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Additional file 3: Figure S1. Determination of sensitivity and false discovery rate based on SBS18 and SBS38. Figure S2. Trinucleotide mutational spectra of the additional 21 samples with GCVsig detected from AACR Project GENIE and Foundation Medicine cohorts. Figure S3. Permutation test to determine cohort-wide false discovery rate. Figure S4. Replication strand bias for cell lines and cancer samples. Figure S5. Mutation burden of GCV positive samples relative to other samples by cancer type. Figure S6. Treatment of cells with ganciclovir and acyclovir. Figure S7. Treatment of cells with ganciclovir (GCV) and mycophenolate mofetil (MMF). Figure S8. Absolute mutations for GCV-induced mutations(CA>AA), C>T and T>C mutations across H414, HCT116 cell line and H023 organoid models. Figure S9. Copy number variation across the genomes of H414 and HCT116 clones. The ploidy values are calculated using Control-FREEC from each sample’s whole genome sequencing data. Figure S10. Histogram showing the distribution variant allele frequency (VAF) of mutations from diploid regions in each clone of H414 (A) and HCT116 (B).

Additional file 2. Supplementary Methods.

Mitochondria are crucial organelles in energy transduction, with an emerging role in cell signaling beginning to be appreciated. Due to the endosymbiotic nature of mitochondria and as a by-product of energy transduction via the electron transport chain (ETC), mitochondria are inherently exposed to many stresses (e.g. reactive oxygen species, genomic damage and proteotoxic stress). We postulated that there would be active intracellular and extracellular pathways of mitochondrial communication engaged to maintain cellular fitness, however this has not been well studied in mammalian cells. The overarching aim of this thesis was to explore how mammalian cells communicate mitochondrial stress. More specifically, to characterise intracellular signaling adaptations to mitochondrial stress and to investigate cell non-autonomous communication of mitochondrial stress through secreted proteins. To address the first aim, a xeno-cybrid model was employed where cells had mismatch between nuclear and mitochondrial genomes resulting in an impairment of ETC function. Compared with controls, cells with ETC dysfunction had substantial oxidative defects, but were viable and maintained cellular ATP. This ‘rescue’ of cell survival appeared to be driven by upregulation of glycolysis and pro-survival Akt and AMPK signaling. To interrogate a potential upstream mediator, ATM kinase was explored, and it was found that a number of adaptations were reversed by a selective ATM kinase inhibitor. These results therefore support a role for ATM kinase as an important adaptation promoting survival of mammalian cells in response to mitochondrial stress. To address cell non-autonomous communication, HEK293 cells, and primary murine hepatocytes and adipocytes were incubated with ETC inhibitors (rotenone or antimycin A) or an oxidative phosphorylation uncoupler (Dinitrophenol), and secreted proteins were analysed by LC-MS/MS to map the mitochondrial stress-sensitive secretome. Significant alterations in secreted proteins were observed for HEK293 cells and adipocytes with ETC complex I and III inhibition and in hepatocytes treated with DNP. Collectively, the work presented in this thesis sheds new light on the pathways employed by mammalian mitochondria to signal and respond to stress.

Mitochondrial dysfunction has been implicated in the aetiology of many complex diseases, as well as the ageing process. Much of the research on mitochondrial dysfunction has focused on how mitochondrial damage may potentiate pathological phenotypes. The purpose of this review is to draw attention to the less well-studied mechanisms by which the cell adapts to mitochondrial perturbations. This involves communication of stress to the cell and successful induction of quality control responses, which include mitophagy, unfolded protein response, upregulation of antioxidant and DNA repair enzymes, morphological changes, and if all else fails apoptosis. The mitochondrion is an inherently stressful environment and we speculate that dysregulation of stress signaling or an inability to switch on these adaptations during times of mitochondrial stress may underpin mitochondrial dysfunction and hence amount to pathological states over time.

Objective: Peanuts contain bioactive nutrients beneficial for vascular function. This study investigated whether consumption of unsalted peanuts (with skins) would enhance cerebrovascular perfusion and cognitive performance. Method: In a randomized crossover trial, 61 volunteers (29 males/32 females, 65 ± 7 years, BMI 31 ± 4 kg/m2) consumed their habitual diet ± high-oleic peanuts (56–84 g/day), each for 12 weeks. Nutrient intakes, vascular and cognitive function were assessed at baseline and at the end of each 12-week phase. Differences between the ends of each phase were compared by general linear repeated measures ANOVA controlling for baseline. Pearson's correlation analyses determined relationships between differences in cerebrovascular reactivity (CVR) and cognitive function. Results: Intakes of bioactive nutrients increased during the peanut phase. CVR was 5% greater in the left middle cerebral artery (MCA) and 7% greater in the right MCA. Small artery elasticity was 10% greater after peanut consumption; large artery elasticity and blood pressure did not differ between phases. Measures of short-term memory, verbal fluency, and processing speed were also higher following the peanut phase; other cognitive measures did not change. Differences in CVR in the left MCA correlated with differences in delayed memory and recognition. Discussion: Regular peanut consumption improved cerebrovascular and cognitive function; increased intakes of bioactive nutrients may have mediated these improvements. Refereed/Peer-reviewed

Nuts are rich in many nutrients that can benefit multiple cardiometabolic functions, including arterial compliance, blood pressure, inflammation, glucoregulation and endothelial vasodilatation. Impaired vasodilatation may contribute to impaired cognitive performance due to poor cerebral perfusion. The present narrative review examines associations between nut consumption, vascular health and cognitive function. It includes a systematic search which identified seventy-one epidemiological or intervention studies in which effects of chronic nut consumption on blood pressure, glucoregulation, endothelial vasodilator function, arterial compliance, inflammatory biomarkers and cognitive performance were evaluated. Weighted mean changes were estimated where data were available; they indicate that nut consumption reduces blood pressure and improves glucoregulation, endothelial vasodilator function and inflammation, whilst a limited number of studies suggest that nut consumption may also improve cognitive performance. Further clinical trials are warranted to explore relationships between nut consumption, endothelial function and cognitive function. Refereed/Peer-reviewed

Snacking is associated with intakes of non-core foods which may predispose to obesity. Peanuts have potential satiety benefits and may assist with weight management; we hypothesized that peanut consumption would reduce intake of non-core snack foods due to compensation. We investigated the effects of adding peanuts to a habitual diet on snacking habits and energy intake. Sixty-one healthy participants (65±7years, body mass index 31±4kg/m2) consumed their habitual diet with or without peanuts (56g/d for 32 women, 84g/d for 29 men) for 12weeks each in a randomized crossover design. Food diaries were analyzed at baseline and after each 12-week period for meal and snack content and timing. Total energy intake was higher (17% for men [P

Epidemiological evidence indicates an inverse association between nut consumption and obesity, inflammation, hyperlipidaemia and glucose intolerance. We investigated effects of high oleic peanut consumption vs. a nut free diet on adiposity and cardio-metabolic risk markers. In a randomised cross-over design, 61 healthy subjects (65 ± 7 years, body mass index (BMI) 31 ± 4 kg/m2) alternated either high oleic peanuts (15%–20% of energy) or a nut free diet for 12 weeks. Body composition and mass, waist circumference, C-reactive protein (CRP), lipids, glucose and insulin were assessed at baseline and after each phase. Repeated measures analysis of variance (ANOVA) compared the two diets. Consistent with other nut studies, there were no differences in lipids, CRP, glucose and insulin with peanut consumption. In contrast, some reports have demonstrated benefits, likely due to differences in the study cohort. Energy intake was 10% higher (853 kJ, p &lt, 0.05), following peanut consumption vs. control, attributed to a 30% increase in fat intake (p &lt, 0.001), predominantly monounsaturated (increase 22 g, p &lt, 0.05). Despite greater energy intake during the peanut phase, there were no differences in body composition, and less than predicted increase (0.5 kg) in body weight for this additional energy intake, possibly due to incomplete nutrient absorption and energy utilisation.

Thesis (PhD)--University of South Australia, 2014. Includes bibliographical references (pages 185-204) Health concerns are growing worldwide as populations’ age and become increasingly overweight. Obesity is associated with increased cardio-metabolic risk and cognitive decline. Peanuts are a snack food rich in unsaturated fatty acids, protein and fibre which have demonstrated satiety benefits and may reduce total energy intake, despite their high energy density. Hi-oleic peanuts have been bred in Australia for their high monounsaturated fat content and are also a source of arginine, resveratrol (in the skins), folate, vitamin E and magnesium which have demonstrated benefits for vascular function and cardio-metabolic health. Epidemiological evidence indicates an inverse association between nut consumption and obesity, inflammation, hyperlipidaemia and glucose intolerance, which all influence vascular health. Studies have suggested that improved vasodilator function in the cerebral arteries with increased blood flow to the brain may be a likely mechanism for improvements in cognitive performance. Hence, this thesis examined the effect of nut consumption on satiety, cardio-metabolic, vascular and cognitive measures. These relationships were examined by conducting two intervention studies and a scoping review of the literature.

Snack foods can contribute a high proportion of energy intake to the diet. Peanuts are a snack food rich in unsaturated fatty acids, protein and fibre which have demonstrated satiety effects and may reduce total energy intake, despite their high energy density. This study examined the effects of consuming Hioleic (oleic acid ~75% of total fatty acids) peanuts and regular peanuts (oleic acid ~50% and higher in polyunsaturated fatty acids) compared with a high carbohydrate snack (potato crisps) on satiety and subsequent energy intake. Using a triple crossover study design, 24 participants (61 ± 1 years) consumed isoenergetic amounts (56-84 g) of Hi-oleic or regular peanuts or (60-90 g) potato crisps after an overnight fast. Hunger and satiety were assessed at baseline, 30, 60, 120 and 180 minutes following snack consumption using visual analogue scales, after which a cold buffet meal was freely consumed and energy intake measured. The same snack was consumed on 3 subsequent days with energy intake assessed from dietary records. This protocol was repeated weekly with each snack food. Total energy intake was lower following consumption of Hi-oleic and regular peanuts compared with crisps, both acutely during the buffet meal (−21%; p < .001 and −17%; p < .01) and over the 4 days (−11%; p < .001 and −9%; p < .01). Despite these reductions in energy intake, no differences in perceived satiety were observed. The findings suggest peanuts may be a preferred snack food to include in the diet for maintaining a healthy weight. Refereed/Peer-reviewed