrome and NPH1, the putative blue-light receptor for second-positive phototropism in seed plants. The fusion of a functional photosensory domain of phytochrome with a nearly full-length NPH1 homolog suggests that this polypeptide could mediate both red/far-red and blue-light responses in Adiantum normally ascribed to distinct photoreceptors.

Serum and antral gastrin levels in fed and fasted rats: relation to aging.

The effect of short fasting for up to 24 h on serum and antral gastrin concentrations and G cell ultrastructure has been examined in the young rat compared with the middle-aged rat. The serum gastrin levels at 24-h fasting were markedly reduced in both young and middle-aged rats. There was also a significant decrease in antral gastrin concentrations after 24 h of fasting in the middle-aged rats. By contrast, the antral gastrin concentrations in the young rats increased progressively and significantly with fasting for up to 24 h. These responses were associated with a significant increase in the content of secretory granules of G cell, which was at its greatest by 24 h. The antral gastrin level in the 48-h fasting rats was markedly reduced to a level below that for the prestarvation group. By 48 h of starvation, the amount of secretory granules in G cell was significantly reduced (P < 0.05) compared with the 24-h fasting group. These results indicate that the effects of fasting on the antral gastrin levels in young rats differ from those of the middle-aged and that starvation for up to 24 h caused a significant increase in the antral gastrin content in the young rats' stomach.