Biomarker antibody concentration appears to dramatically affect the apparent relationship between biomarker expression and outcome.

The role of B-catenin in breast cancer and its prognostic value is controversial. The prognostic value had been assessed previously in a series of nonquantitative immunohistochemical studies with conflicting results. In efforts to clarify the relationship between B-catenin protein expression and breast cancer prognosis, we have assessed a retrospective 600 case cohort of breast cancer tumors from the Yale Pathology archives on tissue microarrays. They were assessed using automated quantitative analysis (AQUA) with a series of arrayembedded cell lines for which the B-catenin concentration was standardized by an ELISA assay. The expression levels of the standard clinical markers HER2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 were also assessed on the same cohort. X-tile software was used to select optimal protein concentration cutpoints and to evaluate the outcome using a training set and a validation set. We found that lowlevel expression of membranous B-catenin is associated with significantly worse outcome (38% versus 76%, 10-year survival, validation set log-rank P = 0.0016). Multivariate analysis of this marker, assessed in a proportional hazards model with tumor size, age, node status, nuclear grade, ER, PR, HER2, and Ki-67, is still highly significant with a hazard ratio of 6.8 (P < 0.0001, 95% confidence interval, 3.1-15.1). These results suggest that loss of B-catenin expression at the membrane, as assessed by objective quantitative analysis methods, may be useful as a prognostic marker or may be part of a useful algorithm for prognosis in breast cancer. (Cancer Res 2006; 66(10): 5487-94)

Objective: Incorporation of fish oil into food products provides a means of increasing n–3 fatty acid intake, particularly in populations where fish consumption remains low. The aim of the present study was to evaluate the bioavailability of n–3 PUFA in microencapsulated fish-oil-enriched foods compared with an equal amount of n–3 PUFAs contained in fish oil capsules. Methods: Twenty-five healthy female volunteers were randomly assigned to one of two groups for the 4-week intervention: one group received 0.9 g of n–3 PUFA/day as fish oil capsule (capsule group), while the second group (food group) received an equal amount of n–3 PUFA/day from enriched foods. Baseline and post-intervention samples were analysed for platelet fatty acid composition. Results: There was no significant difference in the change in platelet arachidonic acid (AA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) between the two groups following the intervention. Conclusions: The results indicate that n–3 PUFA from microencapsulated fish-oil-enriched foods are as bioavailable as n–3 PUFA in a capsule. Fortification of foods with microencapsulated fish oil, therefore, offers an effective way of increasing n–3 PUFA intakes and status in line with current dietary recommendations.

b-catenin is a multifunctional protein involved in both cadherin-mediated adhesion and the wnt signaling cascade. Mutations in exon 3 of b-catenin have been identified in many cancers. In addition to disruption of key serine and threonine residues, mutations are frequently reported in other residues in exon 3 that are not kinase substrates. The most frequently mutated nonserine/ threonine residues are D32 and G34. Since D32 and G34 are part of the ubiquitination destruction motif, DSGUXS, we hypothesize that this motif may contribute to disruption of b-catenin homeostasis and lead to cellular transformation. We demonstrate that the mutants D32A and G34A exhibit no change in phosphorylation by GSK3b, but display reduced ubiquitination compared to wild-type and S33A mutant b-catenin. To assess the functional implications of these mutations, we created stable MDCK cell lines expressing these constructs. We found that stable cell lines harboring D32A-mutated b-catenin were highly transformed, while S33A and G34 demonstrated only weak transforming properties in our assays. Despite altered ubiquitination status and increased transformation, the D32A mutant cell line does not display transcriptional activation of standard target genes. Therefore, D32A mutation may mediate transformation by an alternative b-catenin-mediated signaling pathway.

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Objective: To examine the effect of low-dose ®sh oil supplementation on speci®c growth factors, purported to play a central role in lesion formation, and also on the total growth factor activity of serum, as assessed by the induction of DNA synthesis in cultured human arterial smooth muscle cells. Design: Randomized placebo-controlled double-blind intervention study. Setting: Free-living population. Subjects: Sixty-three healthy volunteers, 37 males and 26 females. Interventions: Four treatment regimes with subjects receiving 0, 0.3,0.6 or 0.9 gaday of n-3 PUFA for an 8 week period. Blood samples were taken at baseline and following the 8 week intervention. All samples were analysed in batch following completion of the study. Results: Consumption of ®sh oil had no effect on serum platelet-derived growth factor (PDGF), or transforming growth factor beta (TGFb) concentration. Furthermore, ®sh oil supplementation did not alter the total growth factor activity of serum. Conclusions: Results indicate that low-dose ®sh oil supplementation, equivalent to about two portions of fatty ®sh per week and providing less than 1 g n-3 PUFAaday, does not alter the levels of the major serum growth factors and does not modify total serum growth factor activity in healthy human volunteers. Sponsorship: European Union shared cost project (FAIR-CT-95-0085).

Despite considerable advancements in the clinical management of PDAC it remains a significant cause of mortality. PDAC is often diagnosed at advanced stages due to vague symptoms associated with early-stage disease and a lack of reliable diagnostic biomarkers. Late diagnosis results in a high proportion of cases being ineligible for surgical resection, the only potentially curative therapy for PDAC. Furthermore, a lack of prognostic biomarkers impedes clinician’s ability to properly assess the efficacy of therapeutic interventions. Advances in our ability to detect circulating nucleic acids allows for the advent of novel biomarkers for PDAC. Tumor derived circulating and exosomal nucleic acids allow for the detection of PDAC-specific mutations through a non-invasive blood sample. Such biomarkers could expand upon the currently limited repertoire of tests available. This review outlines recent developments in the use of molecular techniques for the detection of these nucleic acids and their potential roles, alongside current techniques, in the diagnosis, prognosis and therapeutic governance of PDAC.