Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis.

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.

Characterization of Chemically and Thermally Treated Oil-in-Water Heteroaggregates and Comparison to Conventional Emulsions.

Heteroaggregated oil-in-water (O/W) emulsions formed by targeted combination of oppositely charged emulsion droplets were proposed to be used for the modulation of physical properties of food systems, ideally achieving the formation of a particulate 3-dimensional network at comparably low-fat content. In this study, rheological properties of Quillaja saponins (QS), sugar beet pectin (SBP), and whey protein isolate (WPI) stabilized conventional and heteroaggregated O/W emulsions at oil contents of 10% to 60% (w/w) were investigated. Selected systems having an oil content of 30% (w/w) and different particle sizes (d43 ≤ 1.1 or ≥16.7 µm) were additionally subjected to chemical (genipin or glutaraldehyde) and thermal treatments, aiming to increase network stability. Subsequently, their rheological properties and stability were assessed. Yield stresses (τ0 ) of both conventional and heteroaggregated O/W emulsions were found to depend on emulsifier type, oil content, and initial droplet size. For conventional emulsions, high yield stresses were only observed for SBP-based emulsions (τ0 ,SBP approximately 157 Pa). Highest yield stresses of heteroaggregates were observed when using small droplets stabilized by SBP/WPI (approximately 15.4 Pa), being higher than those of QS/WPI (approximately 1.6 Pa). Subsequent treatments led to significant alterations in rheological properties for SBP/WPI systems, with yield stresses increasing 29-fold (glutaraldehyde) and 2-fold (thermal treatment) compared to untreated heteroaggregates, thereby surpassing yield stresses of similarly treated conventional SBP emulsions. Genipin-driven treatments proved to be ineffective. Results should be of interest to food manufacturers wishing to design viscoelastic food emulsion based systems at lower oil droplet contents.

Quillajasides A and B: New Phenylpropanoid Sucrose Esters from the Inner Bark of Quillaja saponaria Molina.

The phenolic composition of freshly prepared aqueous extracts of the inner bark of Quillaja saponaria Molina was compared to that of commercially available Quillaja extracts, which are currently used as emulsifiers in foods and cosmetics. Major phenolics in both extracts were (+)-piscidic acid and several p-coumaroyl sucrose esters. Among the latter, two new compounds were isolated and characterized: α-l-rhap-(1→4)-α-l-rhap-(1→3)-(4-O-(E)-p-coumaroyl)-α-d-glup-(1→2)-(3-O-(E)-p-coumaroyl)-ß-d-fruf (quillajaside A) and ß-d-apif-(1→4)-α-l-rhap-(1→4)-α-l-rhap-(1→3)-(4-O-(E)-p-coumaroyl)-α-d-glup-(1→2)-(3-O-(E)-p-coumaroyl)-ß-d-fruf (quillajaside B). In addition, a putative biosynthetic pathway of at least 20 structurally related p-coumaroyl sucrose esters was tentatively identified. Besides their antioxidant activity and their potential function as substrate for enzymatic browning reactions, the new compounds are highly characteristic for both the inner bark of Q. saponaria and commercial extracts derived therefrom. Consequently, they might serve as authenticity markers for the detection of Quillaja extracts in food and cosmetic formulations.

Phenolic constituents in commercial aqueous Quillaja (Quillaja saponaria Molina) wood extracts.

Phenolic compounds in aqueous, saponin-rich soapbark tree (Quillaja saponaria Molina) extracts were qualitatively and quantitatively characterized by HPLC-PDA-MS(n) and NMR spectroscopy. (+)-Piscidic acid represented the major constituent (75-87% (w/w) of total phenolics) in all examined extracts (n = 4), ranging from 22.1 ± 0.1 to 34.0 ± 0.2 mg/g of dry matter (DM). Derivatives of p-coumaric acid were present at concentrations from 2.2 to 9.3 mg/g of DM (8.1-20.4% of total phenolics), whereas other phenolic constituents such as glucosyringic acid and vanillic acid derivatives accounted for less than 7% of total phenolics. Generally, all Quillaja extracts showed a highly similar but unique pattern, potentially being useful to authenticate Quillaja extracts in foods, cosmetics, and pharmaceutical formulations. Furthermore, the desired antioxidant activity as well as undesired browning reactions in the final product might also be explained by these phenolic compounds, which were identified for the first time in Q. saponaria extracts.