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Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts
BMC Medicine volume 21, Article number: 80 (2023)
Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts.
Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases.
Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69–0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87–0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75–0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89–1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded.
Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.
Colorectal cancer is the third most common cancer globally, with around 1.9 million cases diagnosed in 2020, and the second most common cause of cancer-related death . There is great potential to reduce this burden since most colorectal cancer cases are sporadic  and are associated with modifiable risk factors such as body fatness , alcohol intake , and diet . Colorectal cancer development is also influenced by metabolic factors [6, 7]. For example, insulin and insulin-like growth factors are thought to play causal roles in colorectal tumorigenesis , likely through the promotion of cell proliferation and growth signaling pathways . Broad metabolic dysfunction may lead to perturbed small-molecule metabolism, which in turn elicits bioactivity at the level of tissues and organs.
Amino acids are among the most abundant circulating metabolites and serve as building blocks of proteins, precursors of many signaling molecules, and an important energy source via the citric acid cycle. Certain amino acids may also fuel cancer development , and marked changes in blood amino acid concentrations have been extensively observed in colorectal cancer patients . For example, levels of amino acids such as glutamine, citrulline, alanine, and histidine have been inversely associated with advancing disease stage [12, 13], while valine and leucine were among the metabolites that distinguished colorectal cancer cases using a discovery-replication strategy . Similarly, the concentrations of several blood amino acids distinguished early-stage colorectal cancer cases from controls in Japanese patients, most notably aspartic acid , as well as ornithine and lysine . Glutamine was a notable discriminant in patients newly diagnosed with colorectal cancer compared to controls in a Chinese hospital-based study . Overall, amino acid levels were generally inversely associated with prevalent colorectal neoplasia, suggesting a depletion of serological concentrations in cases compared to healthy individuals. Amino acid profiling could therefore potentially help identify early-stage disease , as well as providing insights into mechanisms of carcinogenesis.
Despite these observations, few prospective studies have been conducted to test the hypothesis that pre-diagnostic amino acid concentrations are associated with colorectal cancer risk. Two such studies of nested case-control design that analyzed pre-diagnostic serum or plasma by untargeted metabolomics found limited dysregulation of lipophilic metabolites only [19, 20], while in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort that measured tryptophan and serotonin levels, tryptophan was inversely associated with colon cancer . The aim of the current study was thus to test these associations in a larger and more comprehensive analysis. We first employed the EPIC nested case-control study as a discovery cohort, which measured between 13 and 21 amino acids in fasting plasma or serum in relation to colorectal cancer. In a replication step, we tested those amino acids associated with colorectal cancer risk in EPIC in the UK Biobank cohort, in which 9 overlapping compounds had been measured in over 111,000 participants. Together, the two cohorts allow for the largest and most detailed investigation of circulating amino acids and colorectal cancer risk performed to date.
The EPIC cohort
The EPIC cohort includes over 520,000 individuals who were recruited between 1992 and 2000 from 23 study centers across 10 European countries (Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, the Netherlands, and the UK). Participants were 35-70 years of age at recruitment, and approximately 70% of the cohort are women. The study design has been previously described [22, 23]. In brief, extensive questionnaire data on dietary and lifestyle variables were collected at baseline, and approximately 75% of individuals provided non-fasting blood samples.
Incident cases of colorectal cancer were identified through record linkage with regional cancer registries or via a combination of methods, such as the use of health insurance records, contacts with cancer and pathology registries, and active follow-up through participants and their next of kin. Colorectal cancer was defined using the tenth edition of the International Classification of Disease (ICD-10) and the second edition of the International Classification of Disease for Oncology (ICD-O-2). Proximal colon cancers included those found within the cecum, ascending colon, hepatic flexure, transverse colon, and splenic flexure (C18.0 and C18.2–18.5). Distal colon cancers included those found within the descending (C18.6) and sigmoid (C18.7) colon. Overlapping (C18.8) and unspecified (C18.9) lesions of the colon were classed as colon cancers only. Cancer of the rectum included cancers occurring at the recto-sigmoid junction (C19) and rectum (C20).
The current study employed a fasted subset of EPIC data, obtained from two separate metabolomics studies on colorectal cancer, as a discovery cohort. Samples were analyzed using the Biocrates AbsoluteIDQTM p180 kit (467 cases and 467 matched controls) and the p150 kit (1141 cases and 1141 controls). Combining these studies and then excluding non-fasting participants resulted in a final combined sample of 654 fasted cases and 654 controls, of which 354 case-control pairs were analyzed using the p180 kit. Controls were selected using incidence density sampling from all cohort members who were alive and free of cancer (except non-melanoma skin cancer) at the time of diagnosis of the colorectal cancer cases. Controls were matched to cases on age at recruitment (within 6 months), sex, study center, follow-up time since blood collection, time of day at blood collection (within 4 h), and fasting status. Women were further matched on menopausal status (pre-, peri-, and post-menopausal) and, in pre-menopausal women, phase of menstrual cycle at blood collection. Approval for the study was obtained from the International Agency for Research on Cancer (IARC) and local center review boards. All participants provided written informed consent.
The UK Biobank cohort
The UK Biobank aims to investigate the genetic, lifestyle, and environmental causes of a range of diseases . Between 2006 and 2010, 502,656 adults aged between 40 and 69 years (229,182 men and 273,474 women) who were registered with the UK National Health Service were recruited at 22 study assessment centers. Ethical approval was obtained from the North West Multicentre Research Ethics Committee, the National Information Governance Board for Health and Social Care in England and Wales, and the Community Health Index Advisory Group in Scotland. All participants provided written informed consent. The present study was undertaken under application number 25897.
During the baseline recruitment visit, participants completed a self-administered questionnaire on socio-demographics (including age, sex, education, and Townsend deprivation score), health and medical history, lifestyle exposures (including smoking habits, dietary intakes, and alcohol consumption), early life exposures, and medication use. Physical measurements were taken, including weight, height, and waist circumference. Colorectal cancer cases were defined using the 10th Revision of the International Classification of Diseases (ICD-10). Colorectal cancers comprised those of the proximal colon (C18.0 and C18.2–18.5), distal colon (C18.6–C18.7), overlapping and unspecified lesions of the colon (C18.8–C18.9), and rectal cancers (C19–C20), as described above.
Blood samples, with data on time since last meal, were collected from all participants at recruitment and additionally from around 20,000 participants who attended a repeat assessment visit between 2012 and 2013. The current study included all participants for whom metabolite profiling had been performed at the time of the study, and thus had available amino acid measurements. From our supplied dataset that contained observations for 502,524 participants, exclusions were made for voluntary withdrawal from the study (n = 36) and prevalent cancer at recruitment (n = 27,240). Of the remainder, plasma amino acid measurements were available for 111,323 participants, and these were included as the replication cohort (Fig. 1).
In EPIC, targeted metabolomics profiling was performed at the International Agency for Research on Cancer (Biocrates AbsoluteIDQTM p180 kit) and the Helmholtz Centre in Munich (Biocrates AbsoluteIDQTM p150 kit). The samples were prepared as per the Biocrates kit instructions [25, 26]. Assay preparation steps were carried out on 96 well plates and a volume of 10 μL plasma was prepared. The p150 kit allows the quantification of up to 13 amino acids and the p180 kit up to 21 amino acids (Additional file 1: Supplemental Methods) [25, 27]. Liquid chromatography–mass spectrometry (LC-MS) was used to quantify the levels of the amino acids in accordance with the kit manufacturer’s instructions. All 21 amino acids included were fully quantified in μmol/L. The amino acids quantified were arginine, glutamine, glycine, histidine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine (p150 and p180 kits); and alanine, asparagine, aspartate, citrulline, glutamate, isoleucine, leucine, and lysine (p180 kit only). See Additional file 1: Supplemental Methods for full details of sample preparation. Coefficients of variation for amino acids are given in Table S1.
Analysis of plasma from around 118,000 participants of the UK Biobank was performed using nucleic magnetic resonance (NMR) spectroscopy on the Nightingale metabolic biomarker platform (Nightingale Health Ltd, Finland), which comprises 249 metabolic measures, among which are concentrations of 9 amino acids. In brief, stored plasma samples prepared in 96-well plates were thawed, mixed gently, and centrifuged for 3 min at 3400 g to remove the precipitate. Aliquots of each sample were mixed with phosphate buffer, loaded onto a cooled sample changer, and analyzed by NMR spectroscopy. Metabolic biomarkers were identified and quantified from two separate spectra, a pre-saturated proton NMR spectrum, and a T2-relaxation-filtered spectrum. Six identical Bruker AVANCE IIIHD instruments were employed in parallel. The amino acids quantified were alanine, glutamine, glycine, histidine, isoleucine, leucine, valine, phenylalanine, and tyrosine. See Additional file 1: Supplemental Methods for further details.
Pearson correlations between non-log transformed amino acid concentrations were first calculated in the 654 EPIC fasted controls only and in UK Biobank participants with a fasted time of >4 h (n = 56,688). Hierarchical clustering of concentration profiles using Ward’s method was used to visualize and identify notable clusters of correlated metabolites.
Analysis of discovery cohort
In EPIC, case-control status was modeled using conditional logistic regression and odds ratios (OR) and 95% confidence intervals (CI) estimated for each amino acid. Models were adjusted for an a priori determined set of potential confounders comprising smoking status (never, former, current, unknown), alcohol drinking history (never, former, current, lifetime, unknown), Cambridge physical activity index (inactive, moderately inactive, moderately active, active, unknown) and body mass index (BMI; <25, 25–30, and >30kg/m2), all at baseline. The false discovery rate (FDR) procedure was used to adjust P-values and an FDR P-value threshold of 0.05 was used for statistical significance. Continuous models per SD concentration and categorical models by quartile were fit for each amino acid. For the categorical models, inner quartile cut points were determined by the metabolite concentrations among control participants. To test for trends across categories, quartile medians were additionally modeled as continuous variables.
Analysis of replication cohort
Amino acids that were significantly associated with colorectal cancer per SD concentration in EPIC were carried forward for testing in the UK Biobank cohort. Here, time to colorectal cancer diagnosis was modeled using Cox proportional hazards regression and hazard ratios (HR) and 95% CI estimated for each amino acid. Time at study entry was age at recruitment, while exit time was age at incident cancer diagnosis, death, or the last date at which follow-up was considered complete. Multivariable models were kept as similar as possible to those fit in EPIC and were adjusted for BMI category (<25, 25–30, >30 kg/m2), total physical activity (<10, 10–20, 20–40, 40–60, >60 metabolic equivalent of task [MET] h/week), alcohol consumption frequency (never, special occasions only, 1–3 times/month, 1–2 times per week, 3–4 times/week, daily or almost daily, unknown/prefer not to answer), smoking status (smoker, former smoker, never smoker), time since last meal (hours), and family history of colorectal cancer (yes/no). Stratification variables were age at recruitment in 5-year intervals, Townsend deprivation index quintiles, and assessment center region. A raw P-value threshold of 0.05 was used for statistical significance.
Stratified and sensitivity analyses
The above analysis was repeated but excluding individuals diagnosed within the first 2, 5, and 10 years of the study in EPIC, and within the first 2 and 5 years in the UK Biobank. Sex-stratified models were also performed for all amino acids measured in both cohorts and, in UK Biobank, amino acid models were conducted for colon and rectal subsites separately. Heterogeneity by sex and by tumor subsite was tested for by fitting models with and without interaction terms and comparing these by likelihood ratio test. As sensitivity analyses, models for glutamine and histidine only were repeated additionally adjusting for major sources of animal proteins (red and processed meat, poultry, fish, and dairy product intake), and amino acid models were repeated in EPIC only using non-fasted participants as well as fasted participants.
Analyses were conducted either in the R open-source statistical programming language (version 3.6.3 on the RStudio environment) or STATA version 16.1 (StataCorp Inc).
A median follow-up of 14.4 years was observed for the 654 colorectal cancer cases and 654 controls in EPIC while, during a median follow-up of 10.7 years in the UK Biobank, 1221 incident cases of colorectal cancer occurred among the 111,323 participants with available amino acid measurements. The EPIC and UK Biobank populations were of similar ages at baseline and at colorectal cancer diagnosis although, in EPIC, most participants (77.4%) were from Italian or Spanish centers. Full baseline characteristics are shown in Table 1. Glutamine, alanine, and glycine were at the highest circulating concentrations overall, as quantified in EPIC (Fig. 2). Fasting concentrations of amino acids in cancer-free participants were almost always positively correlated, with the following correlated clusters noted in EPIC: glycine and serine; arginine, methionine, and tryptophan; valine, isoleucine, and leucine; and histidine and phenylalanine (Fig. 3). In the UK Biobank, valine, isoleucine, and leucine concentrations (branched-chain amino acids) were strongly intercorrelated.
Associations of pre-diagnostic amino acid concentrations with colorectal cancer risk
In the EPIC discovery phase, histidine concentrations were inversely associated with colorectal cancer risk (OR 0.80 per SD concentration, 95% CI 0.69–0.92, FDR P-value = 0.03) (Table 2). A statistically significant trend was also observed by quartile of histidine concentration (P-trend = 0.002). Lysine was also inversely associated with colorectal cancer risk (OR 0.78 per SD concentration, 95% CI 0.66–0.93, FDR P-value = 0.05), and glutamine was borderline inversely associated with risk (OR 0.85 per SD concentration, 95% CI 0.75–0.97, FDR P-value = 0.08). For both lysine and glutamine, individuals in Q4 of concentrations had a lower risk compared to those in Q1, with an apparent decreasing trend across quartiles (P-trend for both amino acids = 0.01).
Histidine and glutamine, but not lysine, were among the nine amino acids measured in UK Biobank and were thus carried forward to the replication stage. Histidine was also significantly inversely associated with colorectal risk in UK Biobank (HR 0.93 per SD concentration, 95% CI 0.87–0.99, P-value = 0.03), with a significantly decreasing trend across quartiles of concentration. Glutamine was again borderline inversely associated with risk on a continuous scale (HR 0.95 per SD, 95% CI 0.89–1.01 respectively, P-value = 0.09), and individuals in Q4 of concentrations were at a lower risk of colorectal cancer than those in Q1 (HR 0.85, 95% CI 0.72–1.00).
Analysis by follow-up time
In EPIC, ORs for histidine and glutamine did not appreciably change when cases diagnosed within 2, 5, or 10 years were excluded (OR 0.82 per SD concentration, 95% CI 0.67–1.01 and OR 0.82, 95% CI 0.68–0.99 respectively for the two amino acids, exclusion of the first 10 years of follow-up) (Table 3). Similarly, minor changes in HR were observed for the exclusion of 2 and 5-year periods of follow-up for these amino acids in UK Biobank.
Stratified and sensitivity analysis
In EPIC, most available colorectal samples were for cancers of the colon (625/654) and estimates for colon cancer mirrored those of colorectal cancer (Additional file 1: Table S2). Nevertheless, in the UK Biobank where 31.7% of colorectal cases (388/1221) were rectal cancers, HRs for colorectal and colon cancers were also similar. Here, glutamine concentrations were similarly associated with risk of colorectal cancer and colon cancer only (HR 0.92 per SD concentration, 95% CI 0.85–0.99), while no association was observed for rectal cancer (HR 1.02 per SD, 95% CI 0.91-1.13). Heterogeneity between colon and rectal tumor subsites approached but did not reach statistical significance (P=0.13). As regards histidine, hazard ratios were similar for colon cancer (HR 0.95, 95% CI 0.88-1.02), rectal cancer (HR 0.89, 95% CI 0.80–0.99), and colorectal cancer overall (HR 0.93, 95% CI 0.87-0.99). Inverse associations for amino acids were more pronounced in men than in women (Additional file 1: Table S3), and heterogeneity by sex was observed for histidine in UK Biobank (P-heterogeneity = 0.02). Heterogeneity by sex was not observed for any other amino acid measured in UK Biobank or for any amino acid measured in EPIC.
For the EPIC and UK Biobank participants included in the main study, adjustment for major sources of amino acid intake (red and processed meat, poultry, fish, eggs, and dairy products) did not change associations between circulating amino acids and colorectal cancer risk (Additional file 1: Table S4). Likewise, in sensitivity analyses including non-fasting as well as fasting participants in EPIC, associations did not change appreciably (Additional file 1: Table S5).
In this analysis of pre-diagnostic circulating amino acid levels and colorectal cancer risk, histidine was found to be robustly inversely associated and glutamine borderline inversely associated with colorectal cancer risk via a discovery-replication strategy in two large prospective cohorts. In addition, odds ratios and hazards ratios for these amino acids were attenuated minimally by the exclusion of cases diagnosed within 10 years of follow-up. This study provides strong evidence that lower levels of histidine, and possibly glutamine, are associated with subsequent risk of colorectal cancer, even up to 10 years before a colorectal cancer diagnosis.
Circulating levels of several amino acids have previously been found to be inversely associated with colorectal neoplasia, but in studies of cross-sectional design only. Glutamine, for example, was one of several amino acids found to be lower in colorectal cancer patients compared to healthy controls , while histidine was lower among stage IV colorectal cancer cases than stage I cases  and even inversely correlated with tumor stage . Untargeted metabolomics studies using discovery and validation cohorts demonstrated leucine and the dipeptide glutamine-leucine to be among those metabolites that distinguished cases from controls [14, 30]. Nevertheless, few studies have analyzed pre-diagnostic samples to investigate whether amino acid dysregulation precedes tumorigenesis. Two other prospective case-control studies on colorectal cancer with some amino acid measurements also found no significant associations [19, 31]. Our study is therefore the first to observe inverse associations of amino acid levels with colorectal cancer risk in a prospective setting and in independent studies. Although the above evidence suggests that tumor energy requirements give rise to the depletion of circulating glutamine and histidine, the levels of these amino acids among colorectal cancer cases in our prospective cohorts were associated with colorectal cancer risk at least 10 years prior to a colorectal cancer diagnosis, suggesting that alterations in the metabolism of these compounds may either reflect etiological pathways associated with the development of disease or metabolic changes linked to early events in colorectal tumorigenesis.
The most pronounced finding of the current study was a robust inverse association between circulating histidine and colorectal cancer risk in both EPIC and UK Biobank. Histidine, an essential amino acid derived from the diet, is converted by histidine decarboxylase to the biogenic amine histamine , a signaling molecule that mediates an acute inflammatory response by binding to specific receptors . Histidine decarboxylase activity may be upregulated in tumor cells and is thought to accelerate cell proliferation and angiogenesis . For instance, the enzyme was found to be more active in colon cancer cells, particularly metastatic tumor cells, than normal colonic cells . Given that an inverse association between histidine and colorectal cancer risk was apparent as long as 10 years before diagnosis, perturbations to specific etiologic pathways may be hypothesized. Prior evidence suggests that higher histidine concentrations mitigate metabolic dysregulation; for example, dietary supplementation with histidine was found to improve insulin sensitivity, possibly via the suppression of pro-inflammatory cytokine expression, in women with metabolic syndrome . These findings suggested that histidine may even hold potential as a therapeutic agent against metabolic disease. However, levels of histidine have also been found to be positively associated with breast cancer . Therefore, additional laboratory studies are needed to elucidate the potential role of this amino acid in carcinogenesis.
Glutamine was borderline inversely associated with colorectal cancer risk in both cohorts. Glutamine is among the most abundant small-molecule metabolites in circulation and plays a central role in amino acid metabolism. It is used by proliferating cancer cells as an energy source  and is likely an important substrate throughout colorectal tumorigenesis . The reasons for lower circulating glutamine in individuals who went on to develop colorectal cancer compared to those who remained cancer-free are uncertain. Firstly, given the slow development of colorectal cancer, lowered glutamine may reflect the undetected presence of polyps or early cancerous lesions in cases at baseline . Secondly, regardless of the presence of such lesions and even controlling for major risk factors, abnormally low glutamine levels may reflect cancer-promoting metabolism. For instance, as well as being directly related to the tumor stage, glutamine levels have been inversely associated with serum C-reactive protein and inflammatory cytokines [13, 39]. Also, lowered glutamine and the glutamine-glutamate ratio was reported to be associated with incident type II diabetes , an established risk factor for colorectal cancer . Lowered glutamine may represent dysregulation of the glutamine-glutamate axis. Although our study measured glutamate in a subset of EPIC cases and controls only, some evidence for a positive association of glutamate with colorectal cancer risk was observed in the categorical analysis. Glutamine concentrations may influence multiple mechanisms related to cancer development which deserve further investigation in experimental models.
The inverse associations observed between amino acid concentrations and colorectal cancer risk may also reflect cancer-promoting dysbiosis of the gut microbiota. Similar to the protection against colorectal cancer afforded by short-chain fatty acids produced from dietary fiber by microbiota via the mitigation of an inflammatory microenvironment , certain components of the gut microbiota may act upon amino acids in the lumen to influence inflammation and tumorigenesis ,. For example, the production of histidine decarboxylase by gut microbes has been suggested to decrease intestinal inflammation via the binding of histamine to the receptor HR2 in the gut lumen . Also, specific components of the microbiota are also believed to mediate the relationship between branched-chain amino acids and insulin resistance . It is therefore plausible that the associations of histidine and glutamine with colorectal cancer risk in the current study may reflect variability in gut microbial activity and its interaction with host metabolism. Further mechanistic research is needed to investigate links between histidine and glutamine metabolism, the gut microbiota and colorectal tumorigenesis.
The main strengths of this study include the prospective design, the use of large-scale cohorts with extensive participant data, and robust amino acid measurements in participants of well-characterized fasting status. We excluded non-fasted participants from the outset in the EPIC discovery cohort to minimize the effects of recent dietary intake upon amino acid levels which could have complicated interpretation of the results. As an additional safeguard against this bias, we performed sensitivity analyses for fasting status in EPIC and for major dietary sources of amino acids in both cohorts, which did not appreciably attenuate risk estimates. This is consistent with a recent study in EPIC that found weak or no correlations between amino acid intake and their blood concentrations .
In terms of limitations, only 9 of the 21 amino acids were measured in all EPIC and UK Biobank samples, while only 13 were measured all EPIC samples, with limited statistical power for the remainder. It is plausible that levels of amino acids other than glutamine and histidine are associated with colorectal cancer and we note that HR or OR point estimates were lower than 1 for most compounds in both cohorts. With greater statistical power, particularly in UK Biobank, other amino acids would likely have been found inversely associated with colorectal cancer risk via the discovery-replication strategy. Also, measurements of amino acids were taken at the study baseline only, and the technical and biological reproducibility of measurement was therefore not accounted for. However, studies calculating intra-class correlation in blood samples suggest that polar metabolites such as amino acids are measured reproducibly, particularly in fasted participants . Statistical power was limited for individual colorectal cancer subsites, particularly rectal cancer. Also, we were not able to consider amino acids in tissue samples, which may better represent the tumor microenvironment and provider deeper insight into the biological implications of our findings.
Circulating histidine levels were robustly inversely associated with colorectal cancer risk in two independent prospective cohorts with similar, albeit slightly weaker, evidence for glutamine. This knowledge should contribute to a better understanding of the underpinnings of colorectal cancer and metabolism and could potentially support new prevention or early detection strategies. Further research using experimental models to assess potential causality of the identified associations is now needed.
Availability of data and materials
Data from EPIC are not publicly available, but access requests can be made to the to the EPIC Steering Committee (https://epic.iarc.fr/access/submit_appl_access.php). The UK Biobank is an open access resource. This research was conducted under license from the UK Biobank, application number 25897. Data are available upon application to UK Biobank; see http://ukbiobank.ac.uk/register-apply/.
Branched-chain amino acid
Body mass index
European Prospective Investigation into Cancer and Nutrition
False discovery rate
International Agency for Research on Cancer
International Classification of Diseases
Liquid chromatography–mass spectrometry
Metabolic equivalent of task
Nuclear magnetic resonance
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Kuhn T, Floegel A, Sookthai D, Johnson T, Rolle-Kampczyk U, Otto W, et al. Higher plasma levels of lysophosphatidylcholine 18:0 are related to a lower risk of common cancers in a prospective metabolomics study. BMC Med. 2016;14:13. https://doi.org/10.1186/s12916-016-0552-3.
Jutel M, Akdis M, Akdis CA. Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy. 2009;39(12):1786–800.
Smolinska S, Jutel M, Crameri R, O'Mahony L. Histamine and gut mucosal immune regulation. Allergy. 2014;69(3):273–81.
Cianchi F, Cortesini C, Schiavone N, Perna F, Magnelli L, Fanti E, et al. The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clin Cancer Res. 2005;11(19 Pt 1):6807–15.
Feng RN, Niu YC, Sun XW, Li Q, Zhao C, Wang C, et al. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. Diabetologia. 2013;56(5):985–94.
Jobard E, Dossus L, Baglietto L, Fornili M, Lecuyer L, Mancini FR, et al. Investigation of circulating metabolites associated with breast cancer risk by untargeted metabolomics: a case-control study nested within the French E3N cohort. Br J Cancer. 2021;124(10):1734–43.
Cluntun AA, Lukey MJ, Cerione RA, Locasale JW. Glutamine Metabolism in Cancer: Understanding the Heterogeneity. Trends Cancer. 2017;3(3):169–80.
Zhao YQ, Zhao X, Chen V, Feng Y, Wang L, Croniger C, et al. Colorectal cancers utilize glutamine as an anaplerotic substrate of the TCA cycle in vivo. Sci Rep. 2019;9(1):19180.
Ling HH, Pan Y-P, Fan C-W, Tseng W-K, Huang J-S, Wu T-H, et al. Clinical Significance of Serum Glutamine Level in Patients with Colorectal Cancer. Nutrients. 2019;11(4):898.
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Breier M, Wahl S, Prehn C, Fugmann M, Ferrari U, Weise M, et al. Targeted Metabolomics Identifies Reliable and Stable Metabolites in Human Serum and Plasma Samples. PLoS One. 2014;9(2):e89728.
This work was conducted using the UK Biobank Resource (Application Number 25897) and the authors gratefully acknowledge the participants and those involved in building the resource. The authors thank all European Prospective Investigation into Cancer and Nutrition centers for provision of biological samples and participant data. The research was made possible using the data and samples provided by the International Agency for Research on Cancer Biobank.
This paper is dedicated to the memory of our colleague Dr. Bas Bueno-de-Mesquita.
Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.
The authors acknowledge funding from World Cancer Research Fund grant number 2014-02 and EC-BBMRI LPC (MG). RZ-R was supported by the “Miguel Servet” program (CPII20/00009) from the Institute of Health Carlos III (Co-funded by the European Social Fund (ESF) - ESF investing in your future).
Ethics approval and consent to participate
Approval for the EPIC study was obtained from the International Agency for Research on Cancer (IARC) and local center review boards. All participants provided written informed consent. The two colorectal cancer case-control studies were approved by the ethics committee at the International Agency for Research on Cancer (IARC) on 7 April 2014 (IEC 14-08). For the UK Biobank, ethical approval was obtained from the North West Multicentre Research Ethics Committee, the National Information Governance Board for Health and Social Care in England and Wales, and the Community Health Index Advisory Group in Scotland. Ethical approval for the cohort was most recently renewed in 2021 by the National Health Service (NHS) Health Research Authority in 2021 (21/NW/0157). All participants provided written informed consent.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplemental methods for laboratory analyses; Table S1, Reported coefficients of variation for 21 amino acids measured in the EPIC and UK Biobank cohorts; Table S2, Associations between 21 plasma or serum amino acids and colorectal, colon and rectal cancer risk in the EPIC and UK Biobank cohorts; Table S3, Associations between 21 plasma or serum amino acids and colorectal cancer risk in the EPIC and UK Biobank cohorts, by sex; Table S4, Associations between amino acids associated with colorectal cancer in either cohort in the main study, additionally adjusted for intakes of major sources of animal protein (red and processed meat, poultry, fish and dairy products) in the EPIC and UK Biobank cohorts; Table S5, Associations between concentrations of 21 plasma or serum amino acids and colorectal cancer risk in fasted participants only and all available participants in the EPIC nested case-control study.
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Cite this article
Rothwell, J.A., Bešević, J., Dimou, N. et al. Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts. BMC Med 21, 80 (2023). https://doi.org/10.1186/s12916-023-02739-4


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A brand new true crime documentary is creeping out viewers so much they're scared to sleep after watching it.
Netflix's The Sons of Sam: A Descent Into Darkness dropped on Wednesday and it delves into the crimes of serial killer and arsonist David Berkowitz, who murdered six people in 1977.
You can watch the trailer for The Sons of Sam: A Descent Into Darkness below:
Berkowitz claimed he was motivated by demons and went by the self-proclaimed 'Son of Sam' - hence the title of the doc. The name stemmed from his belief that a demon lived inside the black Labrador of his neighbour, Sam Carr. When he committed his crimes, he would write to local newspapers and sign his letters from 'Son of Sam.'
He soon became known in the media as the '.44 Caliber Killer' because he used a 44 caliber Bulldog revolver gun to kill his victims in this attack.
As viewers binge the documentary series, some have detailed how unnerving the case is, with one person writing: "Well I ended up watching all of #SonsOfSam in one go. Compulsively propellant and creepy."
Another viewer joked about only being able to think about the details of the case when trying to sleep. "Me: gonna start prioritising sleep #selfcare also me: inhales all of #SonsofSam in one go."
They followed-up their tweet with the infamous meme of Love Island star Chris Hughes struggling to sleep in the villa.
It appears lots of viewers can relate, with a third sharing: "Watching #SonsofSam hoping I'll be able to sleep."
After the largest manhunt New York City had ever seen, Berkowitz was arrested in August 1977 - 11 days after committing his last crime. It was thanks to a parking ticket on his car, which was found near to the scene of one of the shootings, that he was brought in by police.
After pleading guilty to eight separate shooting attacks in New York City - killing six people and injuring another ten - he was given six life sentences in June 1978.
The Sons of Sam: A Descent Into Darkness is available to stream on Netflix now.
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Do just fine has the benefit of both loans and investment choices for automobiles. This is a selection for men and women to invest in a unique or a great put vehicle. Having a succeed mortgage, you would not need to bother about constraints to decades otherwise sort of vehicles. Almost every other lenders may set men and women limitations. Although not, Do just fine finance is also security a range of automobile. They’re able to additionally be regularly re-finance your existing car loan.
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HELOCs commonly but really available at enough time of creating. Do just fine could be providing HELOCs towards the end of the season. Our home Equity Personal line of credit has a minimal price. This is certainly an excellent revolving credit line that is safeguarded by your household. It truly does work in a similar manner so you can credit cards, giving monetary manage. At present, you might create the mortgage, and you can Prosper usually notify you whenever HELOCs can be found in your city. You just need to complete your email and you will state; there are not any personal debt.

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About the property
- House1600 sq. ft.
- Half Baths0
- Minimum Stay1 - 7 nights
House, 3 Bedrooms + Convertible bed(s), 2 Baths, (Sleeps 6)
Our renovated and charming Bethany Beach house is located 1.3 miles from the beach in the beautiful quiet neighborhood of Lake Bethany. Convenient to the beach and town boardwalk, via bike or Bethany Beach Trolley. We welcome Dogs and provide small and large crates, plus a list of favorite dog friendly activities for both you and your loved dog. Go swimming with your dog at one of several dog friendly beaches close-by.
Keywords: Renovated, Charming, Dog Friendly, Beach House
- Response rate:
- Response time:
- within a few hours
- Calendar last updated:
- May 22, 2018
Local Services & Businesses
Sports & Adventure Activities
Check-in: 3:00 PM
Check-out: 10:00 AM
Canceled bookings will not receive a refund
Charming, comfortable, quiet and clean
We absolutely loved staying in this house. It was quiet, welcoming and comfortable, and you would never know it's dog friendly based on how clean it is. The screened-in porch was my favorite part of the house -- we spent all of our time there. The trolley stop is steps from the house, as is a pretty lake where we saw lots of herons. Restaurants and a convenience store are biking distance, and it took five minutes to drive to downtown and the beach. Even in the height of the summer, parking was never a problem downtown, thanks to the pass the owner left for us. The owner's communication with us was excellent -- quick to respond to questions and helpful. I hope to rent this same house again next summer.
Great spot for a family reunion!
We enjoyed staying here in mid-July. The bunk bed room and two comfy couches were a hit with the kids and the two other rooms allowed 2 couples ample space to relax. The house had everything we could need. Our teenagers loved being able to escape to the screened in porch. We loved being able to catch the trolley but also the parking pass to park in town. We'll be back!
Cute beach house for vacation
This was just right for our family's vacation at Bethany Beach. It was close to the beach (a very short drive). The residential parking permit really came in handy! The owner was so friendly and helpful with my tons of questions before our stay. I had never stayed at Bethany Beach before, so I had plenty of questions and she was always so quick and helpful with my emails to her! The property is definitely clean and well maintained. The only thing I would recommend is possibly dehumidifiers as it seemed humid/damp and I know they want the a/c settings at 75 degrees. I know the week we stayed was also especially hot (towards the end, the heat index stayed above 100.) The master bedroom was especially humid and with plastic mattress protectors, it does make it rather warm to sleep. Otherwise, the home is very charming, spacious and adorable. We really enjoyed our stay and would love to return.
Homey, clean, charming, great location
We liked the photo online, but were pleased to discover that it was even better when we got there. The house is I charming, and sited in a lovely neighborhood. It was quiet. The house was spotless. There were TV's in every room, and the kitchen was practical and very workable. Every exchange with the owner was prompt and kind. I particularly enjoyed quiet time on the screened porch each morning. Bethany is the best, and the trolley stop is just a few steps from the house.
Thank you so much for allowing us to stay in your home in Bethany Beach. The house was perfect for us and our two little dogs. We just loved the neighborhood and enjoyed taking walks in the morning and evening. There was tree, along the canal, full of blue herons that I visited daily as they were so fun to watch. The house was close to everything and we had easy access to a nearby grocery store, the beach, and many local businesses. Thanks again for offering the perfect place for us to unwind. We will be back!
Comfortable and cozy
It was a very comfortable and welcoming place. Everything you need is there, and it was very nice to have dog crates available. the house was well maintained and it's convenient to everything. nice neighborhood, fun porches in the pine trees. we will come back!

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Sports Pet Caricature From Photos in Colored Pencils Style
Get a Custom Pet Caricature Drawing in colored pencils style. One of our animal portrait artists is ready to create a fantastic and original Drawing of any breed of domestic animals in Sport Theme. Imagine French Bulldog, Labrador or Scottish Fold as one of sports fan. Is not it funny and entertaining? Of course, it is!You will get a realistic Сaricature Drawing of your pet or friend's family pet in a sports team uniform upon your wish. We offer you a nice way to surprise your pet lover with such an incredible pet caricature. Mention the Team or attach the photo of your pet and the Uniform you like and we will make it happen! Your Pet Sports Caricature Drawing will be delivered as a ready-to-be-printed, high resolution JPG file. Additional available deliveries, at extra cost: Original Pencil Drawing on A4 or A3 size Paper. Drawing printed on Canvas and Drawing printed on Photo Paper (Fujifilm Crystal Archive Paper) with different sizes. Worldwide shipping is available.
Get a stunning caricature portrait drawn from your own photos by professional caricature artists. Ordering is simple: upload as many photos as you wish and add any relevant description - we will draw a caricature that you, your family and friends will cherish forever! The caricature drawing is a great option for Birthday Gift, Anniversary Gift or Wedding Gift. You can use it both for personal and business use.
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This is a valentines gift for my partner and I couldn't be happier with it!
It took a few days longer than I'd hoped but now that I've seen the result, I'm ecstatic!!!

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Bird Feeding Encouraged By Bonnington Plastics Due To Declining Numbers
Though many birds last through winter via migration, the UK bird population has taken a dangerous hit after extreme weather shortened food supplies even further.
Nottingham (I-Newswire) January 14, 2013 - The Met Office reported 2012 to be the second wettest year the UK has ever experienced, and the wettest to ever occur in England. Some areas found themselves suffering the wettest summers in a century, resulting in the flooding that occurred nationwide.
The damp weather affected the breeding patters of many UK birds this summer, in particular the Swift. Torrential rainfall led to a reduction in the number of aerial insects, which making up the main source of nutrition for the Swift. Many saw the birds abandoning their young less than a week after they hatched, lacking the food to sustain them. This is generally unheard of, with birds being naturally maternal creatures.
Bonnington Plastics, wholesalers of gardening and animal products, are encouraging the UK public to set up food sources for garden birds this year, helping sustain the creatures through a difficult time. A representative from the company commented, “We share a passion for birds at Bonnington Plastics, and recognise they’re essential to ecosystems across the entire planet. We supply a wide variety of products to retailers for feeding birds, and feel it’s important to ensure people are both supporting and feeding birds throughout a wet and difficult winter.”
Species aside from the Swift were seen to suffer at the whim of extreme UK weather. The Blue Tit saw caterpillars, their primary food source, being washed away from trees in the rain. This species also frequents domestic feeders, though more are needed to counteract the damage done to their breeding cycle.
Bonnington Plastics are wholesalers of garden and animal care products, ranging from suet to shovels. They have been providing retailers across the UK with their stock since 1967, and hope to see consumers making good use of their products to aid the bird population this winter.
About Bonnington Plastics Ltd
Bonnington Plastics Ltd
Bonnington Plastics Ltd
Phone : 0116 257 7943
Published On:January 14, 2013
Print Release:Print Release
If you have questions regarding information in this press release contact the company listed above. I-Newswire.com is a press release service and not the author of this press release.The information that is on or available through this site is for informational purposes only and speaks only as of the particular date or dates of that information. As some companies and PR Agencies submit their press releases once per week,month or quarter, make sure to check the official company website for accurate release dates as our site displays the I-Newswire.com press release distribution date only.We do not guarantee the accuracy or completeness of information on or available through this site, and we are not responsible for or omissions in that information or for actions taken in reliance on that information.
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Friday, October 4, 2013
Christian Patterson, Alessandra Sanguinetti, Raymond Meeks, Wolfgang Tillmans - TBW Subscription series #4
TBW books have just announced their latest subscription series, number 4, with bookworks from Christian Patterson, Alessandra Sanguinetti, Raymond Meeks and Wolfgang Tillmans. Each case-bound book is 9 x 11 inches and runs to 40 pages.
BOOK #1 Christian Patterson, Bottom of the Lake
With Bottom of the Lake, Christian Patterson revisits his hometown of Fond du Lac, Wisconsin (French for "Bottom of the Lake") and weaves together visual threads related to the town's iconography, climate and culture.Christian Patterson lives in Brooklyn, New York. His monograph, Redheaded Peckerwood, was published by MACK in 2011 to international critical acclaim, nominated for the 2012 Kraszna-Krausz Book Awards and won the prestigious 2012 Recontres d’Arles Author Book Award. He was awarded a John Simon Guggenheim Memorial Foundation Fellowship in 2013.
BOOK #2 Alessandra Sanguinetti, Sorry, Welcome
Sorry, Welcome is a glimpse into the artists life the way it looked throughout the winter of 2012/13. Sanguinetti shot over a short period of time in which she took a step back and became a voyeur of her own life. The images were made in and around her home in San Francisco Ca. and explores dynamics between the union of two unique families. Alessandra Sanguinetti lives and works in San Francisco and Buenosa Aires. She has published two books with Nazraeli Press: On the Sixth Day and The Adventures of Guille and Belinda and the Enigmatic Meaning of their Dreams. She is a recipient of a John Simon Guggenheim fellowship, a Recontres de Arles Discovery Award, a Hasslblad and a Robert Gardner Fellowship.
BOOK #3 Raymond Meeks, Erasure
Erasure signals a transition from photographic narratives centered on collaboration with Meeks’ immediate family toward an outward gaze; making order of the unfamiliar surroundings of his new home in Providence R.I. Using printing techniques of both over exposing and laying a "base fog" to the image surface, Meeks is literally masking what he deems "the painful and ugly" in his view of the world. This method of darkroom-photoshop creates a truly unsettling yet beautifully unique book. Raymond Meeks currently resides and works in Providence, Rhode Island. His documenting of family and place have been at the cornerstone of his work and in publications with Nazraeli Press, as well as self-published artist books under his imprint, Dumbsaint.
BOOK #4 Wolfgang Tillmans, Utoquai
Tillmans closes out the subscription with his book Utoquai that is both classically his own while still pushing the language of photography forward, something that has become synonymous with his name. With Utoquai, Tillmans focuses on a single subject and openly presents his ongoing friendship and unrequited love in a way that is compelling, adventurous and vulnerable in equal measures. Wolfgang Tillmans is a German artist who lives and works in London and Berlin. He was first recognized in the early 1990s for his affecting and unconventional images of friends and other young people in his social circle. Since then Tillmans’ subject matter has broadened combining portraits, still-lifes and landscapes with abstract and sculptural photographic works hung in carefully considered wall installations. This fusion of different photographic practices and a continuous production of artist books is spurred by his personal experiences of life and a strong political engagement. He won the Turner prize in 2000.
You can preview Christian Patterson's Bottom of the Lake on Vimeo by going HERE.
Posted by Harvey's Blog at 12:01 PM

domain: literature


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Welcome to 8tracks radio: free music streaming for any time, place, or mood. tagged with scottish, rock, alternative rock, and indie. You can also download one of our free apps to enjoy internet radio on your favorite device.
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domain: entertainment


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Washington scored five runs in the eighth inning to rally for an 8-7 nonconference baseball victory over Grand Canyon at Husky Ballpark on Monday.
In the eighth, Austin Rei hit a two-run double and Alex Schmidt doubled in a run. Erik Forgione singled in the tying run and Robert Pehl’s single scored Rei for the go-ahead run.
Branden Berry also homered for the Huskies (33-11-1)
Troy Rallings retired the Antelopes (25-20) in order in the ninth.
- Amazon rolls out free same-day delivery for Prime members
- They were millionaires for 3 months, but Seattle couple didn't know it
- 'Granny panties' making a comeback as women say no to thongs
- Russell Wilson's agent says in 710 ESPN Seattle interview that contract talks are 'encouraging'
- Shopping video undoes woman's case against SPD
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•In U.S. Open qualifiers, Washington’s Jonathan Sanders and Corey Pereira each won their qualifiers, while Chris Babcock also advanced from his local qualifier. In other UW men’s golf news, the team earned the No. 2 seed at the NCAA Regional in Raleigh, N.C., May 15-17.
• Hooch Fagaly of Washington was named Pac-12 softball player of the week after batting .667 with one homer and four runs batted in last weekend.
• Jill Hultquist has resigned from her position as head women’s tennis coach at Washington. Hultquist joined the Huskies in 2005 and led the Huskies to four NCAA tournament appearances. She had a ecord of 97-98 at UW.
• Western Washington shot 309 and is tied for 14th among 20 teams at the NCAA Division II men’s golf South Central/West Regional at the Grey Rock Golf Course in Austin, Texas.
• Western Washington’s Kristen Hansen is tied for 28th at 10-over 82 after the first round of the NCAA Division II women’s golf West Super Regional in Mansfield, Texas.
From sports-information reports.

domain: sports


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How Ebola brought the world together, helped birth a blueprint for virus control
Among the lessons to be learnt from the outbreak of 2014 - 16, is that countries can address shared healthcare challenges when they work together, cut the red tape.health Updated: Oct 21, 2017 21:42 IST
The rVSV-ZEBOV vaccine against Ebola has got the World Health Organization (WHO) nod after it was found to protect against the virus in a large trial in Guinea in West Africa.
The vaccine was tested in Guinea’s coastal region of Basse-Guinée, which was still experiencing new Ebola cases when the trial started in 2015.
It was found to be 100% effective in preventing infection in the trial that involved 11,841 people. None of the 5,837 people vaccinated developed Ebola, while 23 of those who were not vaccinated developed the disease.
The vaccine does not contain any live Ebola virus and works by replacing a gene from a harmless virus known as vesicular stomatitis virus (VSV) with a gene encoding an Ebola virus surface protein.
Vaccinators used the ‘ring vaccination’ approach that was used to eradicate smallpox, where the people at most risk — healthcare workers in the hot zone and the initial and secondary contacts of those infected with Ebola — were vaccinated to stop further spread of the disease.
rVSV-ZEBOV was developed by the Public Health Agency of Canada (PHAC) and licenced to NewLink Genetics, which further licenced it to pharmaceutical company Merck.
The development was funded by WHO, with support from the UK-based biomedical research charity Wellcome Trust, the governments of the UK, Norway and Canada, Médecins Sans Frontières (MSF), and other international partners.
These partnerships enabled faster regulatory review from the US Food and Drug Administration and European Medicines Agency in 2016. An agreement between GAVI, the Vaccine Alliance and Merck made 300,000 doses of the vaccine available.
“The unprecedented partnership and the speed at which it was done should be the model for public health organisations to come up with a vaccine to prevent future outbreaks,” said Dr Beth Ann Griswold Coller, molecular biologist and executive director of global clinical development at Merck.
On average, vaccine development takes 10 to 15 years, but in this case, clinical trials were done in less than two years.
“What helped was that we had a candidate. The PHAC invented the vaccine and did the early development work, so when the West Africa outbreak occurred in 2014, the clinical supplies were ready to be deployed. The Phase 1 trial was in October 2014 and the Combined Phase 2 and Phase 3 clinical trials designed to assess the safety and efficacy took place in February 2015,” said Dr Coller, speaking last week at the Uppsala Health Summit on Tacking Infectious Disease Threats, in Sweden.
Building on the work done to fast-track the development and testing of this vaccine, the WHO published an R&D Blueprint to help cut the time taken in future, to develop vaccines and drugs against new and emerging infectious diseases, including Lassa Fever and MERS-Coronavirus.
“The vaccine is now waiting for a licence, which should come by 2020. In May 2017, the Democratic Republic of the Congo (DRC) approved the use of the unlicenced vaccine under an MSF protocol for vaccination, but the country controlled the outbreak without vaccination,” said Dr Coller.
On 2 July 2017, the WHO declared the end of the last wave of Ebola in the DRC. A total of eight were infected this time, four of whom survived the disease.
First Published: Oct 21, 2017 21:38 IST

domain: medical


QinetiQ North America and Pratt and Miller Defense are partnering on the Robotic Combat Vehicle (RCV) programme.
QinetiQ North America (QNA) and Pratt & Miller will submit a variant of the Expeditionary Modular Autonomous Vehicle (EMAV) tailored to the Robotic Combat Vehicle program’s specific requirements, say the firms.
“The Robotic Combat Vehicle submission will leverage QNA’s modular open architecture unmanned ground vehicle control systems integrated with Pratt & Miller’s advanced mobility platform. The resulting system is a robust non-developmental solution demonstrated to fulfill the Government’s required attributes. The RCV base platform has been proven through direct warfighter experimentation to be agile, powerful, and highly reliable.”
“QinetiQ North America has focused on fielding advanced technical solutions to help our military counter emerging threats for over 25 years,” stated QNA’s President Jeff Yorsz.
“We are excited to team with a company that has equal passion of providing groundbreaking real-world solutions to our warfighters.”
Pratt & Miller Defense say it specialises in the development and manufacturing of advanced vehicles and systems for the demanding requirements of the military.
Matt Carroll, Pratt & Miller CEO, said in a release:
“Our combined cultures of innovation and expertise in supporting the warfighter will provide the US Army with a mature world class solution for the RCV program.”


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Some of the Richest People in the US Live in Naples
It’s no secret that many people are attracted to Southwest Florida for its beaches, its luxury homes and its abundant opportunities for outdoor recreation. One particular city, however, is known for being an especially attractive location for affluent buyers.
Some of the richest people in the nation live in Naples. Sure, there are plenty of millionaires living in Naples, but there are also some billionaires. Naples resident Shahid Khan is said to be the richest person in Florida. Reportedly worth around $8 billion, Khan owns the Jacksonville Jaguars, a UK football club and an auto parts supply business. Another Naples billionaire is Reinhold Schmieding. He founded an orthopedic surgical tools company in Germany, but later moved its headquarters to North Naples. Both men sit on the Forbes 400 list of the nation’s richest people, and also happen to be among the world’s richest billionaires.
Other billionaires who call Naples home include former New York resident and Paychex founder, Tom Golisano. Billionaire William Stone also lives in Naples. He’s the founder of a financial software firm.
One of the city’s newest self-made billionaires is Scott Kapnick. He’s the founder of an investment company.
While most of the city’s billionaires are men, one of the nation’s richest women formerly lived in Naples. Catherine Lozick now lives in Fort Lauderdale but has ties to Southwest Florida. She inherited her wealth from her father, the co-founder of a valve-making business.
Just outside of Naples, another Florida resident can also claim billionaire status. Richard Schulze founded Sound of Music, which eventually became known as Best Buy. He lives in nearby Bonita Springs.
Area billionaires, and millionaires for that matter, have plenty of options when it comes to ultra-high-end real estate in the Naples area. In particular, Port Royal is said to attract some of the nation’s wealthiest families with its exclusive waterfront estates.

domain: geography


What will be named ITV's best ever show? From Coronation Street to the X Factor and Inspector Morse, viewers' poll will mark channel's 60th anniversary
- ITV will celebrate its 60th anniversary next month after launching in 1955
- The Radio Times is launching a poll to find the channel's best ever show
- Readers will pick from a list that has been compiled featuring 60 shows
- Among them are Coronation Street, X Factor and Brideshead Revisited
If you hanker for a golden age of commercial television, prepare to wallow in nostalgia.
Today’s schedules may be dominated by talent contests and reality shows, but there was a time when people rushed home to watch unforgettable dramas on ITV such as Brideshead Revisited.
Now, with ITV approaching its 60th anniversary next month, a poll to mark the occasion is asking viewers to vote for the channel’s greatest ever show.
Scroll down for video
Coronation Street, ITV's longest running show is on the list of the channel's 60 greatest programmes
The survey to find the channel's best programme covers output from the 1950s through to X Factor today
Brideshead and another ITV series from the 1980s, The Jewel in the Crown, both feature in a list of 60 programmes compiled by Radio Times for its poll.
All have been broadcast on the channel since it launched on September 22, 1955.
The survey covers output from Saturday night entertainment shows such as Opportunity Knocks in the 1950s, Blind Date in the 1980s and The X Factor to drama series such as Inspector Morse, first screened in 1987, 90s shows Cracker and Prime Suspect and the more recent Broadchurch.
It also includes classic documentaries such as Seven Up! and The World at War as well as cult children’s TV shows Tiswas and Magpie.
Also on the lost is crime drama Prime Suspect starring Helen Mirren as DCI Jane Tennison alongisde Richard Hawley as DI Haskins
Long-running detective drama Inspector Morse starring John Thaw and Kevin Whately is also in the running
The UK’s longest-running television soap Coronation Street, which was first broadcast in 1960, has also been included.
Alison Graham, Radio Times television editor, said: ‘ITV has always liked to do things differently, to shake things up a bit.
'It brought us the muck and brass of Coronation Street and its flinty northern women and, in another television time altogether, Prime Suspect’s DCI Jane Tennison, flawed, brilliant and impossible to forget.
‘It opened minds and changed lives with World in Action and John Pilger’s unforgettable Year Zero: The Silent Death of Cambodia, and it has never been afraid to give us flat-out, glittery and unapologetic entertainment shows, from Sunday Night at the London Palladium to The X Factor.
Saturday night gameshow Blind Date, hosted by the late Cilla Black also makes the lost of the channel's best 60 programmes
There was a time when people rushed home to watch unforgettable dramas on ITV such as Brideshead Revisited
‘No list can possibly cover everyone’s beloved programmes, but we’d like to think that there’s something on here that stirs your heart and prompts you to vote for the greatest ITV programme of all time.’
Votes can be cast at www.radiotimes.com/itv60 or by post via a coupon in the new issue of Radio Times, with voting closing on September 11.
The winner will be announced in the week beginning September 21.
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This will be the week when UK interest rates almost certainly stay the same and we get a warning that eurozone rates will soon go up.
A relief, you might think, for British home-buyers and a worry for Spanish and Irish ones. Of all the different chunks of the economy, the housing market is the most immediately and powerfully affected by changes in interest rates.
Housing markets are always interesting because they are an indicator of what is happening in an economy and also a shaper of that. In this cycle they have been particularly important because it was the mis-pricing of risk in the US housing market that triggered the global financial meltdown, the sub-prime crisis. Meanwhile, the housing booms in many countries, including the UK, enabled people to live beyond their means for a while, which meant misery for many when the housing market crashed.
The markets continue to be hugely important. In the past couple of months US home prices, which had recovered a little, have dipped again, falling below the bottom of the previous trough. One of the reasons why people have become so worried about the state of the US economy is that there still seems to be no floor yet to its property prices. There are similar concerns in the weaker European markets: in Greece, Spain and Ireland. Here in the UK, where the market had recovered a bit, prices seem to be moving sideways, firming a little in London and the Home Countries, but weakening elsewhere. This would reflect – but also be a cause of – the pause that seems to have happened in growth.
So what happens next? On the one hand, it seems unlikely that there will be any early resumption of a housing boom anywhere. The lenders have a sizeable backlog of bad debts, and while in the UK foreclosures have been limited, in parts of the US much of the supply of houses coming on to the market is from repossessions. But no one in their senses would want another housing boom, for prices in most markets (though maybe not parts of the US) are still high by historical standards.
The macroeconomic conclusion that you reach from all this is that the next growth phase of the world economy will have to take place against a backcloth of stable, maybe even falling prices, at least in real terms.
But housing markets, at least compared to stock markets, are all different. You can catch some feeling for those differences from the main chart, which shows what has happened in a selection of countries since 2000 and 2008. As you can see, in virtually every country house prices are higher now than they were in 2000, the only exception being Germany. Germany had neither a boom nor a bust. By contrast, even in the "worst" housing markets, the ones that have had the biggest crashes, such as Ireland and the US, prices are still up on 2000. And in France, Spain, Belgium and Britain, prices are still nearly double the level they were then. It may not be much fun if you own a house in southern Spain that you can't sell, but if you think in terms of the wealth held in those houses, it is enormous.
The plight of Spain's housing market is one of the subjects highlighted by Jefferies, the global securities and investment banking group, in a new paper. The problem, in a nutshell, is that the country had a huge housing boom but so far at least has not experienced much of a slump, as in the US or Ireland. According to Jefferies' calculations, a rise of 1 percentage point in eurozone interest rates would see debt interest payments for the whole economy rise by the equivalent of 0.3 per cent of GDP. This may not sound a lot. But for the quarter of Spanish households with mortgages the rise would be equivalent to 1 to 1.5 per cent of GDP. Not good.
If Spain is the most challenged housing market in the eurozone, and the US is second only to Ireland in experiencing the largest slump relative to the peak, what about the UK?
The first thing to say is we are not going to be getting big increases in rates at the moment, and the expectation of an increase this summer has now receded to the autumn and beyond. On the other hand, the people on mortgages linked to base rates will not enjoy their ultra-low rates for ever, so there is in a sense an artificial support for the market. Savers subsidising home-buyers bring long-term social and economic consequences.
There are as many house price forecasts as there are economists, and if you are interested, there is a fun website called housepricecrash.co.uk. But ignoring some of the more outlandish predictions, the general view seems to be of flat or slightly falling prices for the next couple of years. You can catch a glimpse of the longer-term trend from the graph on the right. Prices, with these falls, seem now to be back more or less to the long-term trend. In other words, prices are not cheap by any means, but they are no longer ridiculously expensive.
The trouble with that sort of statement is that housing markets are local. They are local within countries and between them. In the UK, the division is north-south, with London influenced by foreign buyers. In the US, distances are so vast and economic conditions so different as to make for totally separated markets. But – a point made in a new paper on the subject by Goldman Sachs – there was a period in the mid-2000s when housing markets did move pretty much in sync. Then global factor accounted for 90 per cent of the price variations. Now we are back to more local markets where about half the variation in prices can be attributed to local factors.
With that proviso, Goldman comments that valuations are much less challenging than before and that its expectation of healthy global growth this year and next should support markets where there is less of a credit-fuelled boom yet to unwind. I would put the point in slightly cooler terms: that housing will not be a drag on growth in most countries, including the UK but not I'm afraid Spain or Ireland, but housing will not positively help the recovery. We are a long way from the next property boom.
Where can we find the 'brave' investors who are in it for the long term?
The role of private equity in funding care homes in the UK has hit the news in the past few days. But the great strength of this source of capital is that private equity houses can make swift decisions, taking on risks that, with two main exceptions, other types of fund are not prepared to accept. But they are not in the main long-term investors, so of course you have to ask whether they are the optimal owners for care homes.
But the other two sources of "brave" capital are not ideal either: rich individuals and sovereign wealth funds. In a perfect world, care for the elderly would be provided by not-for-profit enterprises, and these seem to perform well. But given the scale of the funds needed, it is not realistic to expect them to be able to expand sufficiently quickly to meet demand.
But the wider issue this raises is the extent to which conventional sources of finance, at least in the UK, seem to have too short time horizons. Company executives often complain that shareholders in quoted companies are unreasonably short-term in their performance demands.
It is such an oft-cited concern that you have to ask whether things are really getting worse. Sadly, it seems the answer is yes. A paper last month from Andrew Haldane and Richard Davies, The Short Long, looked at the extent to which equity markets worldwide seemed to be operating on shorter and shorter time horizons.
So what is to be done? The authors concluded the authorities needed to look at transparency of information, sharehold- er action, tax incentives and so on. And that must be right. But I wonder too about the need for brave capital, investors prepared to move against the mood of the market. I am as worried by the herd instinct as I am by short-termism and the evidence of the past five years is that the herd instinct is as strong as ever.Reuse content

domain: news


Location: Hammer Museum, 10899 Wilshire Boulevard, Los Angeles, CA 90024
Date: April 13 at 7pm
Description: This is a little bit off the beaten path for Hollywood Gothique but still interesting: part of a “a citywide series of special exhibitions, performances, symposia, and events centered on LA Opera’s upcoming presentation of Richard Wagner’s Ring cycle, the first time that the epic masterwork will be presented in its entirety in Los Angeles.” Wagner’s quartet of RING operas are sort of the LORD OF THE RINGS of their day, a saga of heroes battling Gods and Monsters. The first complete performance of the entire cycle in Los Angeles is a historic event worth noting, even if opera isn’t usually your thing.
Link out: Click here


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The environment & experiences design for a brand that is owning a large number of mega stores across Australia. This is one of a client projects that I had to consider strong strategic approaches with the usage of the brand toolkit with a range of visual language.
The seamless and inclusive brand experiences were created throughout a customer journey that was empowered by the usage of the visual identity within a modular system. Category headers, Fitting rooms, POS, Wayfinding elements and In-store retailers are all part of the journey that was embraced by a strong yet holistic creative solution.
*A project delivered in 2011 as a creative lead at Moon Communication Group.


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My dear husband and I will celebrate our 22nd wedding anniversary on Friday. I, of course, need a card for him. :) The style/design has been in my mind for a while - or at least, the basic card shape has. The details got worked out as I worked on the card.
One of my goals this year is to use as many of my stamp sets as possible. Since I don't sell or give away any of my retired sets, I have .... a few ... sets (ha ha ha ..... A TON). I pulled out Loads of Love - always a great set to use - for this card. I added SU's new sets - Whimsical Words and Well Scripted. I requested the unmounted version of these sets, and I really like them. The labels for the back of the stamps are a little hard to deal with, but overall, I really like the unmounted option.
The tent card style has just hit me as a lot of fun and very classy at the same time. So, I ran with that on this one, too. I used SCAL to weld a scalloped heart (from an online picture of the Fiskars punch ...) to a rectangle. That's the red base of the card - which is actually mounted on a white pre-cut card from Michael's (LOVE those things ... save me a lot of time). Then, a blue heart and white heart were layered and cut in SCAL. The blue heart was embossed using the Cuttlebug, and the white was stamped with the truck and hearts from Loads of Love. All coloring was done with the Copics, and all paper used is SU.
The label punch was already in SCAL from a previous card, so I used it for this one as well, but had to size it down a bit. Well Scripted was used for the front sentiment. The white ribbon going across reminds me of a seat belt! LOL! That's kind of appropriate with the truck on there. :)
I used the label file again (sizing it a little larger) for the inside of the card. And the red piece here is also embossed using the Cuttlebug.
The front just wasn't complete until I found these adorable beads in my stash! A piece of red satin ribbon is used to tie these cuties to the white ribbon on the card. A dab of glue was used to keep the knot from coming untied and the end from raveling.
Three self-adhesive pearls added just a little touch on the corner and completed the card for me. I hope he likes it!!! He's an amazing man - and he fully supports my stamping habit. :)
Have an awesome Saturday night!!! US folks - Don't forget to set your clocks *forward*. Yeah, we lose an hour tonight. :(
Oh ... and have a great, big, beautiful tomorrow!!!!

domain: design


text:
1/2 cup coconut oil, softened at room temperature (but not melted or liquidy)
1/4 cup (54g) packed brown sugar
3/4 cup (150g) granulated sugar
1 tablespoon flax meal
2 teaspoons pure vanilla extract
1 1/4 cup (170g) gluten-free flour blend, like Bob's Red Mill (See Recipe Note)
1 teaspoon baking soda
1 1/2 teaspoons cornstarch
3/4 teaspoon salt
3/4 cup (125g) bittersweet or semisweet chocolate chips (allergy-friendly, if needed)
Flaky sea salt (like Maldon), to top.
10 inch cast iron skillet
1 Preheat the oven and prepare pan: Preheat the oven to 350°F. Spray a 10-inch cast iron skillet with nonstick cooking spray.
2 Prepare the flax "egg": Combine the flax with 2 1/2 tablespoons of water in a small bowl. Let stand for 7 to 10 minutes to thicken. (This will be used as an egg replacer in this recipe.)
3 Combine the coconut oil and sugar: In the bowl of a stand mixer fitted with the paddle attachment (or using electric hand beaters), beat the coconut oil, brown sugar, and granulated sugar until smooth and combined. The mixture will be a little clumpy and grainy—that’s ok.
4 Add the flax egg and vanilla: With the mixer running on low, slowly add the flax egg and vanilla and beat until combined, using a rubber spatula to scrape down the sides as needed.
5 Add the dry ingredients: In a small mixing bowl, whisk together the flour, baking soda, cornstarch and salt. With the mixer on medium, slowly add the dry ingredients and beat until smooth. The dough will look like large pebbles at first, but keep beating and it will eventually become smooth and uniform in 2 to 3 minutes.
6 Add the chocolate chips and transfer to the skillet: With a spatula, fold the chocolate chips into the batter, then scrape the mixture into the 10-inch cast iron skillet. Using your hands, press the dough evenly into the pan. Sprinkle the top with flaky salt.
7 Bake the cookie: Bake for 20 to 22 minutes, or until outer edges are golden brown. The cookie will still feel soft and even a little wet to the touch, but it’ll firm up as it cools.

domain: food


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Furhaven Pet Dog Bed – Round Plush Long Faux Fur Ultra Calming Deep Sleep Soothing Cushion Cuddler Donut Pet Bed with Removable Cover for Dogs.
Color: (Donut) Long Fur Gray
- PET-FRIENDLY DESIGN: The bed features a bolstered donut shape in a malleable and cushy design that provides the ultimate cozy nesting haven for pets that love to burrow
- SLEEP SURFACE: The bolsters and interior sleep surface area covered with ultra-plush long faux vegan fur that is luxuriously soft to the touch that no pet could ever resist snuggling into its downy comfort
- REFILLABLE: The interior liner is zippered so owners can add more stuffing as needed, or switch it up with old clothes, shredded foam, buckwheat hulls – whatever works for you and your pet
- PRODUCT DETAILS: Gray; Large, 36″ x 36″ x 10″
- AVAILABLE VARIANTS: The bed comes in Taupe and Gray; it’s also available in Small, Medium, and Large
- EASY CARE: Pets can present some unique cleaning challenges, which is why Furhaven made sure the dog bed cover is completely machine washable for your convenience; to avoid matting, make sure to dry completely before use
- CUSTOMER ASSURANCE: The product comes with a 90-day limited coverage against material defects and may also qualify for our 60-Day Worry-Free Program, but restrictions apply: purchases from unauthorized third-party resellers may not be covered by Furhaven
- NOT SUITABLE for pets with excessive teething or destructive chewing behavior
Details: Furhaven Deep Dish Long Faux Fur Calming Donut Pet Dog Beds are designed to embrace pets in warmth and comfort – creating a calm space that soothes anxiety and promotes a deeper and more restorative sleep for your dog or cat. Deep bolstered edges create cozy “pockets” of extra warmth for a self-warming affect your pet will love. These hidden spaces are also perfect for burrowing or hiding favorite toys and treats from other “pack members”! Luxuriously long vegan fur is soft on snouts and paws and is so plush you will be tempted to steal this donut bed for yourself. The 23″ donut bed is fully washable, while the 30″ and 36″ beds come with a removable and washable zippered cover. Make sure to dry completely before use to avoid matting.

domain: pet


The Expert Council on NGO Law published an Opinion on the Romanian draft Law 140/2017 on Associations and Foundations, which has already been adopted by the Senate of Romania and is pending for imminent debate in the Chamber of Deputies. The opinion demonstrates lucidly and irrefutably that the draft Law ignores or contradicts many existing international standards and good practices concerning NGOs. Examples of the potential of the draft Law’s provisions for non-compliance are given in many of the sections of the Opinion, such as the absence of prior impact analysis; inadequate meaningful consultation with NGOs during the drafting process; the need to protect NGOs from discrimination and over-regulation; and the requirement for administrative decisions to be subject to review by an independent court. Read more here.
Source: Council of Europe


In the wrong hands, characters like The Batman Who Laughs and his fellow Dark Knights could have been a disaster for DC. “What if Batman, but evil?” is a question that has lead to disappointingly superficial stories in the past. But with Dark Nights: Metal and now The Batman Who Laughs spinoff, Scott Snyder and company have made the most of their evil Batmen characters. That trend continues in a spinoff issue that shines a brighter light on the newest Dark Knight, the Grim Knight.
As introduced in The Batman Who Laughs #2, the Grim Knight is basically a mash-up of Batman and the Punisher. He has all of Bruce Wayne’s ambition and skills, but none of his compassion. Instead he’s happy to use guns, bombs and any other means at his disposal to end the scourge of crime in Gotham City. The goal of this spinoff issue is to explore the Grim Knight’s origin and what led this particular incarnation of Bruce Wayne so far astray.


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Looking to stay in a community without the worries of a minyan.
The Orlando frum community is located in a more residential area therefore vacation home rentals are limited. See below for some options.
Additionally, there are some 1-2 bedroom Airbnb options at times. These will be a part of someone’s home that is closed off, and will not include a pool.


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text: The direct transmission of H5N1 influenza A viruses from chickens to humans in Hong Kong in 1997 emphasized the need to have information on the pathogenesis of avian influenza virus infection in mammals. H5N1 influenza viruses isolated from patients during the incident killed experimentally infected mice. The principal lesions of the mice were broncho-interstitial pneumonia and nonsuppurative encephalitis. Infectious viruses and/or viral antigens were detected in the brain as well as in the trigeminal and vagal ganglia but not in the blood of the mice. These findings suggest that the virus reached the brain through the vagus and/or trigeminal nerves following replication in the respiratory mucosa. The results imply that neurotropism of the H5N1 virus in mice is a novel characteristic in the pathogenesis of infection by human influenza virus isolates.


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What you will study
Successful completion of the training programme and assessment will enable candidates to understand:
- How food business operators can ensure compliance with food safety legislation
- The application and monitoring of good hygiene practice
- How to implement food safety management procedures
- The role of supervision in food safety management procedures
It is recommended that candidates have achieved the HABC Level 2 Award in Food Safety in Catering (or equivalent) before embarking on the training programme for this qualification.
The course involves a 2 hour multiple choice exam paper consisting of 60 questions. You must answer 40/60 questions correctly to pass this qualification.
This Qualification is available for learners aged 16+, it is advised that learners hold the L2 Award in Food Safety in catering or equivalent and a minimum of Level 2 in English or Maths or equivalent.