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Abstract Objective Current studies have indicated that diabetes mellitus (DM) is highly prevalent in patients with cancer, but there is little research on consequences on the well‐being of patients during cancer treatment. This analysis evaluates the relationship between DM and patient‐reported outcomes (PRO) in patients with cancer, using a large and well‐characterized cohort. Methods This study utilized the Total Cancer Care protocol at the University of Utah Huntsman Cancer Institute. For this analysis, we integrated data from electronic health records, the Huntsman Cancer Registry, and routinely collected PRO questionnaires. We assessed the association between DM in patients with cancer and PRO scores for anxiety, depression, fatigue, pain interference, and physical function using multiple linear regression and t‐tests. Results The final cohort comprised 3512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n = 1724) were female, with 82.0% (n = 2879) patients reporting PROs at least at one time point. Compared with patients who responded, nonresponders were more often female (p = 0.0035), less frequently non‐Hispanic White (p = 0.0058), and had a higher BMI (p = 0.0759). Patients with cancer and diabetes had worse PRO scores for anxiety (p = 0.0003), depression (p

IntroductionCancer survivors experienced poorer health-related quality of life (HRQoL) and greater psychological distress during the COVID-19 pandemic than those without cancer. However, the underlying mechanisms that may explain how negative experiences during the pandemic are associated with distress and HRQoL remain unknown. We examined whether psychosocial risk factors (i.e., healthcare disruption, disruption to daily activities and social interaction [DDASI], and financial hardship) mediated the relationship between negative COVID-19-related experiences and cancer survivors’ HRQoL and psychological distress (i.e., depressive symptoms, and anxiety) and whether the mediating effects were moderated by psychosocial protective factors (i.e., stress management ability and social support).MethodsA total of 9,651 cancer survivors completed a questionnaire assessing negative COVID-19-related experiences, psychosocial and practical experiences, and HRQoL. Conditional process analysis was used to evaluate the proposed moderated mediation models.ResultsParticipants had a mean age of 63.8 years (SD = 12.3) and were mostly non-Hispanic White (82.3%). DDASI and financial hardship mediated the relationship between negative COVID-19-related experiences and cancer survivor’s HRQoL and psychological distress. Stress management ability buffered the indirect effect of DDASI on cancer survivors’ HRQoL and psychological distress. Social support buffered the indirect effect of financial hardship on HRQoL and depressive symptoms.ConclusionFinancial resources and social interactions may buffer negative effects of major disruptions such as the COVID-19 pandemic. Future studies should assess the longitudinal impact of these associations.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value

Abstract Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values

Abstract Background Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes. Methods Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into ‘highly active’ and’not-highly active’(≥ /

Abstract Background Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. Methods We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. Results Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). Conclusions Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

Abstract Background The gut microbiota has been suggested to play a significant role in the development of overweight and obesity. However, the effects of calorie restriction on gut microbiota of overweight and obese adults, especially over longer durations, are largely unexplored. Methods Here, we longitudinally analyzed the effects of intermittent calorie restriction (ICR) operationalized as the 5:2 diet versus continuous calorie restriction (CCR) on fecal microbiota of 147 overweight or obese adults in a 50-week parallel-arm randomized controlled trial, the HELENA Trial. The primary outcome of the trial was the differential effects of ICR versus CCR on gene expression in subcutaneous adipose tissue. Changes in the gut microbiome, which are the focus of this publication, were defined as exploratory endpoint of the trial. The trial comprised a 12-week intervention period, a 12-week maintenance period, and a final follow-up period of 26 weeks. Results Both diets resulted in ~5% weight loss. However, except for Lactobacillales being enriched after ICR, post-intervention microbiome composition did not significantly differ between groups. Overall weight loss was associated with significant metabolic improvements, but not with changes in the gut microbiome. Nonetheless, the abundance of the Dorea genus at baseline was moderately predictive of subsequent weight loss (AUROC of 0.74 for distinguishing the highest versus lowest weight loss quartiles). Despite the lack of consistent intervention effects on microbiome composition, significant study group-independent co-variation between gut bacterial families and metabolic biomarkers, anthropometric measures, and dietary composition was detectable. Our analysis in particular revealed associations between insulin sensitivity (HOMA-IR) and Akkermansiaceae, Christensenellaceae, and Tanerellaceae. It also suggests the possibility of a beneficial modulation of the latter two intestinal taxa by a diet high in vegetables and fiber, and low in processed meat. Conclusions Overall, our results suggest that the gut microbiome remains stable and highly individual-specific under dietary calorie restriction. Trial registration The trial, including the present microbiome component, was prospectively registered at ClinicalTrials.gov NCT02449148 on May 20, 2015.

Obesity-related metabolic disorders such as hypertension, hyperlipidemia and chronic inflammation have been associated with aortic dilatation and resulting in aortic aneurysms in many cases. Whether weight loss may reduce the risk of aortic dilatation is not clear. In this study, the diameter of the descending thoracic aorta, infrarenal abdominal aorta and aortic bifurcation of 144 overweight or obese non-smoking adults were measured by MR-imaging, at baseline, and 12 and 50 weeks after weight loss by calorie restriction. Changes in aortic diameter, anthropometric measures and body composition and metabolic markers were evaluated using linear mixed models. The association of the aortic diameters with the aforementioned clinical parameters was analyzed using Spearman`s correlation. Weight loss was associated with a reduction in the thoracic and abdominal aortic diameters 12 weeks after weight loss (predicted relative differences for Quartile 4: 2.5% ± 0.5 and -2.2% ± 0.8, p < 0.031; respectively). Furthermore, there was a nominal reduction in aortic diameters during the 50-weeks follow-up period. Aortic diameters were positively associated with weight, visceral adipose tissue, glucose, HbA1c and with both systolic and diastolic blood pressure. Weight loss induced by calorie restriction may reduce aortic diameters. Future studies are needed to investigate, whether the reduction of aortic diameters via calorie restriction may help to prevent aortic aneurysms.

Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Abstract Background Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P

Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.

Biomarkers such as 8-oxo-2’deoxy-guanosine (8-oxo-dG), prostaglandin E2 alpha (PGE2 alpha), prostaglandin metabolites (PGEM) and 8-isoprostane (8-iso) may quantitatively reflect individual tumor risk including colorectal cancer (CRC) and may be useful in clinical management and prevention programs. To further clarify their role in a clinical setting we compared urinary excretion levels with regard to physical activity and other clinical and metabolic parameters in patients with longstanding (>5 years) type 2 diabetes (T2D) (moderate risk) and in those with curatively treated CRC (high risk for recurrence). Patients and methods: In this one center case-control study 60 patients with T2D and 40 patients with CRC were compared with 40 healthy controls. Levels of physical activity were assessed in MET-hr/wk. Urinary excretion of 8-oxo-dG, PGE2 alpha, PGEM and 8-iso were determined by HPLC-ESI mass-spectrometry and ELISA, respectively. Results: Urinary 8-oxo-dG excretion was 33.7% higher in T2D compared to controls (P=0.01), in CRC excretion was 83.6% higher (p

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Purpose: Obesity is associated with increased incidence and mortality in rectal cancer (RC). However, an obesity paradox in the sense of a protective effect of obesity is discussed controversially. We evaluated whether adipose tissue distribution has an impact on medical (MC) and surgical complications (SC) after RC surgery. Methods: A total of 296 RC patients underwent oncological surgery and multidetector CT with quantification of total (TAT), visceral (VAT), and subcutaneous adipose tissue (SAT). Logistic regressions on SC (anastomotic leakage [n = 26], wound infection [n = 58], bleeding [n = 12], abscess [n = 32], bladder dysfunction [n = 24], burst abdomen [n = 10]), and MC (pulmonary [n = 22], cardiac [n = 18], urinary tract infection [n = 9], sepsis [n = 5]) were performed. Results: High pelvicVAT was associated with reduced risk for overall SC (OR = 0.915, p = 0.012) and anastomotic leakage (OR = 0.587, p = 0.024, CI: 0.369/0.934). In contrast, CT-quantified obesity was associated with increased risk for wound infection, bladder dysfunction, burst abdomen, overall MC, and cardiac complications (ORs up to 1.423). BMI was not associated with any SC or MC. Conclusion: An obesity paradox with a protective effect of CT-quantified adipose tissue was confirmed for anastomotic leakage and overall SC. In contrast, high adipose tissue was associated with higher risk for other SC and MC. These results show a more complex influence of body composition on MC and SC. CT-quantified obesity is able to provide deeper insights to explain the obesity paradox beyond BMI.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Abstract Background Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. Methods/design This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. Discussion A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. Trial registration EudraCT Number: 2015–004824-77; ClinicalTrial.gov Identifier: NCT03047837. Registered on February 1, 2017.

Summary: Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91–1.29; p = 0.4) and 1.01 (95% CI, 0.78–1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.

Abstract Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HRhet = 0.82, 95% CI: 0.68–0.99 and rs2847149: HRhet = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet = 1.28, 95% CI: 1.07–1.53; HRhzv = 2.02, 95% CI:1.46–2.80; HRlogAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P

Abstract Backround Non-alcoholic fatty liver disease (NAFLD) comprises non-progressive steatosis and non-alcoholic steatohepatitis (NASH), the latter of which may cause cirrhosis and hepatocellular carcinoma (HCC). As NAFLD detection is imperative for the prevention of its complications, we evaluated whether a combination of blood-based biomarkers and anthropometric parameters can be used to predict NAFLD among overweight and obese adults. Methods 143 overweight or obese non-smokers free of diabetes (50% women, age: 35–65 years) were recruited. Anthropometric indices and routine biomarkers of metabolism and liver function were measured to predict magnetic resonance (MR) - derived NAFLD by multivariable logistic regression models. In addition, we evaluated to which degree the use of more novel biomarkers (adiponectin, leptin, resistin, C-reactive protein, TNF-α, IL-6, IL-8 and interferon-γ) could improve prediction models. Results NAFLD was best predicted by a combination of age, sex, waist circumference, ALT, HbA1c, and HOMA-IR at an area under the receiver operating characteristic curve (AUROC) of 0.87 (95% CI: 0.81, 0.93) before and 0.85 (95% CI: 0.78, 0.91) after internal bootstrap validation. The use of additional biomarkers of inflammation and metabolism did not improve NAFLD prediction. Previously published indices predicted NAFLD at AUROCs between 0.71 and 0.82. Conclusions The AUROC of > 0.8 obtained by our regression model suggests the feasibility of a non-invasive detection of NAFLD by anthropometry and circulating biomarkers, even though further increments in the capacity of prediction models may be needed before NAFLD indices can be applied in routine clinical practice.

DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene-specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo-methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92

Hypertension represents one of the most common maladies of western civilizations caused by bad dietary practices and lack of exercise. Angiotensin-I-converting enzyme inhibitors (ACEi) have been shown to be very efficient in the prevention of hypertension. ACEi are also implicated (by their ability to reduce the product of ACE activity namely angiotensin-II levels, which has oncogenic and increased cell proliferation effects) to be efficient anticancer agents. Therefore, we evaluated the potential antihypertension capacities of anacardic acids purified from Cashew (Anacardium occidentale Linn.) nut shell liquid by inhibition of ACE using analytical reverse-phase high performance liquid chromatography. The ability to inhibit ACE showed the following relation: anacardic-3 (IC50 = 12 µM) > anacardic acid-4 (IC50 = 20 µM) > anacardic acid-2 (IC50 = 33 µM) > anacardic acid-1 (IC50 = 39 µM) as compared to the positive control captopril (IC50 = 6.85 nM). Salicylic acid lacking a phytyl side chain was negative. The capacity of purified anacardic acids to inhibit ACE thereby represents the most potent naturally available plant chemicals described so far, as a potential means of reducing hypertension. The inhibition of angiotensin II production indicated that anacardic acids could also have utility in cancer prevention and recurrence, and reduction of cardiotoxicity during chemotherapy.

Background: Altered levels of markers of oxidative stress, DNA repair, and telomere integrity have been detected in obese individuals and may underlie the pathogenesis of obesity-related diseases. However, whether or not such effects are reversed by intentional weight loss has not been systematically reviewed. Methods: A literature search in PubMed/Medline identified 2,388 articles of which 21 studies (randomized controlled trial (RCT) (n = 10) and non-randomized intervention studies (n = 11)) were classified as testing the effects of intentional weight loss on i) oxidative stress (n = 15), ii) DNA repair (n = 2), and iii) telomere length (n = 4). Results: Across a broad range of intervention designs, diet-, exercise-, surgery-, balloon-induced weight loss regimens decreased oxidative stress measures. Studies investigating DNA repair capacity or telomere length as endpoints after weight loss were less common in number and yielded null or inconsistent results, respectively. Conclusion: While this systematic review supports a role for intentional weight loss in reducing obesity-associated oxidative stress, it is not clear whether the effects are primary outcomes or secondary to improvement in obesity-associated insulin resistance and/or chronic inflammation. Although the lack of effect of intentional weight loss on DNA repair capacity might be anticipated given that oxidative stress is reduced, additional studies are needed. The inconsistent effects of weight loss on telomere length or DNA repair suggest the need for a re-assessment of intervention designs and assay methodology to definitively address this topic.

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P+ cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of n = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells (r = 0.05, p = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P+ malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis.

BackgroundMobilization and activation of natural killer cells (NK cells) have been hypothesized to contribute to observed protective effects of exercise on cancer development and progression. Some evidence exists for acute effects of aerobic exercise on NK cell mobilization and function, i.e., alteration of the gene expression profile of NK cells. Yet, the chronic effects of exercise training, and effects of other modalities than endurance exercise are still understudied. Here, we investigated the chronic effects of a 12-week resistance exercise program on NK cell gene expression in breast cancer patients undergoing adjuvant chemo- or radiotherapy.MethodsBreast cancer patients were randomly assigned to either a 12-week resistance exercise program or a relaxation control group concomitant to adjuvant therapy. In a subsample of 19 participants, RNA was extracted from magnet bead isolated NK cells and subsequently analyzed for differential gene expression using microarray Illumina HumanHT-12 v4 before and after the intervention.ResultsAfter chronic exercise intervention several genes showed higher differential expression compared to the control group. However, after correction for multiple testing, baseline-adjusted analyses of covariance indicated no significant differences between the intervention and the control group with regard to the gene expression profile.DiscussionOur findings suggest that 12-week resistance-exercise did not alter the gene expression profile of NK cells in breast cancer patients undergoing adjuvant therapy on the long term. Further studies with larger sample sizes and specifically designed to investigate whether exercise-induced changes in NK cell function are attributed to acute effects are warranted.

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups—patients who suffered from postoperative complications (n = 30) and those without complication (n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications (p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans. The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism p = 0.04; pFDR = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.

Abstract Background The aim of this study is to review accelerometer wear methods and correlations between accelerometry and physical activity questionnaire data, depending on participant characteristics. Methods We included 57 articles about physical activity measurement by accelerometry and questionnaires. Criteria were to have at least 100 participants of at least 18 years of age with manuscripts available in English. Accelerometer wear methods were compared. Spearman and Pearson correlation coefficients between questionnaires and accelerometers and differences between genders, age categories, and body mass index (BMI) categories were assessed. Results In most investigations, requested wear time was seven days during waking hours and devices were mostly attached on hips with waist belts. A minimum of four valid days with wear time of at least ten hours per day was required in most studies. Correlations (r = Pearson, ρ = Spearman) of total questionnaire scores against accelerometer measures across individual studies ranged from r = 0.08 to ρ = 0.58 (P

Demographic, lifestyle and biospecimen-related factors at the time of blood collection can influence metabolite levels in epidemiological studies. Identifying the major influences on metabolite concentrations is critical to designing appropriate sample collection protocols and considering covariate adjustment in metabolomics analyses. We examined the association of age, sex, and other short-term pre-blood collection factors (time of day, season, fasting duration, physical activity, NSAID use, smoking and alcohol consumption in the days prior to collection) with 133 targeted plasma metabolites (acylcarnitines, amino acids, biogenic amines, sphingolipids, glycerophospholipids, and hexoses) among 108 individuals that reported exposures within 48 h before collection. The differences in mean metabolite concentrations were assessed between groups based on pre-collection factors using two-sided t-tests and ANOVA with FDR correction. Percent differences in metabolite concentrations were negligible across season, time of day of collection, fasting status or lifestyle behaviors at the time of collection, including physical activity or the use of tobacco, alcohol or NSAIDs. The metabolites differed in concentration between the age and sex categories for 21.8% and 14.3% metabolites, respectively. In conclusion, extrinsic factors in the short period prior to collection were not meaningfully associated with concentrations of selected endogenous metabolites in a cross-sectional sample, though metabolite concentrations differed by age and sex. Larger studies with more coverage of the human metabolome are warranted.

Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I−IV) from the ColoCare Study in Heidelberg, Germany. Patients were classified as cachectic (n = 16), pre-cachectic (n = 13), or non-cachectic (n = 23) based on standard criteria on weight loss over time at two time points. Urine samples were collected pre-surgery, and 6 and 12 months thereafter. Fat and muscle mass area were assessed utilizing computed tomography scans at the time of surgery. N = 152 compounds were detected using untargeted metabolomics with gas chromatography−mass spectrometry and n = 154 features with proton nuclear magnetic resonance spectroscopy. Thirty-four metabolites were overlapping across platforms. We calculated differences across groups and performed discriminant and overrepresentation enrichment analysis. We observed a trend for 32 compounds that were nominally significantly different across groups, although not statistically significant after adjustment for multiple testing. Nineteen compounds could be identified, including acetone, hydroquinone, and glycine. Comparing cachectic to non-cachectic patients, higher levels of metabolites such as acetone (Fold change (FC) = 3.17; p = 0.02) and arginine (FC = 0.33; p = 0.04) were observed. The two top pathways identified were glycerol phosphate shuttle metabolism and glycine and serine metabolism pathways. Larger subsequent studies are needed to replicate and validate these results.

Vitamin D and folate are associated with decreased colorectal cancer risk and their association with colorectal cancer prognosis is under investigation. We assessed the levels of plasma 25-hydroxyvitamin D3 (25(OH)D3), folate and vitamin B12 in an international pilot study in order to determine variability of these biomarkers based on geographical location. Plasma 25(OH)D3, folate and vitamin B12 concentrations were measured in 149 invasive, newly diagnosed colorectal cancer cases from Heidelberg (Germany), Seattle (WA, USA), and Tampa (FL, USA) and in ninety-one age- and sex-matched controls. Their associations with potential predictors were assessed using multivariate linear regression analyses. Plasma 25(OH)D3, folate and vitamin B12 concentrations differed by location. Other predictors were season for 25(OH)D3 and tumour stage (vitamin B12). Season-corrected average 25(OH)D3 concentrations were higher in Heidelberg (31·7 ng/ml; range 11·0–83·0 ng/ml) than in Seattle (23·3 ng/ml; range 4·0–80·0 ng/ml) and Tampa (21·1 ng/ml; range 4·6–51·6 ng/ml). In Heidelberg, a strong seasonal variation was observed. Folate (11·1 ng/ml) and vitamin B12 (395 pg/ml) concentrations in Heidelberg were lower than those in Seattle (25·3 ng/ml and 740 pg/ml, respectively) and Tampa (23·8 ng/ml and 522 pg/ml, respectively). Differences in plasma 25(OH)D3 and folate concentrations between Heidelberg and the US sites were observed, probably reflecting variation in outdoor activities and sun-avoidance behaviour during summer as well as in folic acid fortification and supplement use. Intra-site differences at each study location were greater than between-location variability, suggesting that individual health behaviours play a significant role. Nevertheless, the intra-site differences we observed may be due to chance because of the limited sample size. Our pilot study illustrates the value of an international cohort in studying colorectal cancer prognosis to discern geographical differences in a broad range of exposures.