Surrogate threshold effect based on a meta-analysis for the predictive value of progression-free survival for overall survival in hormone receptor-positive, HER2-negative metastatic breast cancer.

PURPOSE: Clinical trials investigating therapies for metastatic breast cancer (mBC) generally use progression-free survival (PFS) as primary endpoint, which is not accepted as patient-relevant outcome within the German benefit assessment. Hence a validation of PFS as surrogate endpoint for overall survival (OS) is needed, e.g., in the indication of HR+, HER2-negative mBC. METHODS: A systematic search was conducted. RCT were included if at least one study arm investigated fulvestrant, letrozole, tamoxifen, exemestane, or anastrozole. Additionally, hazard ratios reported for OS/PFS including confidence interval or standard error were mandatory. Pearson correlation coefficient was calculated to estimate the relation of surrogate endpoint PFS and patient-relevant outcome OS as well as the surrogate threshold effect (STE) which is used to determine thresholds for the estimate of the surrogate endpoint. RESULTS: 16 studies with 5324 patients in total were included in the analyses. The correlation between hazard ratios of PFS and OS was statistically significant (r = 0.72, 95% CI 0.35-0.90) representing a positive linear relationship. STE analysis was applied. The meta-regression model revealed a STE for HRPFS of 0.60 and sensitivity analyses underlined robustness of the results. CONCLUSIONS: Based on the derived STE, it is possible to draw conclusions on a significant effect in OS for a hypothetical trial demonstrating an upper confidence limit of HRPFS < 0.60 in PFS. However, only final OS results are able to confirm if a clinical relevant difference in survival time can be achieved.

Fra a 1.02 Is the Most Potent Isoform of the Bet v 1-like Allergen in Strawberry Fruit.

The strawberry fruit proteins Fra a 1.01E-1.08 are homologues of the major birch pollen allergen Bet v 1. Three of the proteins are known to have essential biological functions in pigment formation during fruit ripening and seem to be responsible for allergic reactions to strawberry fruit. We evaluated the cross-reactive allergenic potential of these putative strawberry allergens in patients allergic to birch pollen. Activation of basophils of eight atopic patients was studied using different concentrations of Fra a 1 isoforms. Bet v 1a was used as control and as atopic patient selection criterion. Although Fra a 1.01E-1.08 have amino acid sequence identities of 74.5-97.5% with Fra a 1.02, the basophil activation mediated by the eight Fra a 1 proteins differed substantially. Fra a 1.03 and Fra a 1.02 showed the highest activation of basophils, 73 and 66% of total basophils, respectively. On the basis of the high relative expression of the gene Fra a 1.02 in ripe strawberry fruits of allergenic varieties, Fra a 1.02 was identified as the main strawberry allergen of the Bet v 1 superfamily. Knowledge of the allergenic potential of Fra a 1.02/1.03 will help to improve food safety and can serve as a valuable marker for the development of red-fruited hypoallergenic strawberry cultivars.

Metabolic interaction between anthocyanin and lignin biosynthesis is associated with peroxidase FaPRX27 in strawberry fruit.

Plant phenolics have drawn increasing attention due to their potential nutritional benefits. Although the basic reactions of the phenolics biosynthetic pathways in plants have been intensively analyzed, the regulation of their accumulation and flux through the pathway is not that well established. The aim of this study was to use a strawberry (Fragaria × ananassa) microarray to investigate gene expression patterns associated with the accumulation of phenylpropanoids, flavonoids, and anthocyanins in strawberry fruit. An examination of the transcriptome, coupled with metabolite profiling data from different commercial varieties, was undertaken to identify genes whose expression correlated with altered phenolics composition. Seventeen comparative microarray analyses revealed 15 genes that were differentially (more than 200-fold) expressed in phenolics-rich versus phenolics-poor varieties. The results were validated by heterologous expression of the peroxidase FaPRX27 gene, which showed the highest altered expression level (more than 900-fold). The encoded protein was functionally characterized and is assumed to be involved in lignin formation during strawberry fruit ripening. Quantitative trait locus analysis indicated that the genomic region of FaPRX27 is associated with the fruit color trait. Down-regulation of the CHALCONE SYNTHASE gene and concomitant induction of FaPRX27 expression diverted the flux from anthocyanins to lignin. The results highlight the competition of the different phenolics pathways for their common precursors. The list of the 15 candidates provides new genes that are likely to impact polyphenol accumulation in strawberry fruit and could be used to develop molecular markers to select phenolics-rich germplasm.

Evolution of rosmarinic acid biosynthesis.

Rosmarinic acid and chlorogenic acid are caffeic acid esters widely found in the plant kingdom and presumably accumulated as defense compounds. In a survey, more than 240 plant species have been screened for the presence of rosmarinic and chlorogenic acids. Several rosmarinic acid-containing species have been detected. The rosmarinic acid accumulation in species of the Marantaceae has not been known before. Rosmarinic acid is found in hornworts, in the fern family Blechnaceae and in species of several orders of mono- and dicotyledonous angiosperms. The biosyntheses of caffeoylshikimate, chlorogenic acid and rosmarinic acid use 4-coumaroyl-CoA from the general phenylpropanoid pathway as hydroxycinnamoyl donor. The hydroxycinnamoyl acceptor substrate comes from the shikimate pathway: shikimic acid, quinic acid and hydroxyphenyllactic acid derived from l-tyrosine. Similar steps are involved in the biosyntheses of rosmarinic, chlorogenic and caffeoylshikimic acids: the transfer of the 4-coumaroyl moiety to an acceptor molecule by a hydroxycinnamoyltransferase from the BAHD acyltransferase family and the meta-hydroxylation of the 4-coumaroyl moiety in the ester by a cytochrome P450 monooxygenase from the CYP98A family. The hydroxycinnamoyltransferases as well as the meta-hydroxylases show high sequence similarities and thus seem to be closely related. The hydroxycinnamoyltransferase and CYP98A14 from Coleus blumei (Lamiaceae) are nevertheless specific for substrates involved in RA biosynthesis showing an evolutionary diversification in phenolic ester metabolism. Our current view is that only a few enzymes had to be "invented" for rosmarinic acid biosynthesis probably on the basis of genes needed for the formation of chlorogenic and caffeoylshikimic acid while further biosynthetic steps might have been recruited from phenylpropanoid metabolism, tocopherol/plastoquinone biosynthesis and photorespiration.