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BACKGROUND & AIMS: Cancers of the alimentary tract, including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one's risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signal of nutritional excess, alter stem cell behaviors to influence cancer risk. METHODS: We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism. RESULTS: SPT, which diverts dietary fatty acids and amino acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are up-regulated in human intestinal adenomas. They produce ceramides, which serve as prostemness signals that stimulate peroxisome-proliferator activated receptor-α and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors. CONCLUSIONS: Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk.
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Adenoma , Ceramidas , Humanos , Animales , Ratones , Ceramidas/metabolismo , Ácidos Grasos , Esfingolípidos/metabolismo , Serina C-Palmitoiltransferasa/metabolismoRESUMEN
BACKGROUND: Longer overnight fasting (ONF) is a potential strategy for weight control. Although promising, the evidence from large population-based studies is limited. OBJECTIVES: To examine the association of self-reported ONF duration with 3- and 6-y weight change in the American Cancer Society's Cancer Prevention Study-3 prospective cohort. METHODS: United States adult Cancer Prevention Study-3 participants completed a 24-h validated meal and snack timing and frequency grid (weekday and weekend) in 2015, from which weighted ONF hours were calculated. Participants reported body weight in 2015, 2018, and 2021. Three- and 6-y weight change (kg, and % body weight) were assessed. RESULTS: Among 104,420 mostly female (78.5%) participants aged 52.7 ± 9.5 (standard deviation) y followed for 6 y, a 1-h increase in ONF length was associated with a small but statistically significant reduction in weight gain over 3- and 6-y periods [multivariable-adjusted mean difference in % body weight = -0.02, 95% confidence interval (CI): -0.05, -0.00, P = 0.03 and -0.04, 95% CI: -0.07, -0.01, P = 0.007, respectively]. The mean difference of 6-y % reduction in weight gain was slightly greater among individuals with overweight (-0.05, 95% CI: -0.10, 0.00, P = 0.05) and obesity (-0.06, 95% CI: -0.12, 0.01, P = 0.08) compared with those with healthy body mass index (-0.03, 95% CI:-0.07, 0.01, P = 0.13) or underweight (0.16, 95% CI: -0.04, 0.36, P = 0.13, Pinteraction < 0.0001). Stronger associations were observed among those ≤55 y than 56+ (Pinteraction = 0.01), and those with higher waist circumference (Pinteraction < 0.0001) but not by sex or earlier/later fasting period. CONCLUSIONS: Longer ONF was associated with slightly lower body weight in adult males and females over 6 y that was stronger among those with overweight or obesity, higher waist circumference, and those aged ≤55 y. The magnitude of weight change, although in the hypothesized direction, suggests that prolonged ONF may have modest impact on weight control over time.
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BACKGROUND: Risk factors for cancer-related fatigue are understudied in colorectal cancer. PURPOSE: This study aimed to address this critical gap in the literature by (a) describing changes in colorectal cancer-related fatigue and health behavior (physical activity, sleep problems) and (b) examining if physical activity and sleep problems predict fatigue trajectories from baseline (approximately at the time of diagnosis), to 6- and 12 months after enrollment. METHODS: Patients participating in the international ColoCare Study completed self-report measures at baseline (approximately time of diagnosis), 6-, and 12 months assessing physical activity using the International Physical Activity Questionnaire (IPAQ) and fatigue and sleep using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Mixed-effect models examined changes in physical activity, sleep problems, and fatigue. Cross-lagged panel models examined bidirectional relationships between physical activity or sleep and fatigue across time. RESULTS: Colorectal cancer patients (n = 649) had a mean age of 61 ± 13 years. Most were male (59%), non-Hispanic White (91%), diagnosed with Stages III-IV (56%) colon cancer (58%), and treated with surgery (98%). Within-person cross-lagged models indicated higher physical activity at Month 6 was associated with higher fatigue at Month 12 (ß = 0.26, p = .016). When stratified by cancer stage (I-II vs. III-IV), the relationship between physical activity at Month 6 and fatigue at Month 12 existed only for patients with advanced cancer (Stages III and IV, ß = 0.43, p = .035). Cross-lagged associations for sleep and fatigue from baseline to Month 6 were only observed in patients with Stages III or IV cancer, however, there was a clear cross-sectional association between sleep problems and fatigue at baseline and Month 6. CONCLUSIONS: Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced colorectal cancer the first year after diagnosis. In addition, sleep problems were consistently associated with higher fatigue in the first year, regardless of cancer stage. TRIAL REGISTRATION: The international ColoCare Study was registered on clinicaltrials.gov, NCT02328677, in December 2014.
Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced (Stages III and IV) colorectal cancer the first year after diagnosis.
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Neoplasias Colorrectales , Trastornos del Sueño-Vigilia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Colorrectales/complicaciones , Estudios Transversales , Ejercicio Físico , Fatiga/complicaciones , Calidad de Vida , Sueño , Trastornos del Sueño-Vigilia/complicacionesRESUMEN
AIM: This study sought to identify groups of colorectal cancer patients based upon trajectories of fatigue and examine how demographic, clinical and behavioural risk factors differentiate these groups. METHOD: Patients were from six cancer centres in the United States and Germany. Fatigue was measured using the fatigue subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at five time points (baseline/enrolment and 3, 6, 12 and 24 months after diagnosis). Piecewise growth mixture models identified latent trajectories of fatigue. Logistic regression models examined differences in demographic, clinical and behavioural characteristics between fatigue trajectory groups. RESULTS: Among 1615 participants (57% men, 86% non-Hispanic White, mean age 61 ± 13 years at diagnosis), three distinct groups were identified. In the high fatigue group (36%), fatigue significantly increased in the first 6 months after diagnosis and then showed statistically and clinically significant improvement from 6 to 24 months (P values < 0.01). Throughout the study period, average fatigue met or exceeded cutoffs for clinical significance. In the moderate (34%) and low (30%) fatigue groups, fatigue levels remained below or near population norms across the study period. Patients who were diagnosed with Stage II-IV disease and/or current smokers were more likely to be in the high fatigue than in the moderate fatigue group (P values < 0.05). CONCLUSION: A large proportion of colorectal cancer patients experienced sustained fatigue after initiation of cancer treatment. Patients with high fatigue at the time of diagnosis may benefit from early supportive care.
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Neoplasias Colorrectales , Calidad de Vida , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Fatiga/etiología , Fatiga/epidemiología , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/diagnóstico , Factores de Riesgo , Alemania/epidemiología , Encuestas y CuestionariosRESUMEN
PURPOSE: No evidence-based prevention strategies currently exist for cancer-related cognitive decline (CRCD). Although patients are often advised to engage in healthy lifestyle activities (e.g., nutritious diet), little is known about the impact of diet on preventing CRCD. This secondary analysis evaluated the association of pre-treatment diet quality indices on change in self-reported cognition during chemotherapy. METHODS: Study participants (n = 96) completed the Block Brief Food Frequency Questionnaire (FFQ) before receiving their first infusion and the PROMIS cognitive function and cognitive abilities questionnaires before infusion and again 5 days later (i.e., when symptoms were expected to be their worst). Diet quality indices included the Dietary Approaches to Stop Hypertension (DASH), Alternate Mediterranean Diet (aMED), and a low carbohydrate diet index and their components. Descriptive statistics were generated for demographic and clinical variables and diet indices. Residualized change models were computed to examine whether diet was associated with change in cognitive function and cognitive abilities, controlling for age, sex, cancer type, treatment type, depression, and fatigue. RESULTS: Study participants had a mean age of 59 ± 10.8 years and 69% were female. Although total diet index scores did not predict change in cognitive function or cognitive abilities, higher pre-treatment ratio of aMED monounsaturated/saturated fat was associated with less decline in cognitive function and cognitive abilities at 5-day post-infusion (P ≤ .001). CONCLUSIONS: Higher pre-treatment ratio of monounsaturated/saturated fat intake was associated with less CRCD early in chemotherapy. Results suggest greater monounsaturated fat and less saturated fat intake could be protective against CRCD during chemotherapy.
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Disfunción Cognitiva , Dieta Mediterránea , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Dieta , Cognición , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/prevención & controlRESUMEN
BACKGROUND: Metabolomics has proven useful for detecting objective biomarkers of diet that may help to improve dietary measurement. Studies to date, however, have focused on a relatively narrow set of lipid classes. OBJECTIVE: The aim of this study was to uncover candidate dietary biomarkers by identifying serum metabolites correlated with self-reported diet, particularly metabolites in underinvestigated lipid classes, e.g. triglycerides and plasmalogens. METHODS: We assessed dietary questionnaire data and serum metabolite correlations from 491 male and female participants aged 55-75 y in an exploratory cross-sectional study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Self-reported intake was categorized into 50 foods, food groups, beverages, and supplements. We examined 522 identified metabolites using 2 metabolomics platforms (Broad Institute and Massachusetts General Hospital). Correlations were identified using partial Pearson's correlations adjusted for age, sex, BMI, smoking status, study site, and total energy intake [Bonferroni-corrected level of 0.05/(50 × 522) = 1.9 × 10-6]. We assessed prediction of dietary intake by multiple-metabolite linear models with the use of 10-fold crossvalidation least absolute shrinkage and selection operator (LASSO) regression. RESULTS: Eighteen foods, beverages, and supplements were correlated with ≥1 serum metabolite at the Bonferroni-corrected significance threshold, for a total of 102 correlations. Of these, only 5 have been reported previously, to our knowledge. Our strongest correlations were between citrus and proline betaine (r = 0.55), supplements and pantothenic acid (r = 0.46), and fish and C40:9 phosphatidylcholine (PC) (r = 0.35). The multivariate analysis similarly found reasonably large correlations between metabolite profiles and citrus (r = 0.59), supplements (r = 0.57), and fish (r = 0.44). CONCLUSIONS: Our study of PLCO participants identified many novel food-metabolite associations and replicated 5 previous associations. These candidate biomarkers of diet may help to complement measures of self-reported diet in nutritional epidemiology studies, though further validation work is still needed.
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Neoplasias Colorrectales/sangre , Dieta , Neoplasias Pulmonares/sangre , Metabolómica , Neoplasias Ováricas/sangre , Neoplasias de la Próstata/sangre , Anciano , Animales , Biomarcadores/sangre , Estudios Transversales , Registros de Dieta , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).
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Epidemiología/organización & administración , Salud Global , Metabolómica/organización & administración , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Índice de Masa Corporal , Niño , Métodos Epidemiológicos , Femenino , Conductas Relacionadas con la Salud , Pruebas Hematológicas , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores Socioeconómicos , Adulto JovenRESUMEN
Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the "athlete's paradox." We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.
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Ejercicio Físico/fisiología , Lipogénesis/fisiología , Músculo Esquelético/metabolismo , Triglicéridos/metabolismo , Adulto , Atletas , Transporte Biológico , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/fisiopatología , Resistencia Física/fisiología , DescansoRESUMEN
BACKGROUND: Alcohol consumption is associated with an increased risk of several cancers. Potential mechanisms include altered oestrogen metabolism. Parent oestrogens metabolise into alternate pathways of oestrogen metabolites that may have variable effects on cancer pathogenesis. We examined associations of alcohol consumption with circulating oestrogen/oestrogen metabolites in postmenopausal women in the Women's Health Initiative (WHI)-Observational Study (OS). METHODS: We conducted a cross-sectional analysis of prediagnosis ovarian/endometrial cancer case-control data within WHI-OS (N=1864). Alcohol consumption was measured by validated food frequency questionnaire. Fasting serum parent oestrogens/oestrogen metabolites were assayed using liquid chromatography tandem mass-spectrometry. Geometric mean analyte concentrations (GM, pmol l-1) were calculated by alcohol category using inverse-probability weighted linear regression, adjusting for venepuncture age/year, race, smoking, body mass index, years since menopause, oral contraceptive duration, caffeine intake, and physical activity. RESULTS: There was evidence for a positive association between alcohol consumption and oestrone, oestradiol and 2-hydroxylation oestrogen metabolite concentrations among menopausal hormone therapy (MHT) users. We observed an association between liquor consumption and parent oestrogens among non-MHT users, who consumed larger doses of liquor than MHT users. CONCLUSIONS: Among postmenopausal women, the association between alcohol intake and parent oestrogen, but not oestrogen metabolite concentrations, may be influenced by MHT and type of alcohol.
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Consumo de Bebidas Alcohólicas/sangre , Neoplasias Endometriales/sangre , Estradiol/sangre , Estrógenos/sangre , Estrona/sangre , Neoplasias Ováricas/sangre , Anciano , Estudios de Casos y Controles , Estudios Transversales , Neoplasias Endometriales/diagnóstico , Terapia de Reemplazo de Estrógeno , Estrógenos/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Posmenopausia/sangre , Encuestas y CuestionariosRESUMEN
BACKGROUND: The relationship between diet and survival after ovarian cancer diagnosis is unclear as a result of a limited number of studies and inconsistent findings. METHODS: We examined the association between pre-diagnostic diet and overall survival in a population-based cohort (n=811) of Australian women diagnosed with invasive epithelial ovarian cancer between 2002 and 2005. Diet was measured by validated food frequency questionnaire. Deaths were ascertained up to 31 August 2014 via medical record review and Australian National Death Index linkage. We conducted Cox proportional hazards regression analysis, controlling for diagnosis age, tumour stage, grade and subtype, residual disease, smoking status, body mass index, physical activity, marital status, and energy intake. RESULTS: We observed improved survival with highest compared with lowest quartile of fibre intake (hazard ratio (HR)=0.69, 95% CI: 0.53-0.90, P-trend=0.002). There was a suggestion of better survival for women with highest compared with lowest intake category of green leafy vegetables (HR=0.79, 95% CI: 0.62-0.99), fish (HR=0.74, 95% CI: 0.57-0.95), poly- to mono-unsaturated fat ratio (HR=0.76, 95% CI: 0.59-0.98), and worse survival with higher glycaemic index (HR=1.28, 95% CI: 1.01-1.65, P-trend=0.03). CONCLUSIONS: The associations we observed between healthy components of diet pre-diagnosis and ovarian cancer survival raise the possibility that dietary choices after diagnosis may improve survival.
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Dieta , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Ováricas/mortalidad , Anciano , Australia/epidemiología , Estudios de Cohortes , Grasas Insaturadas en la Dieta , Fibras de la Dieta , Ácidos Grasos Monoinsaturados , Femenino , Índice Glucémico , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Modelos de Riesgos Proporcionales , Alimentos Marinos , Encuestas y Cuestionarios , Tasa de Supervivencia , VerdurasRESUMEN
BACKGROUND: Metabolomics has the potential to enhance dietary assessment by revealing objective measures of many aspects of human food intake. Although metabolomics studies indicate that hundreds of metabolites are associated with dietary intake, correlations have been modest (e.g., r < 0.50), and few have been evaluated in controlled feeding studies. OBJECTIVES: The aim of this study was to evaluate associations between metabolites and weighed food and beverage intake in a controlled feeding study of habitual diet. METHODS: Healthy postmenopausal females from the Women's Health Initiative (N = 153) were provided with a customized 2-wk controlled diet designed to emulate their usual diet. Metabolites were measured by liquid chromatography tandem mass spectrometry in end-of-study 24-h urine and fasting serum samples (1293 urine metabolites; 1113 serum metabolites). We calculated partial Pearson correlations between these metabolites and intake of 65 food groups, beverages, and supplements during the feeding study. The threshold for significance was Bonferroni-adjusted to account for multiple testing (5.94 × 10-07 for urine metabolites; 6.91 × 10-07 for serum metabolites). RESULTS: Significant diet-metabolite correlations were identified for 23 distinct foods, beverages, and supplements (171 distinct metabolites). Among foods, strong metabolite correlations (r ≥ 0.60) were evident for citrus (highest r = 0.80), dairy (r = 0.65), and broccoli (r = 0.63). Among beverages and supplements, strong correlations were evident for coffee (r = 0.86), alcohol (r = 0.69), multivitamins (r = 0.69), and vitamin E supplements (r = 0.65). Moderate correlations (r = 0.50-0.60) were also observed for avocado, fish, garlic, grains, onion, poultry, and black tea. Correlations were specific; each metabolite correlated with one food, beverage, or supplement, except for metabolites correlated with juice or multivitamins. CONCLUSIONS: Metabolite levels had moderate to strong correlations with weighed intake of habitually consumed foods, beverages, and supplements. These findings exceed in magnitude those previously observed in population studies and exemplify the strong potential of metabolomics to contribute to nutrition research. The Women's Health Initiative is registered at clinicaltrials.gov as NCT00000611.
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Dieta , Metabolómica , Femenino , Humanos , Biomarcadores , Suplementos Dietéticos , Ingestión de Alimentos , Ayuno , Metabolómica/métodos , VitaminasRESUMEN
BACKGROUND: Food biodiversity in human diets has potential co-benefits for both public health and sustainable food systems. However, current evidence on the potential relationship between food biodiversity and cancer risk, and particularly gastrointestinal cancers typically related to diet, remains limited. This study evaluated how dietary species richness (DSR) was associated with gastrointestinal cancer risk in a pan-European population. METHODS: Associations between DSR and subsequent gastrointestinal cancer risk were examined among 450,111 adults enrolled in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC, initiated in 1992), free of cancer at baseline. Usual dietary intakes were assessed at recruitment with country-specific dietary questionnaires. DSR of an individual's yearly diet was calculated based on the absolute number of unique biological species in each food and drink item. Associations between DSR and cancer risk were assessed by multivariable Cox proportional hazards regression models. FINDINGS: During a median follow-up time of 14.1 years (SD=3.9), 10,705 participants were diagnosed with gastrointestinal cancer. Hazard ratios (HRs) and 95 % confidence intervals (CIs) comparing overall gastrointestinal cancer risk in the highest versus lowest quintiles of DSR indicated inverse associations in multivariable-adjusted models [HR (95 % CI): 0.77 (0.69-0.87); P-value < 0·0001] (Table 2). Specifically, inverse associations were observed between DSR and oesophageal squamous cell carcinoma, proximal colon, colorectal, and liver cancer risk (p-trend<0.05 for all cancer types). INTERPRETATION: Greater food biodiversity in the diet may lower the risk of certain gastrointestinal cancers. Further research is needed to replicate these novel findings and to understand potential mechanisms.
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Body weight change is defined as one or more periods of weight gain or weight loss that can vary in terms of magnitude, timeframe over which the change(s) occurs, and the number of times the pattern changes. Epidemiological and clinical data provide evidence of increased lifetime risk for breast cancer due to adult weight gain and a reduction of risk with weight loss. These findings parallel the majority of preclinical carcinogenesis experiments in which caloric intake in excess of basal metabolic requirements in rodents permits the development of cancer in proportion to the level of caloric intake. Dieting has been unsuccessful in reducing cancer risk unless a lower body weight was maintained at the end of weight change. Based on this evidence, it is recommended that consideration be given to the inclusion of the following recommendations in clinical practice guidelines for managing lifetime risk for breast cancer: (1) maintain adult body mass index in the desirable range (18.5-24.9 kg/m2) by preventing adult weight gain in both pre- and postmenopausal women, and (2) actively monitor BMI and, when BMI is above the defined ideal range, prescribe corrective lifestyle changes until body weight returns to the target range.
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Índice de Masa Corporal , Neoplasias de la Mama/etiología , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Adulto , Animales , Restricción Calórica , Dieta , Femenino , Humanos , Estilo de Vida , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/fisiopatología , Factores de Riesgo , Aumento de Peso , Pérdida de PesoRESUMEN
While diet and nutrition are modifiable risk factors for many chronic and infectious diseases, their role in cancer prevention and control remains under investigation. The lack of clarity of some diet-cancer relationships reflects the ongoing debate about the relative contribution of genetic factors, environmental exposures, and replicative errors in stem cell division as determinate drivers of cancer risk. In addition, dietary guidance has often been based upon research assuming that the effects of diet and nutrition on carcinogenesis would be uniform across populations and for various tumor types arising in a specific organ, i.e., that one size fits all. Herein, we present a paradigm for investigating precision dietary patterns that leverages the approaches that led to successful small-molecule inhibitors in cancer treatment, namely understanding the pharmacokinetics and pharmacodynamics of small molecules for targeting carcinogenic mechanisms. We challenge the scientific community to refine the paradigm presented and to conduct proof-in-concept experiments that integrate existing knowledge (drug development, natural products, and the food metabolome) with developments in artificial intelligence to design and then test dietary patterns predicted to elicit drug-like effects on target tissues for cancer prevention and control. We refer to this precision approach as dietary oncopharmacognosy and envision it as the crosswalk between the currently defined fields of precision oncology and precision nutrition with the goal of reducing cancer deaths.
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Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Inteligencia Artificial , Medicina de Precisión , Dieta , Estado NutricionalRESUMEN
BACKGROUND: Although unopposed estrogen exposure is considered a major driver of endometrial carcinogenesis, chronic inflammation and insulin resistance and hyperinsulinemia are also major endometrial cancer risk factors. However, it is unclear whether diets with inflammatory or insulinemic potential are associated with risk of endometrial cancer. METHODS: We followed 48â330 women from the Nurses' Health Study (1984-2016) and 85â426 women from the Nurses' Health Study II (1989-2017). Using food frequency questionnaires, we calculated repeated measures of empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which characterize the potential of the whole diet to modulate circulating biomarkers of inflammation or C-peptide, respectively. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for type I endometrial cancer risk. RESULTS: We documented 1462 type I endometrial cancer cases over 2â823â221 person-years of follow-up. In the pooled multivariable-adjusted analyses, women in the highest compared with lowest quintiles were at higher risk of type I endometrial cancer (EDIP HRQ5vsQ1 = 1.46, 95% CI = 1.24 to 1.73; Ptrend < .001; EDIH HRQ5vsQ1 = 1.58, 95% CI = 1.34 to 1.87; Ptrend < .001). Additional adjustment for body mass index attenuated the associations (EDIP HR = 1.03, 95% CI = 0.87 to 1.22; EDIH HR = 1.01, 95% CI = 0.85 to 1.21), and mediation analyses showed that body mass index may explain 60.4% (95% CI = 37.4% to 79.6%; P < .001) and 71.8% (95% CI = 41.0% to 90.4%; P < .001) of the association of endometrial cancer with EDIP and EDIH, respectively. CONCLUSIONS: In this large cohort study, higher dietary inflammatory and insulinemic potential were each associated with increased endometrial cancer incidence, and this association may be almost entirely mediated by adiposity.
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Neoplasias Endometriales , Hiperinsulinismo , Femenino , Humanos , Estudios de Cohortes , Dieta/efectos adversos , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/etiología , Hiperinsulinismo/complicaciones , Hiperinsulinismo/epidemiología , Inflamación/complicaciones , Factores de Riesgo , Estados UnidosRESUMEN
BACKGROUND: Metabolic syndrome (MetS), a group of risk factors that define metabolic dysfunction in adults, is strongly associated with obesity and is an emerging risk factor for cancer. However, the association of MetS and degree of metabolic dysfunction with obesity-related cancer is unknown. METHODS: Using National Health and Nutrition Examination Survey data from 1999 to 2018, we identified 528 obesity-related cancer cases and 18,972 cancer-free participants. MetS was defined as the presence of or treatment for ≥3 of hyperglycemia, hypertension, hypertriglyceridemia, low HDL-cholesterol, and abdominal obesity. A metabolic syndrome score (MSS) was computed as the total number of abnormal MetS parameters to determine the severity of metabolic dysfunction. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models, adjusting for sociodemographic and lifestyle factors. RESULTS: About 45.7% of obesity-related cancer cases were classified as having MetS compared with only 33.0% of cancer-free participants. Overall, MetS and MSS were not associated with obesity-related cancer. However, MSS was associated with higher obesity-related cancer risk among participants under 50 years of age (OR [95% CI] = 1.28 [1.08-1.52]). When evaluating MSS categorically, compared with healthy participants with no abnormal MetS parameters (MSS = 0), participants with one or two abnormal parameters had a statistically significant higher risk of obesity-related cancer (OR [95% CI] = 1.73 [1.06-2.83]). CONCLUSIONS: Metabolic dysfunction is associated with a higher risk of obesity-related cancer, particularly in young adults under 50 years of age, and among participants with one or two abnormal metabolic parameters. A more accurate indicator of metabolic dysfunction, beyond metabolic syndrome, is needed to better assist in stratifying individuals for obesity-related cancer risk.
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Síndrome Metabólico , Neoplasias , Adulto Joven , Humanos , Síndrome Metabólico/epidemiología , Encuestas Nutricionales , Estudios Transversales , Obesidad/complicaciones , Obesidad/epidemiología , Factores de Riesgo , Neoplasias/etiología , Neoplasias/complicacionesRESUMEN
The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C22 lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C22 lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C22 lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases.
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Neoplasias Colorrectales , Neoplasias Ováricas , Masculino , Humanos , Femenino , Próstata , Detección Precoz del Cáncer , Cromatografía de Gases y Espectrometría de Masas , Vitamina E , Suplementos Dietéticos , Metabolómica/métodos , Esteroides , Pulmón , Neoplasias Ováricas/diagnósticoRESUMEN
Obesity is a chronic, relapsing, progressive disease of excess adiposity that increases the risk of developing at least 13 types of cancer. This report provides a concise review of the current state of the science regarding metabolic and bariatric surgery and obesity pharmacotherapy related to cancer risk. Meta-analyses of cohort studies report that metabolic and bariatric surgery is independently associated with a lower risk of incident cancer than nonsurgical obesity care. Less is known regarding the cancer-preventive effects of obesity pharmacotherapy. The recent approval and promising pipeline of obesity drugs will provide the opportunity to understand the potential for obesity therapy to emerge as an evidence-based cancer prevention strategy. There are myriad research opportunities to advance our understanding of how metabolic and bariatric surgery and obesity pharmacotherapy may be used for cancer prevention.
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Cirugía Bariátrica , Neoplasias , Humanos , Adiposidad , Cirugía Bariátrica/efectos adversos , Neoplasias/epidemiología , Neoplasias/etiología , Neoplasias/prevención & control , Obesidad/complicaciones , Obesidad/cirugía , RiesgoRESUMEN
INTRODUCTION: Body mass index (BMI) fails to identify up to one-third of normal weight individuals with metabolic dysfunction who may be at increased risk of obesity-related cancer (ORC). Metabolic obesity phenotypes, an alternate metric to assess metabolic dysfunction with or without obesity, were evaluated for association with ORC risk. METHODS: National Health and Nutrition Examination Survey participants from 1999 to 2018 (N = 19,500) were categorized into phenotypes according to the metabolic syndrome (MetS) criteria and BMI: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obese (MHO) and metabolically unhealthy overweight/obese (MUO). Adjusted multivariable logistic regression models were used to evaluate associations with ORC. RESULTS: With metabolic dysfunction defined as ≥1 MetS criteria, ORC cases (n = 528) had higher proportions of MUNW (28.2% vs. 17.4%) and MUO (62.6% vs. 60.9%) phenotypes than cancer-free individuals (n = 18,972). Compared with MHNW participants, MUNW participants had a 2.2-times higher ORC risk [OR (95%CI) = 2.21 (1.27-3.85)]. MHO and MUO participants demonstrated a 43% and 56% increased ORC risk, respectively, compared to MHNW, but these did not reach statistical significance [OR (95% CI) = 1.43 (0.46-4.42), 1.56 (0.91-2.67), respectively]. Hyperglycaemia, hypertension and central obesity were all independently associated with higher ORC risk compared to MHNW. CONCLUSIONS: MUNW participants have a higher risk of ORC than other abnormal phenotypes, compared with MHNW participants. Incorporating metabolic health measures in addition to assessing BMI may improve ORC risk stratification. Further research on the relationship between metabolic dysfunction and ORC is warranted.
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Síndrome Metabólico , Neoplasias , Humanos , Sobrepeso , Encuestas Nutricionales , Obesidad/complicaciones , Síndrome Metabólico/epidemiología , Síndrome Metabólico/etiología , Síndrome Metabólico/diagnóstico , Fenotipo , Neoplasias/epidemiología , Neoplasias/etiologíaRESUMEN
BACKGROUND: Regulating meal timing may have efficacy for improving metabolic health for preventing or managing chronic disease. However, the reliability of measuring meal timing with commonly used dietary assessment tools needs characterization prior to investigating meal timing and health outcomes in epidemiologic studies. OBJECTIVES: To evaluate the reliability of estimating meal timing parameters, including overnight fasting duration, the midpoint of overnight fasting time, the number of daily eating episodes, the period with the largest percentage of daily caloric intake, and late last eating episode (> 09:00 pm) from repeated 24-h dietary recalls (24HRs). METHODS: Intraclass correlation coefficients (ICC), Light's Kappa estimates, and 95% CIs were calculated from repeated 24HR administered in 3 epidemiologic studies: The United States-based Interactive Diet and Activity Tracking in AARP (IDATA) study (n = 996, 6 24HR collected over 12-mo), German EPIC-Potsdam Validation Study (European Prospective Investigation into Cancer and Nutrition Potsdam Germany cohort) (n = 134, 12 24HR collected over 12-mo) and EPIC-Potsdam BMBF-II Study (Federal Ministry of Education and Research, "Bundesministerium für Bildung und Forschung") (n = 725, 4 24HR collected over 36 mo). RESULTS: Measurement reliability of overnight fasting duration based on a single 24HR was "poor" in all studies [ICC range: 0.27; 95% CI: 0.23, 0.32 - 0.46; 95% CI: 0.43, 0.50]. Reliability was "moderate" with 3 24HR (ICC range: 0.53; 95% CI: 0.47, 0.58 in IDATA, 0.62; 95% CI: 0.52, 0.69 in the EPIC-Potsdam Validation Study, and 0.72; 95% CI: 0.70-0.75 in the EPIC-Potsdam BMBF-II Study). Results were similar for the midpoint of overnight fasting time and the number of eating episodes. Reliability of measuring late eating was "fair" in IDATA (Light's Kappa: 0.30; 95% CI: 0.21, 0.39) and "slight" in the EPIC-Potsdam Validation study and the EPIC-Potsdam BMBF-II study (Light's Kappa: 0.19; 95% CI: 0.15, 0.25 and 0.09; 95% CI: 0.06, 0.12, respectively). Reliability estimates differed by sex, BMI, weekday, and season of 24HR administration in some studies. CONCLUSIONS: Our results show that ≥ 3 24HR over a 1-3-y period are required for reliable estimates of meal timing variables.