Development and internal validation of prediction models for colorectal cancer survivors to estimate the 1-year risk of low health-related quality of life in multiple domains
Révész, Dóra ; Kuijk, Sander M.J. van; Mols, Floortje ; Duijnhoven, Fränzel J.B. van; Winkels, Renate M. ; Hoofs, Huub ; Kant, IJ. ; Smits, Luc J. ; Breukink, Stéphanie O. ; Poll-Franse, Lonneke V. van de; Kampman, Ellen ; Beijer, Sandra ; Weijenberg, Matty P. ; Bours, Martijn J.L. - \ 2020
BMC Medical Informatics and Decision Making 20 (2020). - ISSN 1472-6947
Cancer survivors - Colorectal cancer - Internal validation - Model development - Prediction models - Quality of life
Background: Many colorectal cancer (CRC) survivors experience persisting health problems post-treatment that compromise their health-related quality of life (HRQoL). Prediction models are useful tools for identifying survivors at risk of low HRQoL in the future and for taking preventive action. Therefore, we developed prediction models for CRC survivors to estimate the 1-year risk of low HRQoL in multiple domains. Methods: In 1458 CRC survivors, seven HRQoL domains (EORTC QLQ-C30: Global QoL; cognitive, emotional, physical, role, social functioning; fatigue) were measured prospectively at study baseline and 1 year later. For each HRQoL domain, scores at 1-year follow-up were dichotomized into low versus normal/high. Separate multivariable logistic prediction models including biopsychosocial predictors measured at baseline were developed for the seven HRQoL domains, and internally validated using bootstrapping. Results: Average time since diagnosis was 5 years at study baseline. Prediction models included both non-modifiable predictors (age, sex, socio-economic status, time since diagnosis, tumor stage, chemotherapy, radiotherapy, stoma, micturition, chemotherapy-related, stoma-related and gastrointestinal complaints, comorbidities, social inhibition/negative affectivity, and working status) and modifiable predictors (body mass index, physical activity, smoking, meat consumption, anxiety/depression, pain, and baseline fatigue and HRQoL scores). Internally validated models showed good calibration and discrimination (AUCs: 0.83-0.93). Conclusions: The prediction models performed well for estimating 1-year risk of low HRQoL in seven domains. External validation is needed before models can be applied in practice.
One-carbon metabolites, B-vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: Results from the ColoCare Study
Kiblawi, Rama ; Holowatyj, Andreana N. ; Gigic, Biljana ; Brezina, Stefanie ; Geijsen, Anne J.M.R. ; Ose, Jennifer ; Lin, Tengda ; Hardikar, Sheetal ; Himbert, Caroline ; Warby, Christy A. ; Böhm, Jürgen ; Bours, Martijn J.L. ; Duijnhoven, Fränzel J.B. Van; Gumpenberger, Tanja ; Kok, Dieuwertje E. ; Koole, Janna L. ; Roekel, Eline H. Van; Schrotz-King, Petra ; Ulvik, Arve ; Gsur, Andrea ; Habermann, Nina ; Weijenberg, Matty P. ; Ueland, Per Magne ; Schneider, Martin ; Ulrich, Alexis ; Ulrich, Cornelia M. ; Playdon, Mary - \ 2020
The British journal of nutrition 123 (2020)10. - ISSN 0007-1145 - p. 1187 - 1200.
B-vitamins - colorectal cancer - CRPangiogenesis - folate - folic acid - inflammation - One-carbon metabolism - Vitamin B
B-vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- A nd angiogenesis-related chronic diseases, such as colorectal cancer. Yet, the role of one-carbon metabolism in inflammation and angiogenesis among colorectal cancer patients remains unclear.The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed colorectal cancer patients (n=238) in the prospective ColoCare Study, Heidelberg.We cross-sectionally analyzed associations between 12 B-vitamins and one-carbon metabolites and 10 inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesized that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers.We observed that PLP was inversely associated with CRP (r=-0.33, plinear<0.0001), SAA (r=-0.23, plinear=0.003), IL-6 (r=-0.39, plinear <0.0001), IL-8 (r=-0.20, plinear=0.02) and TNFα (r=-0.12, plinear=0.045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r=-0.14), SAA (r=-0.14) and TNFα (r=-0.15) among colorectal cancer patients. Folate catabolite apABG was positively correlated with IL-6 (r= 0.27, plinear<0.0001) and pABG was positively correlated with IL-8 (r= 0.21, plinear<0.0001), indicating higher folate utilization during inflammation.Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among colorectal cancer patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for colorectal cancer patients.
Chemotherapy and vitamin D supplement use are determinants of serum 25-hydroxyvitamin D levels during the first six months after colorectal cancer diagnosis
Wesselink, Evertine ; Bours, Martijn J.L. ; Wilt, Johannes H.W. de; Aquarius, Michiel ; Breukink, Stephanie O. ; Hansson, Bibi ; Keulen, Eric T.P. ; Kok, Dieuwertje E. ; Ouweland, Jody van den; Roekel, Eline H. van; Snellen, Merel ; Winkels, Renate ; Witkamp, Renger F. ; Zutphen, Moniek van; Weijenberg, Matty P. ; Kampman, Ellen ; Duijnhoven, Fränzel J.B. van - \ 2020
Journal of Steroid Biochemistry and Molecular Biology 199 (2020). - ISSN 0960-0760
Changes over time - Colorectal cancer - Lifestyle and clinical determinants - Patients - serum 25(OH)D - Vitamin D
Vitamin D metabolites, including 25-hydroxyvitamin D3 (25(OH)D3), may inhibit colorectal cancer (CRC) progression. Here we investigated cross-sectional and longitudinal associations of demographic, lifestyle and clinical characteristics with 25(OH)D3 serum concentrations in CRC patients at diagnosis and six months later. In 1201 newly-diagnosed stage I-III CRC patients, 25(OH)D3 levels were analysed twice. Multivariable linear regression was used to assess demographic, lifestyle and clinical determinants of 25(OH)D3 levels at diagnosis and six months later. Linear mixed models were used to assess characteristics associated with changes in 25(OH)D3 levels over time. Results of our study showed that vitamin D intake from diet or supplements, use of calcium supplements, BMI and disease stage were associated with 25(OH)D3 levels at both time points. Six months after diagnosis, gender and having received chemo- and/or radiotherapy were also associated with 25(OH)D3 levels. A stronger decrease in 25(OH)D3 levels was observed in patients who underwent chemotherapy, compared to surgery only (β-6.9 nmol/L 95 %CI -9.8; -4.0). Levels of 25(OH)D3 levels increased in patients using vitamin D supplements compared to non-users (β 4.0 nmol/L 95 %CI 1.2; 6.8). In conclusion, vitamin D supplement use and treatment appear to be important determinants of 25(OH)D3 levels during the first six months after CRC diagnosis, although the difference in 25(OH)D3 levels was minor. ClinicalTrials.gov Identifier: NCT03191110
Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome
Weerts, Zsa Zsa R.M. ; Masclee, Ad A.M. ; Witteman, Ben J.M. ; Clemens, Cees H.M. ; Winkens, Bjorn ; Brouwers, Jacobus R.B.J. ; Frijlink, Henderik W. ; Muris, Jean W.M. ; Wit, Niek J. De; Essers, Brigitte A.B. ; Tack, Jan ; Snijkers, Johanna T.W. ; Bours, Andrea M.H. ; Ruiter-van der Ploeg, Annieke S. de; Jonkers, Daisy M.A.E. ; Keszthelyi, Daniel - \ 2020
Gastroenterology 158 (2020)1. - ISSN 0016-5085 - p. 123 - 136.
Functional Gastrointestinal Disorder - PERSUADE Study - RCT - Treatment
Background & Aims: Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal–release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. Methods: We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal–release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. Results: Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal–release peppermint oil group had a response (46.8%, P =. 170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P =. 385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P =. 317 and 1.6%, P =. 351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P =. 016), discomfort (P =. 020), and IBS severity (P =. 020). Adverse events, although mild, were more common in both peppermint oil groups (P <. 005). Conclusions: In a randomized trial of patients with IBS, we found that neither small-intestinal–release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal–release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285.
Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium
Geijsen, Anne J.M.R. ; Roekel, Eline H. van; Duijnhoven, Fränzel J.B. van; Achaintre, David ; Bachleitner-Hofmann, Thomas ; Baierl, Andreas ; Bergmann, Michael M. ; Boehm, Jürgen ; Bours, Martijn J.L. ; Brenner, Hermann ; Breukink, Stéphanie O. ; Brezina, Stefanie ; Chang-Claude, Jenny ; Herpel, Esther ; Wilt, Johannes H.W. de; Gicquiau, Audrey ; Gigic, Biljana ; Gumpenberger, Tanja ; Hansson, Bibi M.E. ; Hoffmeister, Michael ; Holowatyj, Andreana N. ; Karner-Hanusch, Judith ; Keski-Rahkonen, Pekka ; Keulen, Eric T.P. ; Koole, Janna L. ; Leeb, Gernot ; Ose, Jennifer ; Schirmacher, Peter ; Schneider, Martin A. ; Schrotz-King, Petra ; Stift, Anton ; Ulvik, Arve ; Vogelaar, Jeroen F. ; Wesselink, Evertine ; Zutphen, Moniek van; Gsur, Andrea ; Habermann, Nina ; Kampman, Ellen ; Scalbert, Augustin ; Ueland, Per M. ; Ulrich, Alexis B. ; Ulrich, Cornelia M. ; Weijenberg, Matty P. ; Kok, Dieuwertje E. - \ 2019
International Journal of Cancer 146 (2019)12. - ISSN 0020-7136 - p. 3256 - 3266.
colorectal cancer - disease stage - epidemiology - metabolomics - plasma metabolites
Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I–IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I–IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.
Adherence to the World Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention is associated with better health–related quality of life among long-term colorectal cancer survivors : results of the PROFILES registry
Veen, Merel R. van; Mols, Floortje ; Bours, Martijn J.L. ; Weijenberg, Matty P. ; Kampman, Ellen ; Beijer, Sandra - \ 2019
Supportive Care in Cancer 27 (2019)12. - ISSN 0941-4355 - p. 4565 - 4574.
Body composition - Colorectal cancer survivors - Dietary guidelines - Health-related quality of life - Physical activity - WCRF guidelines
Since colorectal cancer (CRC) survivors often suffer from long-term adverse health effects of the cancer and its treatment, having a negative impact on their health-related quality of life (HRQL), this study focuses on the association between adherence to WCRF/AICR recommendations and HRQL among CRC survivors. In a cross-sectional PROFILES registry study in 1096 CRC survivors (mean time since diagnosis 8.1 years), WCRF/AICR adherence scores (range 0–8, with a higher score for better adherence) were calculated, and HRQL was assessed using the EORTC QLQ-C30. Associations between adherence scores and HRQL scores were investigated using linear regression analyses. Additionally, associations with adherence to guidelines for body mass index (BMI) (normal weight, overweight and obese), physical activity (PA) (score 0/1) and diet (score < 3, 3– < 4 and > 4) were evaluated separately. Mean adherence score was 4.81 ± 1.04. Higher WCRF/AICR scores were associated with better global health status (β 1.64; 95%CI 0.69/2.59), physical functioning (β 2.71; 95%CI 1.73/3.68), role functioning (β 2.87; 95%CI 1.53/4.21), cognitive functioning (β 1.25; 95%CI 0.19/2.32), social functioning (β 2.01; 95%CI 0.85/3.16) and fatigue (β − 2.81; 95%CI − 4.02/− 1.60). Adherence versus non-adherence PA was significantly associated with better physical, role, emotional and social functioning, global health status and less fatigue. Except for the association between being obese and physical functioning (β − 4.15; 95%CI − 47.16/− 1.15), no statistically significant associations with physical functioning were observed comparing adherence to non-adherence to BMI and dietary recommendations. Better adherence to the WCRF/AICR recommendations was positively associated with global health status, most functioning scales and less fatigue among CRC survivors. PA seemed to be the main contributor.
Low radiographic muscle density is associated with lower overall and disease-free survival in early-stage colorectal cancer patients
Baar, Harm van; Beijer, S. ; Bours, M.J.L. ; Weijenberg, M.P. ; Zutphen, M. van; Duijnhoven, F.J.B. van; Slooter, G.D. ; Pruijt, J.F.M. ; Dronkers, J.J. ; Haringhuizen, A. ; Spillenaar Bilgen, E.J. ; Hansson, B.M.E. ; Wilt, J.H.W. de; Kampman, E. ; Winkels, R.M. - \ 2018
Journal of Cancer Research and Clinical Oncology 144 (2018)11. - ISSN 0171-5216 - p. 2139 - 2147.
Colorectal cancer - Mortality - Skeletal muscle density - Survival
Background: In cancer patients with a poor prognosis, low skeletal muscle radiographic density is associated with higher mortality. Whether this association also holds for early-stage cancer is not very clear. We aimed to study the association between skeletal muscle density and overall mortality among early-stage (stage I–III) colorectal cancer (CRC) patients. Furthermore, we investigated the association between skeletal muscle density and both CRC-specific mortality and disease-free survival in a subset of the study population. Methods: Skeletal muscle density was assessed in 1681 early-stage CRC patients, diagnosed between 2006 and 2015, using pre-operative computed tomography images. Adjusted Cox proportional hazard models were used to evaluate the association between muscle density and overall mortality, CRC-specific mortality and disease-free survival. Results: The median follow-up time was 48 months (range 0–119 months). Low muscle density was detected in 39% of CRC patients. Low muscle density was significantly associated with higher mortality (low vs. normal: adjusted HR 1.91, 95% CI 1.53–2.38). After stratification for comorbidities, the association was highest in patients with ≥ 2 comorbidities (HR 2.11, 95% CI 1.55–2.87). Furthermore, low skeletal muscle density was significantly associated with poorer disease-free survival (HR 1.68, 95% CI 1.14–2.47), but not with CRC-specific mortality (HR 1.68, 95% CI 0.89–3.17) in a subset of the study population. Conclusion: In early-stage CRC patients, low muscle density was significantly associated with higher overall mortality, and worse disease-free survival.
An exploration of needs and preferences for dietary support in colorectal cancer survivors : A mixed-methods study
Hoedjes, Meeke ; Kruif, Anja De; Mols, Floortje ; Bours, Martijn ; Beijer, Sandra ; Winkels, Renate ; Westerman, Marjan J. ; Seidell, Jaap C. ; Kampman, Ellen - \ 2017
PLoS ONE 12 (2017)12. - ISSN 1932-6203
Purpose To describe the proportion of colorectal cancer (CRC) survivors who perceive a need for dietary support; to examine which socio-demographic, cancer-related, and health-related characteristics are associated with this need; to explore reasons for (not) needing support; and to explore CRC survivors’ specific needs and preferences with regard to lifestyle (i.e., dietary, exercise, and/or weight management) support. Methods This mixed-methods study comprised a cross-sectional survey among 1774 Dutch CRC survivors and three focus groups (n = 16). To examine associations, logistic regression analyses were conducted. Focus groups were audio-taped, transcribed verbatim, and analyzed using a thematic approach. Results Of 1458 respondents (82%), 1198 (67.5%) were included for analyses. 17.5% reported a need for dietary support. Characteristics associated with this need were: being younger, living without a partner, having a stoma, having diabetes, and being overweight or obese. The main reason for needing support was being unable to initiate and maintain lifestyle changes without support. CRC survivors preferred receiving information soon after diagnosis to make an autonomous, informed decision on improving their lifestyle. They preferred to receive individually-tailored lifestyle support in an autonomy-supportive environment, preferably with involvement of their family and fellow-sufferers. Conclusions This study has provided knowledge on appropriate support for CRC survivors in need for dietary support to improve health outcomes by promoting adherence to lifestyle and body weight recommendations. Findings can be used to better identify CRC survivors in need for dietary support, and to tailor lifestyle support to their needs and preferences in order to promote uptake, adherence, and effectiveness.
The Impact of Body Mass Index and Waist Circumference on Health-related Quality of Life Among Colorectal Cancer Survivors : Results from the PROFILES Registry
Vissers, Pauline A.J. ; Martucci, Renata B. ; Mols, Floortje ; Bours, Martijn J.L. ; Winkels, Renate M. ; Kampman, Ellen ; Weijenberg, Matty P. ; Poll-Franse, Lonneke V. van de; Beijer, Sandra - \ 2017
Nutrition and Cancer 69 (2017)8. - ISSN 0163-5581 - p. 1177 - 1184.
Background: We aimed to assess the association of waist circumference (WC) and body mass index (BMI) with health-related quality of life (HRQL) among colorectal cancer (CRC) survivors. Methods: CRC survivors diagnosed between 2000 and 2009 completed questionnaires in August 2013 (with self-reported weight, height, and self-assessed WC) and January 2014 (with HRQL using the EORTC-QLQ-C30). Clinical characteristics were retrieved from the Netherlands Cancer Registry. In multivariable linear regression analyses associations of BMI only, WC only and both BMI and WC with HRQL outcomes were assessed. Results: 1,111 CRC survivors were included of whom 34% had a normal weight (18.5 ≤ BMI < 25 kg/m2), 49% had overweight (25 ≤ BMI < 30 kg/m2), 17% had obesity (BMI ≥ 30 kg/m2), and 44% had an increased WC (i.e., >102 and >88 cm for men and women, respectively). Both BMI and WC were separately associated with worse global health status, functioning, and more symptoms of fatigue. Increased WC was associated with lower physical, role and emotional functioning, regardless of BMI, with average differences ranging between 3 and 5 points. Conclusion: Future research on HRQL among CRC survivors should consider both BMI and WC. Furthermore, weight reduction trials should not only focus on general weight loss but also on the loss of abdominal fat.
Adherence to the World Cancer Research Fund/American Institute for Cancer Research lifestyle recommendations in colorectal cancer survivors : results of the PROFILES registry
Winkels, Renate M. ; Lee, Linde van; Beijer, Sandra ; Bours, Martijn J. ; Duijnhoven, Fränzel J.B. van; Geelen, Anouk ; Hoedjes, Meeke ; Mols, Floortje ; Vries, Jeanne de; Weijenberg, Matty P. ; Kampman, Ellen - \ 2016
Cancer Medicine 5 (2016)9. - ISSN 2045-7634 - p. 2587 - 2595.
Colon and rectal cancer - lifestyle recommendations - survivorship
We examined adherence to the eight The World Cancer Research Foundation/American Institute for Cancer Research (WCRF/AICR) recommendations on diet, physical activity, and body weight among colorectal cancer survivors, and whether adherence was associated with intention to eat healthy and with the need for dietary advice. Adherence to these recommendations may putatively reduce the risk of recurrence and death. Studies on adherence to these recommendations in colorectal cancer (CRC) survivors are lacking. Adherence was assessed in a cross-sectional study among 1196 CRC survivors and could range between 0 (no adherence) and 8 points (complete adherence). Participants completed questionnaires on dietary intake, physical activity, and body weight. Prevalence Ratios were calculated to assess whether adherence to recommendations were associated with dietary intentions and needs. Twelve percentage of the survivors adhered to 6 or more recommendations; 65% had a score between >4 and 6 points; 23% scored no more than 4 points. The recommendation for to be modest with consumption of meat showed lowest adherence: 8% adhered; whereas the recommendation not to use dietary supplements showed highest adherence (75%). 18% reported a need for dietary advice, but this was not associated with adherence to recommendations. Survivors with higher adherence reported less often that they had received dietary advice, were less likely to have the intention to eat healthier, but reported more often that they had changed their diet since diagnosis. There is ample room for improvement of lifestyle recommendations in virtually all CRC survivors. A minor part of CRC survivors expressed a need for dietary advice which was not associated with adherence to the recommendations.
Candidate predictors of Health-Related quality of life of colorectal cancer survivors : A systematic review
Bours, Martijn J.L. ; Linden, Bernadette W.A. van der; Winkels, Renate M. ; Duijnhoven, Fränzel J. van; Mols, Floortje ; Roekel, Eline H. van; Kampman, Ellen ; Beijer, Sandra ; Weijenberg, Matty P. - \ 2016
Oncologist 21 (2016)4. - ISSN 1083-7159 - p. 433 - 452.
Candidate predictors - Colorectal cancer survivors - Disability and health - Health-related quality of life - International classification of functioning - Systematic review
The population of colorectal cancer (CRC) survivors is growing and many survivors experience deteriorated health-related quality of life (HRQoL) in both early and late post-treatment phases. Identification of CRC survivors at risk for HRQoL deterioration can be improved by using prediction models. However, such models are currently not available for oncology practice. As a starting point for developing prediction models of HRQoL for CRC survivors, a comprehensive overview of potential candidate HRQoL predictors is necessary. Therefore, a systematic literature review was conducted to identify candidate predictors of HRQoL of CRC survivors. Original research articles on associations of biopsychosocial factors with HRQoL of CRC survivors were searched in PubMed, Embase, and Google Scholar. Two independent reviewers assessed eligibility and selected articles for inclusion (N=53). Strength of evidence for candidate HRQoL predictors was graded according to predefined methodological criteria. The World Health Organization’s International Classification of Functioning, Disability and Health (ICF) was used to develop a biopsychosocial framework in which identified candidate HRQoL predictors were mapped across the main domains of the ICF: health condition, body structures and functions, activities, participation, and personal and environmental factors. The developed biopsychosocial ICF framework serves as a basis for selecting candidate HRQoL predictors, thereby providing conceptual guidance for developing comprehensive, evidence-based prediction models of HRQoL for CRC survivors. Such models are useful in clinical oncology practice to aid in identifying individual CRC survivors at risk for HRQoL deterioration and could also provide potential targets for a biopsychosocial intervention aimed at safeguarding the HRQoL of at-risk individuals.
Genome-wide association mapping and genomic prediction elucidate the genetic architecture of morphological traits in arabidopsis
Kooke, Rik ; Kruijer, Willem ; Bours, Ralph ; Becker, Frank ; Kuhn, A. ; Geest, Henri van de; Buntjer, Jaap ; Doeswijk, Timo ; Guerra, José ; Bouwmeester, Harro ; Vreugdenhil, Dick ; Keurentjes, Joost J.B. - \ 2016
Plant Physiology 170 (2016)4. - ISSN 0032-0889 - p. 2187 - 2203.
Quantitative traits in plants are controlled by a large number of genes and their interaction with the environment. To disentangle the genetic architecture of such traits, natural variation within species can be explored by studying genotype-phenotype relationships. Genome-wide association studies that link phenotypes to thousands of single nucleotide polymorphism markers are nowadays common practice for such analyses. In many cases, however, the identified individual loci cannot fully explain the heritability estimates, suggesting missing heritability. We analyzed 349 Arabidopsis accessions and found extensive variation and high heritabilities for different morphological traits. The number of significant genome-wide associations was, however, very low. The application of genomic prediction models that take into account the effects of all individual loci may greatly enhance the elucidation of the genetic architecture of quantitative traits in plants. Here, genomic prediction models revealed different genetic architectures for the morphological traits. Integrating genomic prediction and association mapping enabled the assignment of many plausible candidate genes explaining the observed variation. These genes were analyzed for functional and sequence diversity, and good indications that natural allelic variation in many of these genes contributes to phenotypic variation were obtained. For ACS11, an ethylene biosynthesis gene, haplotype differences explaining variation in the ratio of petiole and leaf length could be identified.
Thermoperiodic control of hypocotyl elongation depends on auxin-induced ethylene signaling that controls downstream PHYTOCHROME INTERACTING FACTOR3 ACTIVITY
Bours, Ralph ; Kohlen, Wouter ; Bouwmeester, H.J. ; Krol, Alexander van der - \ 2015
Plant Physiology 167 (2015)2. - ISSN 0032-0889 - p. 517 - 530.
We show that antiphase light-temperature cycles (negative day-night temperature difference [2DIF]) inhibit hypocotyl growth in Arabidopsis (Arabidopsis thaliana). This is caused by reduced cell elongation during the cold photoperiod. Cell elongation in the basal part of the hypocotyl under 2DIF was restored by both 1-aminocyclopropane-1-carboxylic acid (ACC; ethylene precursor) and auxin, indicating limited auxin and ethylene signaling under 2DIF. Both auxin biosynthesis and auxin signaling were reduced during 2DIF. In addition, expression of several ACC Synthase was reduced under 2DIF but could be restored by auxin application. In contrast, the reduced hypocotyl elongation of ethylene biosynthesis and signaling mutants could not be complemented by auxin, indicating that auxin functions upstream of ethylene. The PHYTOCHROME INTERACTING FACTORS (PIFs) PIF3, PIF4, and PIF5 were previously shown to be important regulators of hypocotyl elongation. We now show that, in contrast to pif4 and pif5 mutants, the reduced hypocotyl length in pif3 cannot be rescued by either ACC or auxin. In line with this, treatment with ethylene or auxin inhibitors reduced hypocotyl elongation in PIF4 overexpressor (PIF4ox) and PIF5ox but not PIF3ox plants. PIF3 promoter activity was strongly reduced under 2DIF but could be restored by auxin application in an ACC Synthase-dependent manner. Combined, these results show that PIF3 regulates hypocotyl length downstream, whereas PIF4 and PIF5 regulate hypocotyl length upstream of an auxin and ethylene cascade. We show that, under 2DIF, lower auxin biosynthesis activity limits the signaling in this pathway, resulting in low activity of PIF3 and short hypocotyls.
Dietary changes and dietary supplement use, and underlying motives for these habits reported by colorectal cancer survivors of the Patient Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship (PROFILES) registry
Bours, Martijn J. ; Beijer, Sandra ; Winkels, Renate M. ; Duijnhoven, Fränzel van; Mols, Floortje ; Breedveld-Peters, José J. ; Kampman, Ellen ; Weijenberg, Matty P. ; De Poll-Franse, Lonneke V. Van - \ 2015
The British journal of nutrition 114 (2015)2. - ISSN 0007-1145 - p. 286 - 296.
Colorectal cancer survivors - Dietary habits - Dietary supplements - Lifestyle behaviours
In the present study, we aimed to describe dietary changes made post-diagnosis and current dietary supplement use by survivors of colorectal cancer (CRC), and explore the underlying motives for these lifestyle habits. Cross-sectional analyses were performed for 1458 stage I-IV CRC survivors of the Patient Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship (PROFILES) registry, diagnosed between 2000 and 2009. Lifestyle, sociodemographic and clinical information was collected. Prevalence of and motivations for dietary changes and supplement use were assessed. Associations between lifestyle, sociodemographic and clinical variables were analysed by multivariable logistic regression. CRC survivors (57 % male) were on average 70 (sd 9) years of age and diagnosed 7 (sd 3) years ago. Dietary changes post-diagnosis were reported by 36 % of the survivors and current supplement use by 32 %. Motivations for dietary changes were mostly cancer-related (44 % reported 'prevention of cancer recurrence' as the main reason), while motivations for supplement use were less frequently related to the cancer experience (38 % reported 'to improve health and prevent disease in general' as the main reason). Dietary changes were significantly associated with dietary supplement use (OR 1·5, 95 % CI 1·1, 2·1). Survivors who had received dietary advice, were non-smokers, under 65 years of age, and had no stoma were more likely to have changed their diet. Survivors who were female, had multiple co-morbidities, and no overweight or obesity were more likely to use supplements. In conclusion, many CRC survivors alter their diet post-diagnosis and use dietary supplements, in part for different reasons. Insights into motivations behind these lifestyle habits and characteristics of CRC survivors adopting these habits can improve the tailoring of lifestyle counselling strategies.
Antiphase light and temperature cycles disrupt rhythmic plant growth : the Arabidopsis jetlag
Bours, R.M.E.H. - \ 2014
Wageningen University. Promotor(en): Harro Bouwmeester, co-promotor(en): Sander van der Krol. - Wageningen : Wageningen University - ISBN 9789461739575 - 165
arabidopsis - groei - licht - temperatuur - biologische ritmen - plantenontwikkeling - modellen - arabidopsis - growth - light - temperature - biological rhythms - plant development - models
Light and temperature are important determinants of plant growth and development. Plant elongation is stimulated by positively increasing differences between day and night temperature (+DIF, phased cycles). In contrast, a negative temperature difference (-DIF, antiphased cycles) reduces elongation growth. In chapter 1the different responses of plants to light and temperature are described. We focus on how light and temperature are perceived and integrated with physiological and molecular pathways to control plant development and architecture. As both light and temperature converge at the circadian oscillator attention is given to temperature entrainment and temperature compensation of the Arabidopsis circadian clock. Finally we discuss the importance of temperature effects on plant growth for horticulture. -DIF is frequently applied in commercial greenhouses to inhibit unwanted elongation of crops. Despite the economic importance, the response of plants to -DIF was poorly understood. Using Arabidopsis thaliana,our research aimed to understand the mechanisms underlying the -DIF response. The main questions that needed to be answered at the start of this project were:
(1) At what time during the diurnal day is growth affected by -DIF?
(2) What are key genes in the diurnal signalling pathways that result in reduced growth under -DIF?
(3) Is the temporal effect of -DIF on growth linked to the circadian clock, and if so how?
To answer question 1 (when is growth affected by -DIF?) it was important to develop a monitoring system through which growth could be analysed over the full day, including the dark period. This would allow us to determine how growth proceeds over the day and whether there is a specific period of the day at which growth is most affected by the -DIF regime. Elongation in plants is not constant throughout the day, but exhibits a diurnal rhythm. However, the effect of treatments on growth is usually scored as a cumulative effect after many days. Thus the precise relationship between environmental changes and the daily cycles in the growth of the plant remain mostly unnoticed. More detailed analysis can reveal whether the window of growth or the growth rate itself is affected by the environmental conditions. For this purpose, OSCILLATOR, a growth monitoring system, which allows the analysis and parameterisation of diurnal growth of rosette plants was constructed. The demonstration and validation of OSCILLATOR as growth monitoring system is described in chapter 2. The system consists of IR sensitive cameras and allows time-lapse imaging and subsequent analysis of leaf growth and leaf movement of Arabidopsis, tomato and petunia. We use this system to examine how fluctuating diurnal temperature cycles affect leaf movement in different Arabidopsis ecotypes, demonstrating that this approach allows comparison of various genotypes through parameterisation of rhythmic growth. The analysis by OSCILLATOR showed that diurnal growth is accompanied by a cyclic movement of the growing leaves, and parameters (phase and amplitude) of this diurnal leaf movement can be used as a proxy for growth rate. This facilitated the characterisation of the effect of -DIF on growth.
To answer question 2 (what are key genes affected by -DIF) we tested many different mutants impaired in either light signalling, hormone perception, or hormone biosynthesis and studied their response to -DIF in comparison with wild-type plants. Chapter 3 describes how, using this approach, we unravel the light and hormonal signalling processes that mediate the effect of -DIF on leaf movement. Pharmacological treatments combined with the genetic screens identify ethylene signalling as limiting for leaf growth and movement under -DIF. We demonstrate that specifically the activity of the ethylene biosynthesis gene ACC synthase 2activity in the petiole relates to the -DIF leaf phenotype. In addition, the effect of -DIF on ethylene sensitivity and biosynthesis is shown to depend on active PHYB.
To further characterise how light and hormone signalling affect growth under -DIF, we set out to identify factors limiting cell elongation. In chapter 4, local cell elongation in the hypocotyl is linked to local auxin signalling capacity. We demonstrate that ethylene, similar to its role in rosette leaves, becomes limiting in this tissue under -DIF as a result of reduced auxin production. While previously overall auxin was shown to be reduced in Arabidopsis inflorescence tissue developed under -DIF, we now demonstrate that it is mainly the effect of tissue specific auxin signalling that limits growth under -DIF. Moreover, we show that auxin can complement growth inhibition under -DIF in wild-type plants but not in ethylene signalling or biosynthesis mutants, placing the effect of auxin on growth upstream of ethylene. Downstream, ethylene signalling activates the growth promoting transcription factor PIF3, which is known to activate genes controlling cell elongation. In contrast, PIF5 acts upstream, possibly regulating the input of the signalling cascade. Remarkably, PIF4, which is a main regulator of heat induced hypocotyl elongation, is not required for the response to -DIF.
To answer question 3 (does -DIF affect the clock?) we used luciferase reporter plants and developed a unique luminometer set-up with which we could monitor gene promoter activity in mature rosette plants under different diurnal light regimes. This system was used in penultimate chapter 5 where we demonstrate that an altered function of the circadian clock under -DIF is responsible for altered output processes identified in the other chapters. Analysis of expression patterns of core clock genes under diurnal conditions reveals that -DIF reduces the amplitude of most clock genes and differentially shifts the phase of core clock components. The magnitude and direction of these shifts differ for each clock gene, suggesting that -DIF alters the coordination within the circadian clock itself. We subsequently showed that the phase shifts occurring under -DIF relate to a temperature compensation mechanism controlled by GI. GIwas previously identified to be required for temperature compensation in the amplitude of clock controlled genes at low and high temperature. Moreover, GIwas identified to be responsible for the effect of -DIF on the phase of clock genes. Indeed, gi loss-of-function mutants are insensitive to the effects of -DIF on growth. We demonstrate that under –DIF starch biosynthesis during the day, and starch degradation rates at night are altered. Carbohydrate availability during the night is essential for growth and therefore part of the sugars generated during the photoperiod are stored as starch. Throughout the night this starch is degraded in a controlled rate, which is adjusted to the predicted length of the dark period. The starch degradation rate under different photoperiod lengths is therefore tightly controlled by the circadian clock in anticipation of the expected dawn, to prevent running out of carbohydrates at the end of the night. Indeed, under -DIF starch metabolism is disturbed, resulting in an apparent starch shortage at the end of the night. This was monitored by activation of a reporter gene for carbohydrate starvation under -DIF. Furthermore, the phase of leaf movement of starch mutants under control (+DIF) conditions resembles the phase of wild-type plants developing under -DIF, indicating that the carbohydrate status of a plants determines rhythmic leaf movement.
In chapter 6the results obtained in this thesis are discussed and a conceptual model that aims to integrate all findings with recently published literature is proposed. In this model, -DIF affects growth by directly affecting the phase and amplitude of clock genes, which in turn control downstream processes such as starch metabolism and hormone signalling pathways. The auxin and ethylene signalling pathways affected by -DIF show significant crosstalk and interconnect with the circadian clock at several positions, by direct interaction with the PIFs, which are regulated by PHYB, of which transcription is under circadian control. Therefore, special focus is given to the unique position of the photoreceptor PHYB in this model. PHYB is essential for PIF protein stability and in addition is an important component for light entrainment of the clock. Finally we discuss the potential applications of the results described for horticulture and speculate on possible ways to improve the efficiency of DIF like treatments.
Antiphase light and temperature cycles affect PHYTOCHROME B-controlled ethylene sensitivity and biosynthesis, limiting leaf movement and growth of Arabidopsis.
Bours, R.M.E.H. ; Zanten, M. van; Pierik, R. ; Bouwmeester, H.J. ; Krol, A.R. van der - \ 2013
Plant Physiology 163 (2013)2. - ISSN 0032-0889 - p. 882 - 895.
gene family - thermoperiodic responses - night temperature - circadian-rhythms - identify ethylene - stem elongation - thaliana - gibberellins - morphology - mutations
In the natural environment, days are generally warmer than the night, resulting in a positive day/night temperature difference (+DIF). Plants have adapted to these conditions, and when exposed to antiphase light and temperature cycles (cold photoperiod/warm night [-DIF]), most species exhibit reduced elongation growth. To study the physiological mechanism of how light and temperature cycles affect plant growth, we used infrared imaging to dissect growth dynamics under +DIF and -DIF in the model plant Arabidopsis (Arabidopsis thaliana). We found that -DIF altered leaf growth patterns, decreasing the amplitude and delaying the phase of leaf movement. Ethylene application restored leaf growth in -DIF conditions, and constitutive ethylene signaling mutants maintain robust leaf movement amplitudes under -DIF, indicating that ethylene signaling becomes limiting under these conditions. In response to -DIF, the phase of ethylene emission advanced 2 h, but total ethylene emission was not reduced. However, expression analysis on members of the 1-aminocyclopropane-1-carboxylic acid (ACC) synthase ethylene biosynthesis gene family showed that ACS2 activity is specifically suppressed in the petiole region under -DIF conditions. Indeed, petioles of plants under -DIF had reduced ACC content, and application of ACC to the petiole restored leaf growth patterns. Moreover, acs2 mutants displayed reduced leaf movement under +DIF, similar to wild-type plants under -DIF. In addition, we demonstrate that the photoreceptor PHYTOCHROME B restricts ethylene biosynthesis and constrains the -DIF-induced phase shift in rhythmic growth. Our findings provide a mechanistic insight into how fluctuating temperature cycles regulate plant growth.
Tomato strigolactones: a more detailed look
Kohlen, W. ; Charnikova, T. ; Bours, R.M.E.H. ; Lopez-Raez, J.A. ; Bouwmeester, H.J. - \ 2013
Plant Signaling & Behavior 8 (2013)1. - ISSN 1559-2316
Strigolactones are plant signaling molecules that induce germination of parasitic plant seeds, initiate host plant - arbuscular mycorrhizal fungus symbiosis and act as plant hormones controlling shoot branching and root architecture. To date four unique strigolactones (e.g., orobanchol, didehydroorobanchol isomers 1 and 2 and the aromatic strigolactone solanacol) have been reported in the root exudates and extracts of tomato (Solanum lycopersicum). Here we report on the presence of several additional strigolactones in tomato root exudates and extracts, orobanchyl acetate, two 7-hydroxyorobanchol isomers, 7-oxoorobanchol and two additional didehydroorobanchol isomers and discuss their possible biological relevance.
Adenosine 5 '-triphosphate (ATP) supplements are not orally bioavailable: a randomized, placebo-controlled cross-over trial in healthy humans
Arts, I.C.W. ; Coolen, E.J.C.M. ; Bours, M.J.L. ; Huyghebaert, N. ; Cohen Stuart, M.A. ; Bast, A. ; Dagnelie, P.C. - \ 2012
Journal of the International Society of Sports Nutrition 9 (2012). - ISSN 1550-2783
low-back-pain - uric-acid - nucleoside transporters - cancer-patients - small-intestine - crohns-disease - nucleotide - triphosphate - transit - urate
Background: Nutritional supplements designed to increase adenosine 5'-triphosphate (ATP) concentrations are commonly used by athletes as ergogenic aids. ATP is the primary source of energy for the cells, and supplementation may enhance the ability to maintain high ATP turnover during high-intensity exercise. Oral ATP supplements have beneficial effects in some but not all studies examining physical performance. One of the remaining questions is whether orally administered ATP is bioavailable. We investigated whether acute supplementation with oral ATP administered as enteric-coated pellets led to increased concentrations of ATP or its metabolites in the circulation. Methods: Eight healthy volunteers participated in a cross-over study. Participants were given in random order single doses of 5000 mg ATP or placebo. To prevent degradation of ATP in the acidic environment of the stomach, the supplement was administered via two types of pH-sensitive, enteric-coated pellets (targeted at release in the proximal or distal small intestine), or via a naso-duodenal tube. Blood ATP and metabolite concentrations were monitored by HPLC for 4.5 h (naso-duodenal tube) or 7 h (pellets) post-administration. Areas under the concentration vs. time curve were calculated and compared by paired-samples t-tests. Results: ATP concentrations in blood did not increase after ATP supplementation via enteric-coated pellets or naso-duodenal tube. In contrast, concentrations of the final catabolic product of ATP, uric acid, were significantly increased compared to placebo by similar to 50% after administration via proximal-release pellets (P = 0.003) and naso-duodenal tube (P = 0.001), but not after administration via distal-release pellets. Conclusions: A single dose of orally administered ATP is not bioavailable, and this may explain why several studies did not find ergogenic effects of oral ATP supplementation. On the other hand, increases in uric acid after release of ATP in the proximal part of the small intestine suggest that ATP or one of its metabolites is absorbed and metabolized. Uric acid itself may have ergogenic effects, but this needs further study. Also, more studies are needed to determine whether chronic administration of ATP will enhance its oral bioavailability.
A petunia ABC protein controls strigolactone-dependent symbiotic signalling and branching
Kretzschmar, T. ; Kohlen, W. ; Sasse, J. ; Borghi, L. ; Schlegel, M. ; Bachelier, J.B. ; Reinhardt, D. ; Bours, R.M.E.H. ; Bouwmeester, H.J. ; Martinoia, E. - \ 2012
Nature 483 (2012)7389. - ISSN 0028-0836 - p. 341 - 344.
arbuscular-mycorrhizal fungi - medicago-truncatula - auxin transport - abscisic-acid - gene family - arabidopsis - pcr - germination - inhibition - pathway
Strigolactones were originally identified as stimulators of the germination of root-parasitic weeds1 that pose a serious threat to resource-limited agriculture2. They are mostly exuded from roots and function as signalling compounds in the initiation of arbuscular mycorrhizae3, which are plant–fungus symbionts with a global effect on carbon and phosphate cycling4. Recently, strigolactones were established to be phytohormones that regulate plant shoot architecture by inhibiting the outgrowth of axillary buds5, 6. Despite their importance, it is not known how strigolactones are transported. ATP-binding cassette (ABC) transporters, however, are known to have functions in phytohormone translocation7, 8, 9. Here we show that the Petunia hybrida ABC transporter PDR1 has a key role in regulating the development of arbuscular mycorrhizae and axillary branches, by functioning as a cellular strigolactone exporter. P. hybrida pdr1 mutants are defective in strigolactone exudation from their roots, resulting in reduced symbiotic interactions. Above ground, pdr1 mutants have an enhanced branching phenotype, which is indicative of impaired strigolactone allocation. Overexpression of Petunia axillaris PDR1 in Arabidopsis thaliana results in increased tolerance to high concentrations of a synthetic strigolactone, consistent with increased export of strigolactones from the roots. PDR1 is the first known component in strigolactone transport, providing new opportunities for investigating and manipulating strigolactone-dependent processes.
OSCILLATOR: A system for analysis of diurnal leaf growth using infrared photography combined with wavelet transformation
Bours, R.M.E.H. ; Muthuraman, M. ; Bouwmeester, H.J. ; Krol, A.R. van der - \ 2012
Plant Methods 8 (2012). - ISSN 1746-4811
arabidopsis-thaliana - circadian clock - ethylene - plant - movement - mutants - rhythms - angle
Background Quantification of leaf movement is an important tool for characterising the effects of environmental signals and the circadian clock on plant development. Analysis of leaf movement is currently restricted by the attachment of sensors to the plant or dependent upon visible light for time-lapse photography. The study of leaf growth movement rhythms in mature plants under biological relevant conditions, e.g. diurnal light and dark conditions, is therefore problematic. Results Here we present OSCILLATOR, an affordable system for the analysis of rhythmic leaf growth movement in mature plants. The system contains three modules: (1) Infrared time-lapse imaging of growing mature plants (2) measurement of projected distances between leaf tip and plant apex (leaf tip tracking growth-curves) and (3) extraction of phase, period and amplitude of leaf growth oscillations using wavelet analysis. A proof-of-principle is provided by characterising parameters of rhythmic leaf growth movement of different Arabidopsis thaliana accessions as well as of Petunia hybrida and Solanum lycopersicum plants under diurnal conditions. The amplitude of leaf oscillations correlated to published data on leaf angles, while amplitude and leaf length did not correlate, suggesting a distinct leaf growth profile for each accession. Arabidopsis mutant accession Landsberg erecta displayed a late phase (timing of peak oscillation) compared to other accessions and this trait appears unrelated to the ERECTA locus. Conclusions OSCILLATOR is a low cost and easy to implement system that can accurately and reproducibly quantify rhythmic growth of mature plants for different species under diurnal light/dark cycling.