Beatrix Jones

Gene expression profiling and genetic markers in glioblastoma survival

Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we did analyses of genes commonly mutated, amplified, or deleted in glioblastomas and DNA microarray gene expression data from tumors of glioblastoma patients of age >50 for whom survival is known. No prognostic significance was associated with genetic changes in epidermal growth factor receptor (amplified in 17 of 41 patients), TP53 (mutated in 11 of 41 patients), p16INK4A (deleted in 15 of 33 patients), or phosphatase and tensin homologue (mutated in 15 of 41 patients). Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across such multiple regression models involve three key genes-SPARC (Osteonectin), Doublecortex, and Semaphorin3B-which play key roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals other genes which support the view that multiple mediators of tumor invasion may be important prognostic factor in glioblastomas in older patients.

Inflammatory status modulates plasma lipid and inflammatory marker responses to kiwifruit consumption in hypercholesterolaemic men

BACKGROUND AND AIMS Kiwifruit has the potential to improve markers of metabolic dysfunction, but the response may be influenced by inflammatory state. We aimed to investigate whether inflammatory state would modulate the effect of consuming two green kiwifruit daily on plasma lipids and markers of inflammation. METHODS AND RESULTS Eighty-five hypercholesterolaemic men completed a 4-week healthy diet run-in, before randomisation to a controlled cross-over study of two 4-week interventions of two green kiwifruit/day plus healthy diet (intervention) or healthy diet alone (control). Anthropometric measures and fasting blood samples (plasma lipids, serum apolipoproteins A1 and B, high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6, tumour necrosis factor-alpha (TNF-α) and IL-10) were taken at baseline, 4 and 8 weeks. Subjects were divided into low and medium inflammatory groups, using pre-intervention hs-CRP concentrations (hs-CRP <1 and 1-3 mg/L, respectively). In the medium inflammatory group the kiwifruit intervention resulted in significant improvements in plasma high-density lipoprotein cholesterol (HDL-C) (mean difference 0.08 [95% CI: 0.03, 0.12] mmol/L [P < 0.001]), total cholesterol (TC)/HDL-C ratio (-0.29 [-0.45, -0.14] mmol/L [P = 0.001]), plasma hs-CRP (-22.1 [-33.6, -4.97]% [P = 0.01]) and IL-6 (-43.7 [-63.0, -14.1]% [P = 0.01]) compared to control treatment. No effects were seen in the low inflammatory group. There were significant between inflammation group differences for TC/HDL-C (P = 0.02), triglyceride (TG)/HDL-C (P = 0.05), and plasma IL-6 (P = 0.04). CONCLUSIONS Inflammatory state modulated responses to the kiwifruit intervention by improving inflammatory markers and lipid profiles in subjects with modestly elevated CRP, suggesting this group may particularly benefit from the regular consumption of green kiwifruit. Registered 16th March 2010, Australian New Zealand Clinical Trials Registry (no. ACTRN12610000213044), www.ANZCTR.org.au.

Metabolite Profile of Cervicovaginal Fluids from Early Pregnancy Is Not Predictive of Spontaneous Preterm Birth

In our study, we used a mass spectrometry-based metabolomic approach to search for biomarkers that may act as early indicators of spontaneous preterm birth (sPTB). Samples were selected as a nested case-control study from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Cervicovaginal swabs were collected at 20 weeks from women who were originally assessed as being at low risk of sPTB. Samples were analysed using gas chromatography-mass spectrometry (GC-MS). Despite the low amount of biomass (16–23 mg), 112 compounds were detected. Statistical analysis showed no significant correlations with sPTB. Comparison of reported infection and plasma inflammatory markers from early pregnancy showed two inflammatory markers were correlated with reported infection, but no correlation with any compounds in the metabolite profile was observed. We hypothesise that the lack of biomarkers of sPTB in the cervicovaginal fluid metabolome is simply because it lacks such markers in early pregnancy. We propose alternative biofluids be investigated for markers of sPTB. Our results lead us to call for greater scrutiny of previously published metabolomic data relating to biomarkers of sPTB in cervicovaginal fluids, as the use of small, high risk, or late pregnancy cohorts may identify metabolite biomarkers that are irrelevant for predicting risk in normal populations.

Associations between dietary patterns, socio-demographic factors and anthropometric measurements in adult New Zealanders: an analysis of data from the 2008/09 New Zealand Adult Nutrition Survey

PurposeTo investigate associations between dietary patterns, socio-demographic factors and anthropometric measurements in adult New Zealanders.MethodsDietary patterns were identified using factor analysis in adults 15 years plus (n = 4657) using 24-h diet recall data from the 2008/09 New Zealand Adult Nutrition Survey. Multivariate regression was used to investigate associations between dietary patterns and age, gender and ethnicity. After controlling for demographic factors, associations between dietary patterns and food insecurity, deprivation, education, and smoking were investigated. Associations between dietary patterns and body mass index and waist circumference were examined adjusting for demographic factors, smoking and energy intake.ResultsTwo dietary patterns were identified. ‘Healthy’ was characterised by breakfast cereal, low fat milk, soy and rice milk, soup and stock, yoghurt, bananas, apples, other fruit and tea, and low intakes of pies and pastries, potato chips, white bread, takeaway foods, soft drinks, beer and wine. ‘Traditional’ was characterised by beef, starchy vegetables, green vegetables, carrots, tomatoes, savoury sauces, regular milk, cream, sugar, tea and coffee, and was low in takeaway foods. The ‘healthy’ pattern was positively associated with age, female gender, New Zealand European or other ethnicity, and a secondary school qualification, and inversely associated with smoking, food insecurity, area deprivation, BMI and waist circumference. The ‘traditional’ pattern was positively associated with age, male gender, smoking, food insecurity and inversely associated with a secondary school qualification.ConclusionsA ‘Healthy’ dietary pattern was associated with higher socio-economic status and reduced adiposity, while the ‘traditional’ pattern was associated with lower socio-economic status.

Predictors and risks of body fat profiles in young New Zealand European, Māori and Pacific women: study protocol for the women's EXPLORE study

BackgroundBody mass index (BMI) (kg/m2) is used internationally to assess body mass or adiposity. However, BMI does not discriminate body fat content or distribution and may vary among ethnicities. Many women with normal BMI are considered healthy, but may have an unidentified “hidden fat” profile associated with higher metabolic disease risk. If only BMI is used to indicate healthy body size, it may fail to predict underlying risks of diseases of lifestyle among population subgroups with normal BMI and different adiposity levels or distributions. Higher body fat levels are often attributed to excessive dietary intake and/or inadequate physical activity. These environmental influences regulate genes and proteins that alter energy expenditure/storage. Micro ribonucleic acid (miRNAs) can influence these genes and proteins, are sensitive to diet and exercise and may influence the varied metabolic responses observed between individuals. The study aims are to investigate associations between different body fat profiles and metabolic disease risk; dietary and physical activity patterns as predictors of body fat profiles; and whether these risk factors are associated with the expression of microRNAs related to energy expenditure or fat storage in young New Zealand women. Given the rising prevalence of obesity globally, this research will address a unique gap of knowledge in obesity research.Methods/DesignA cross-sectional design to investigate 675 NZ European, Māori, and Pacific women aged 16–45 years. Women are classified into three main body fat profiles (n = 225 per ethnicity; n = 75 per body fat profile): 1) normal BMI, normal body fat percentage (BF%); 2) normal BMI, high BF%; 3) high BMI, high BF%. Regional body composition, biomarkers of metabolic disease risk (i.e. fasting insulin, glucose, HbA1c, lipids), inflammation (i.e. IL-6, TNF-alpha, hs-CRP), associations between lifestyle factors (i.e. dietary intake, physical activity, taste perceptions) and microRNA expression will be investigated.DiscussionThis research targets post-menarcheal, premenopausal women, potentially exhibiting lifestyle behaviours resulting in excess body fat affecting metabolic health. These behaviours may be characterised by specific patterns of microRNA expression that will be explored in terms of tailored solutions specific to body fat profile groups and ethnicities.Trial registrationACTRN12613000714785

Blood donation, being Asian, and a history of iron deficiency are stronger predictors of iron deficiency than dietary patterns in premenopausal women.

This study investigated dietary patterns and nondietary determinants of suboptimal iron status (serum ferritin < 20 μg/L) in 375 premenopausal women. Using multiple logistic regression analysis, determinants were blood donation in the past year [OR: 6.00 (95% CI: 2.81, 12.82); P < 0.001], being Asian [OR: 4.84 (95% CI: 2.29, 10.20); P < 0.001], previous iron deficiency [OR: 2.19 (95% CI: 1.16, 4.13); P = 0.016], a “milk and yoghurt” dietary pattern [one SD higher score, OR: 1.44 (95% CI: 1.08, 1.93); P = 0.012], and longer duration of menstruation [days, OR: 1.38 (95% CI: 1.12, 1.68); P = 0.002]. A one SD change in the factor score above the mean for a “meat and vegetable” dietary pattern reduced the odds of suboptimal iron status by 79.0% [OR: 0.21 (95% CI: 0.08, 0.50); P = 0.001] in women with children. Blood donation, Asian ethnicity, and previous iron deficiency were the strongest predictors, substantially increasing the odds of suboptimal iron status. Following a “milk and yoghurt” dietary pattern and a longer duration of menstruation moderately increased the odds of suboptimal iron status, while a “meat and vegetable” dietary pattern reduced the odds of suboptimal iron status in women with children.

Association between maternal exposure to phthalates and lower language ability in offspring derived from hair metabolome analysis

The fetus undergoes a crucial period of neurodevelopment in utero. The maternal hair metabolome provides an integrated record of the metabolic state of the mother prior to, and during pregnancy. We investigated whether variation in the maternal hair metabolome was associated with neurodevelopmental differences across infants. Maternal hair samples and infant neurocognitive assessments (using the Bayley III Scales of Infant Development at 24 months) were obtained for 373 infant-mother dyads between 26–28 weeks’ gestation from the Growing Up in Singapore Towards Healthy Outcomes cohort. The hair metabolome was analysed using gas chromatography-mass spectrometry. Intensity measurements were obtained for 276 compounds. After controlling for maternal education, ethnicity, and infant sex, associations between metabolites and expressive language skills were detected, but not for receptive language, cognitive or motor skills. The results confirm previous research associating higher levels of phthalates with lower language ability. In addition, scores were positively associated with a cluster of compounds, including adipic acid and medium-chain fatty acids. The data support associations between the maternal hair metabolome and neurodevelopmental processes of the fetus. The association between phthalates and lower language ability highlights a modifiable risk factor that warrants further investigation.

A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with Autism Spectrum Disorder

Irritability and hyperactivity are common in children with Autism Spectrum Disorder (ASD). Because pharmacological treatments may have adverse effects, and despite limited evidence, caregivers/parents often use dietary supplements such as vitamin D and omega-3 fatty acids to address these behavioural symptoms. As a secondary objective of the VIDOMA (Vitamin D and Omega-3 in ASD) trial, we evaluated the efficacy of vitamin D, omega-3 long chain polyunsaturated fatty acid [omega-3 LCPUFA; docosahexaenoic acid (DHA)], or both on irritability and hyperactivity. New Zealand children with ASD (aged 2.5-8 years) participated in a 12-month randomized, double-blind, placebo-controlled trial of vitamin D (2000 IU/day, VID), omega-3 LCPUFA (722 mg/day DHA, OM), or both (2000 IU/day vitamin D + 722 mg/day DHA, VIDOM). The primary outcomes were the Aberrant Behaviour Checklist (ABC) domains of irritability and hyperactivity. Biomarkers (serum 25-hydroxyvitamin D [25(OH)D] and omega-3 index) and primary outcomes were measured at baseline and 12-months. Out of 111 children who completed baseline data collection, 66% completed the study (VID = 19, OM = 23, VIDOM = 15, placebo = 16). After 12 months, children receiving OM (-5.0 ± 5.0, P = 0.001) and VID (-4.0±4.9, P = 0.01) had greater reduction in irritability than placebo (0.8±6.1). Compared to placebo, children on VID also had greater reduction in hyperactivity (-5.2±6.3 vs. -0.8±5.6, P = 0.047). Serum 25(OH)D concentration (nmol/L, mean±SD) increased by 27±14 in VID and by 36±17 in VIDOM groups (P < 0.0001), and omega-3 index (%, median (25th, 75th percentiles)) by 4.4 (3.3, 5.9) in OM and by 4.0 (2.0, 6.0) in VIDOM groups (P < 0.0001), indicating a good compliance rate. The results indicate that vitamin D and omega-3 LCPUFA reduced irritability symptoms in children with ASD. Vitamin D also reduced hyperactivity symptoms in these children.

Population Social Structure Facilitates Indirect Fitness Benefits from Extra-Pair Mating

Despite decades of research, empirical support for the ‘compatible genes’ and ‘good genes’ hypotheses as explanations for adaptive female extra-pair mating remains discordant. One largely un-tested theoretical prediction that could explain equivocal findings is that mating for compatible genes benefits should reduce selection for good genes. However, this prediction does not consider demographic parameters, such as social structuring, that can indirectly influence extra-pair paternity (EPP) outcomes. Drawing on evidence from a previous study, we re-evaluate this hypothesis whilst considering social structuring in a population of tui, Prosthemadera novaeseelandiae, a socially monogamous passerine. Previous research has found possible evidence for mating for good genes because male ornament size correlates with EPP success in this population. Here, we test whether non-random inbreeding of social-pairs indirectly provides the opportunity to gain compatibility benefits from EPP, and thus whether selection for compatible genes and good genes can operate simultaneously. We found that 1) social mates were more closely related than expected through random mating, 2) extra-pair males were less closely related to females than were the females’ within-pair mates, and 3) genetically dissimilar males sired offspring with faster growth rates. These results demonstrate that females gain compatible genes benefits from EPP. However, contrary to the compatible genes hypothesis, females in highly-related pairs did not engage more frequently in extra-pair mating. Together with previous research investigating female mate choice in this population, our findings suggest that social pairings between relatives provide a pathway for females to gain compatible genes benefits whilst engaging in extra-pair mating for good genes. This study provides evidence that some fitness benefits from EPP arise automatically through non-random social mating rather than through direct selection on extra-pair mate choice. We argue that when variance in compatibility benefits is an outcome of population structuring, compatible genes benefits need not be gained at the expense of good genes benefits.