PURPOSETo provide an overview of relationships between sedentary behavior and mortality as well as incidence of several noncommunicable diseases and weight status reported in the 2018 Physical ...Activity Guidelines Advisory Committee Scientific Report (2018 PAGAC Scientific Report), and to update the evidence from recent studies.
METHODSEvidence related to sedentary behavior in the 2018 PAGAC Scientific Report was summarized, and a systematic review was undertaken to identify original studies published between January 2017 and February 2018.
RESULTSThe 2018 PAGAC Scientific Report concluded there was strong evidence that high amounts of sedentary behavior increase the risk for all-cause and cardiovascular disease (CVD) mortality and incident CVD and type 2 diabetes. Moderate evidence indicated sedentary behavior is associated with incident endometrial, colon and lung cancer. Limited evidence suggested sedentary behavior is associated with cancer mortality and weight status. There was strong evidence that the hazardous effects of sedentary behavior are more pronounced in physically inactive people. Evidence was insufficient to determine if bout length or breaks in sedentary behavior are associated with health outcomes. The new literature search yielded seven new studies for all-cause mortality, two for CVD mortality, two for cancer mortality, four for type 2 diabetes, one for weight status, and four for cancer; no new studies were identified for CVD incidence. Results of the new studies supported the conclusions in the 2018 PAGAC Scientific Report.
CONCLUSIONSThe results of the updated search add further evidence on the association between sedentary behavior and health. Further research is required on how sex, age, race/ethnicity, socioeconomic status, and weight status may modify associations between sedentary behavior and health outcomes.
Guidelines for initiating colorectal cancer (CRC) screening are based on family history but do not consider lifestyle, environmental, or genetic risk factors. We developed models to determine risk of ...CRC, based on lifestyle and environmental factors and genetic variants, and to identify an optimal age to begin screening.
We collected data from 9748 CRC cases and 10,590 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colorectal Transdisciplinary study, from 1992 through 2005. Half of the participants were used to develop the risk determination model and the other half were used to evaluate the discriminatory accuracy (validation set). Models of CRC risk were created based on family history, 19 lifestyle and environmental factors (E-score), and 63 CRC-associated single-nucleotide polymorphisms identified in genome-wide association studies (G-score). We evaluated the discriminatory accuracy of the models by calculating area under the receiver operating characteristic curve values, adjusting for study, age, and endoscopy history for the validation set. We used the models to project the 10-year absolute risk of CRC for a given risk profile and recommend ages to begin screening in comparison to CRC risk for an average individual at 50 years of age, using external population incidence rates for non-Hispanic whites from the Surveillance, Epidemiology, and End Results program registry.
In our models, E-score and G-score each determined risk of CRC with greater accuracy than family history. A model that combined both scores and family history estimated CRC risk with an area under the receiver operating characteristic curve value of 0.63 (95% confidence interval, 0.62–0.64) for men and 0.62 (95% confidence interval, 0.61–0.63) for women; area under the receiver operating characteristic curve values based on only family history ranged from 0.53 to 0.54 and those based only E-score or G-score ranged from 0.59 to 0.60. Although screening is recommended to begin at age 50 years for individuals with no family history of CRC, starting ages calculated based on combined E-score and G-score differed by 12 years for men and 14 for women, for individuals with the highest vs the lowest 10% of risk.
We used data from 2 large international consortia to develop CRC risk calculation models that included genetic and environmental factors along with family history. These determine risk of CRC and starting ages for screening with greater accuracy than the family history only model, which is based on the current screening guideline. These scoring systems might serve as a first step toward developing individualized CRC prevention strategies.
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PURPOSEThis article reviews and updates the evidence on the associations between physical activity and risk for cancer, and for mortality in persons with cancer, as presented in the 2018 Physical ...Activity Guidelines Advisory Committee Scientific Report.
METHODSSystematic reviews of meta-analyses, systematic reviews, and pooled analyses were conducted through December 2016. An updated systematic review of such reports plus original research through February 2018 was conducted. This article also identifies future research needs.
RESULTSIn reviewing 45 reports comprising hundreds of epidemiologic studies with several million study participants, the report found strong evidence for an association between highest versus lowest physical activity levels and reduced risks of bladder, breast, colon, endometrial, esophageal adenocarcinoma, renal, and gastric cancers. Relative risk reductions ranged from approximately 10% to 20%. Based on 18 systematic reviews and meta-analyses, the report also found moderate or limited associations between greater amounts of physical activity and decreased all-cause and cancer-specific mortality in individuals with a diagnosis of breast, colorectal, or prostate cancer, with relative risk reductions ranging almost up to 40% to 50%. The updated search, with five meta-analyses and 25 source articles reviewed, confirmed these findings.
CONCLUSIONSLevels of physical activity recommended in the 2018 Guidelines are associated with reduced risk and improved survival for several cancers. More research is needed to determine the associations between physical activity and incidence for less common cancers and associations with survival for other cancers. Future studies of cancer incidence and mortality should consider these associations for population subgroups, to determine dose–response relationships between physical activity and cancer risk and prognosis, and to establish mechanisms to explain these associations.
Diabetes is a major predictor of death from heart disease and stroke; its impact on nonvascular mortality, including specific cancers, is less understood. We examined the association of diabetes with ...cause-specific mortality, including deaths from specific cancers.
A prospective cohort of 1,053,831 U.S. adults, without cancer at baseline, enrolled in the Cancer Prevention Study-II in 1982 and was followed for mortality until December 2008. At baseline, participants completed a self-administered questionnaire that included information on diabetes, smoking, physical activity, height, and weight. Multivariable-adjusted relative risks (RRs) (95% CI) were estimated using Cox proportional hazards regression.
During 26 years of follow-up, 243,051 men and 222,109 women died. In multivariable models that controlled for age, BMI, and other variables, diabetes was associated with higher risk of all-cause mortality (women RR 1.90 95% CI 1.87-1.93; men 1.73 1.70-1.75). Among women, diabetes was associated with higher risk of death from cancers of the liver (1.40 1.05-1.86), pancreas (1.31 1.14-1.51), endometrium (1.33 1.08-1.65), colon (1.18 1.04-1.33), and breast (1.16 1.03-1.29). Among men, diabetes was associated with risk of death from cancers of the breast (4.20 2.20-8.04), liver (2.26 1.89-2.70), oral cavity and pharynx (1.44 1.07-1.94), pancreas (1.40 1.23-1.59), bladder (1.22 1.01-1.47), colon (1.15 1.03-1.29), and (inversely) prostate (0.88 0.79-0.97). Diabetes was also associated with higher risks of death involving the circulatory system, respiratory system, digestive system, genitourinary system, and external causes/accidental deaths.
Diabetes is associated with higher risk of death for many diseases, including several specific forms of cancer.
Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, ...germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
Over the past several decades, the incidence of early-onset cancers, often defined as cancers diagnosed in adults <50 years of age, in the breast, colorectum, endometrium, oesophagus, extrahepatic ...bile duct, gallbladder, head and neck, kidney, liver, bone marrow, pancreas, prostate, stomach and thyroid has increased in multiple countries. Increased use of screening programmes has contributed to this phenomenon to a certain extent, although a genuine increase in the incidence of early-onset forms of several cancer types also seems to have emerged. Evidence suggests an aetiological role of risk factor exposures in early life and young adulthood. Since the mid-20th century, substantial multigenerational changes in the exposome have occurred (including changes in diet, lifestyle, obesity, environment and the microbiome, all of which might interact with genomic and/or genetic susceptibilities). However, the effects of individual exposures remain largely unknown. To study early-life exposures and their implications for multiple cancer types will require prospective cohort studies with dedicated biobanking and data collection technologies. Raising awareness among both the public and health-care professionals will also be critical. In this Review, we describe changes in the incidence of early-onset cancers globally and suggest measures that are likely to reduce the burden of cancers and other chronic non-communicable diseases.
Intestinal health relies on the immunosuppressive activity of CD4
regulatory T (T
) cells
. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by ...dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)
. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced T
(pT
) cells
, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids
with a range of physiological functions
. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pT
cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of T
cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing T
cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.
IMPORTANCE: The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of ...aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. OBJECTIVE: To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. DESIGN, SETTING, AND PARTICIPANTS: We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661 137 men and women (median age, 62 years; range, 21-98 years) and 116 686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. EXPOSURES: Leisure time moderate- to vigorous-intensity physical activity. MAIN OUTCOMES AND MEASURES: The upper limit of mortality benefit from high levels of leisure time physical activity. RESULTS: Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 95% CI, 0.78-0.82), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 95% CI, 0.67-0.70), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 95% CI, 0.62-0.65). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 95% CI, 0.59-0.62); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 95% CI, 0.59-0.78). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. CONCLUSIONS AND RELEVANCE: Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.
The relationship between dietary factors and liver disease remains poorly understood. This study evaluated the associations of whole grain and dietary fiber intake with liver cancer risk and chronic ...liver disease mortality. The National Institutes of Health-American Association of Retired Persons Diet and Health Study cohort recruited 485, 717 retired U.S. participants in 1995-1996. Follow-up through 2011 identified 940 incident liver cancer cases and 993 deaths from chronic liver disease. Compared with the lowest, the highest quintile of whole grain intake was associated with lower liver cancer risk (Hazard ratio HR
= 0.78, 95% confidence interval CI: 0.63-0.96) and chronic liver disease mortality (HR
= 0.44, 95% CI: 0.35-0.55) in multivariable Cox models. Dietary fiber was also associated with lower liver cancer risk (HR
= 0.69, 95% CI: 0.53-0.90) and chronic liver disease mortality (HR
= 0.37, 95% CI: 0.29-0.48). Fiber from vegetables, beans and grains showed potential protective effect. Here, we show that higher intake of whole grain and dietary fiber are associated with lower risk of liver cancer and liver disease mortality.
Little is known about the association of recreational physical activity or leisure time spent sitting with survival after colorectal cancer diagnosis. This study examined the associations of ...prediagnosis and postdiagnosis recreational physical activity and leisure time spent sitting with mortality among patients with colorectal cancer.
From a cohort of adults without colorectal cancer at baseline in 1992-1993, we identified 2,293 participants who were diagnosed with invasive, nonmetastatic colorectal cancer up to mid-2007. At baseline, before their cancer diagnosis, and again after their cancer diagnosis, participants completed detailed questionnaires that included information concerning recreational physical activity and leisure time spent sitting.
During a maximum follow-up of 16.1 years after colorectal cancer diagnosis, 846 patients with colorectal cancer died, 379 of them from colorectal cancer. Engaging in 8.75 or more metabolic equivalent (MET) hours per week of recreational physical activity (equivalent to approximately 150 minutes per week of walking) compared with fewer than 3.5 MET hours per week was associated with lower all-cause mortality (prediagnosis physical activity: relative risk RR, 0.72; 95% CI, 0.58 to 0.89; postdiagnosis physical activity: RR, 0.58; 95% CI, 0.47 to 0.71). Spending 6 or more hours per day of leisure time sitting compared with fewer than 3 hours per day was associated with higher all-cause mortality (prediagnosis sitting time: RR, 1.36; 95% CI, 1.10 to 1.68; postdiagnosis sitting time: RR, 1.27; 95% CI, 0.99 to 1.64).
More recreational physical activity before and after colorectal cancer diagnosis was associated with lower mortality, whereas longer leisure time spent sitting was associated with higher risk of death.
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