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2.
PLoS Med ; 18(2): e1003522, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33524029

RESUMO

BACKGROUND: Healthy lifestyle and screening represent 2 major approaches to colorectal cancer (CRC) prevention. It remains unknown whether the CRC-preventive benefit of healthy lifestyle differs by endoscopic screening status, and how the combination of healthy lifestyle with endoscopic screening can improve CRC prevention. METHODS AND FINDINGS: We assessed lifestyle and endoscopic screening biennially among 75,873 women (Nurses' Health Study, 1988 to 2014) and 42,875 men (Health Professionals Follow-up Study, 1988 to 2014). We defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet. We calculated hazard ratios (HRs) and population-attributable risks (PARs) for CRC incidence and mortality in relation to healthy lifestyle score according to endoscopic screening. Participants' mean age (standard deviation) at baseline was 54 (8) years. During a median of 26 years (2,827,088 person-years) follow-up, we documented 2,836 incident CRC cases and 1,013 CRC deaths. We found a similar association between healthy lifestyle score and lower CRC incidence among individuals with and without endoscopic screening, with the multivariable HR per one-unit increment of 0.85 (95% CI, 0.80 to 0.90) and 0.85 (95% CI, 0.81 to 0.88), respectively (P-interaction = 0.99). The fraction of CRC cases that might be prevented (PAR) by endoscopic screening alone was 32% (95% CI, 31% to 33%) and increased to 61% (95% CI, 42% to 75%) when combined with healthy lifestyle (score = 5). The corresponding PAR (95% CI) increased from 15% (13% to 16%) to 51% (17% to 74%) for proximal colon cancer and from 47% (45% to 50%) to 75% (61% to 84%) for distal CRC. Results were similar for CRC mortality. A limitation of our study is that our study participants are all health professionals and predominantly whites, which may not be representative of the general population. CONCLUSIONS: Our study suggests that healthy lifestyle is associated with lower CRC incidence and mortality independent of endoscopic screening. An integration of healthy lifestyle with endoscopic screening may substantially enhance prevention for CRC, particularly for proximal colon cancer, compared to endoscopic screening alone.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33627383

RESUMO

BACKGROUND: The TMPRSS2: ERG gene fusion and PTEN loss are two of the most common somatic molecular alterations in prostate cancer. Here we investigated the association of pre-diagnostic circulating metabolomics and prostate cancer defined by ERG or PTEN status to improve understanding of these etiologically distinct molecular prostate cancer subtypes. METHODS: The study was performed among 277 prostate cancer cases with ERG status, 211 with PTEN status, and 294 controls nested in the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS). We profiled 223 polar and non-polar metabolites using liquid chromatography-mass spectrometry in pre-diagnostic plasma specimens. We applied enrichment analysis and multinomial logistic regression models to identify biological metabolite classes and individual metabolites associated with prostate cancer defined by ERG or PTEN status. RESULTS: Compared to non-cancer controls, sphingomyelins (P: 0.01), ceramides (P: 0.04), and phosphatidylethanolamines (P: 0.03) circulating levels were enriched among ERG-positive prostate cancer cases. Sphingomyelins (P: 0.02), ceramides (P: 0.005), and amino acids (P: 0.02) were enriched among tumors exhibiting PTEN-loss; unsaturated diacylglycerols (P: 0.003) were enriched among PTEN-intact cases; unsaturated triacylglycerols were enriched among both PTEN-loss (P: 0.001) and PTEN-intact (P: 0.0001) cases. While several individual metabolites identified in the above categories were nominally associated with ERG or PTEN defined prostate cancer, none remained significant after accounting for multiple testing. CONCLUSIONS: The molecular process of prostate carcinogenesis may be distinct for men with different metabolomic profiles. IMPACT: These novel findings provide insights into the metabolic environment for the development of prostate cancer.

4.
Cancer Res ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574088

RESUMO

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% CI 0.82-0.93; former smokers 1.00, 95 CI 0.91-1.07; current smokers 1.25, 95%CI 1.12-1.40, interaction P-value=3.08x10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high LD with rs1818613 (r2=0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.

5.
J Natl Cancer Inst ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33528007

RESUMO

BACKGROUND: Prior epidemiological and intervention studies have not been able to separate independent effects of dose, timing and duration of aspirin use in colorectal cancer (CRC) chemoprevention. We examined aspirin-based CRC chemoprevention according to timing in the Nurses' Health Study and Health Professionals Follow-Up Study. METHODS: The exposures include cumulative average dose and total duration of aspirin use in > 10 years before follow-up started (remote period), and in the immediate 10 years before follow-up started (recent period). Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals for exposures and CRC risk. RESULTS: Aspirin use >10 years before follow-up started (HR = 0.88, 95% CI = 0.83 to 0.94) per 5 year increment) and immediate 10 years before follow-up started (HR = 0.90, 95% CI = 0.84 to 0.96) were similarly important in CRC chemoprevention, though a 5-year lag was required for a clear benefit in the recent period. In the remote period, the association was not dose-dependent; compared to < 0.5 standard (325 mg)-dose tablets/week; hazard ratios were HR = 0.78, 95% CI = 0.63 to 0.98, HR = 0.81, 95% CI = 0.72 to 0.91, and HR = 0.74, 95% CI = 0.64 to 0.86 for doses of 0.5 to < 1.5, 1.5 to < 5, ≥5 tablets/week, respectively. However, there was dose dependency in the recent period (with respective HR = 0.91, 95% CI = 0.79 to 1.06; HR = 0.87, 95% CI = 0.77 to 0.98; and HR = 0.76, 95% CI = 0.64 to 0.91). CONCLUSION: A suggestive benefit necessitates at least 6-10 years and most clearly after approximately 10 years since initiation of aspirin. Remote use and use within the previous 10 years both contribute independently to decreased risk, though a lower dose may be required for a benefit with longer term use.

6.
Clin Cancer Res ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632927

RESUMO

PURPOSE: While evidence indicates that Fusobacterium nucleatum may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain. EXPERIMENTAL DESIGN: We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole exome sequencing, and M1/M2-type tumor-associated macrophages [by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets. RESULTS: The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes (multivariable odds ratio, 0.47, 95% confidence interval, 0.28-0.79, for F. nucleatum-high vs. negative category; P trend=0.0004) and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable odds ratio, 0.52, 95% confidence interval, 0.32-0.85; P trend=0.003). These relationships did not substantially differ by MSI status, neoantigen loads, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with T-cell subset densities in tumor intraepithelial regions or with macrophage densities. CONCLUSIONS: The amount of tissue F. nucleatum is associated with lower densities of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.

7.
Int J Cancer ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527363

RESUMO

Population attributable risk (PAR) is becoming more widely used for quantifying preventability of cancer. However, its estimations have had a wide range, leading to questions about the true preventability. Our study aimed to compare the two PAR estimation methods (ie, literature-based method and low-risk method) for colorectal cancer (CRC) in the US population based on the same set of modifiable risk factors: physical activity, body mass index, alcoholic drinks, red meat, processed meat, dietary fiber, dietary calcium and cigarette smoking. For the literature-based method, 65% and 53%, and for the low-risk method, 62% and 49% of CRC cases for males and females, respectively, were attributable to the eight dietary and lifestyle risk factors. Additional sensitivity analyses were conducted with respect to the different choices of risk factors, relative risks (RRs) and exposure prevalence estimates used in the literature-based method. The PARs including only the "convincing" factors and excluding "probable" factors defined by the WCRF/AICR were 50% for males and 34% for females. Using RRs derived from different studies changed the PARs considerably (57%-74% for males and 37%-60% for females). Our study assessed the robustness of PAR calculations through a direct comparison between the two methods using different assumptions and data and generally found high concordance. From the additional analyses, we found that the choice of risk factors and RRs could substantially influence the PAR estimates. Given the findings, future studies reporting PAR should consider presenting a range of PAR estimates based on choices of risk factors and RRs.

8.
JAMA Netw Open ; 4(2): e2037341, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33591366

RESUMO

Importance: Several meta-analyses have summarized evidence for the association between dietary factors and the incidence of colorectal cancer (CRC). However, to date, there has been little synthesis of the strength, precision, and quality of this evidence in aggregate. Objective: To grade the evidence from published meta-analyses of prospective observational studies that assessed the association of dietary patterns, specific foods, food groups, beverages (including alcohol), macronutrients, and micronutrients with the incidence of CRC. Data Sources: MEDLINE, Embase, and the Cochrane Library were searched from database inception to September 2019. Evidence Review: Only meta-analyses of prospective observational studies with a cohort study design were eligible. Evidence of association was graded according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant. Results: From 9954 publications, 222 full-text articles (2.2%) were evaluated for eligibility, and 45 meta-analyses (20.3%) that described 109 associations between dietary factors and CRC incidence were selected. Overall, 35 of the 109 associations (32.1%) were nominally statistically significant using random-effects meta-analysis models; 17 associations (15.6%) demonstrated large heterogeneity between studies (I2 > 50%), whereas small-study effects were found for 11 associations (10.1%). Excess significance bias was not detected for any association between diet and CRC. The primary analysis identified 5 (4.6%) convincing, 2 (1.8%) highly suggestive, 10 (9.2%) suggestive, and 18 (16.5%) weak associations between diet and CRC, while there was no evidence for 74 (67.9%) associations. There was convincing evidence of an association of intake of red meat (high vs low) and alcohol (≥4 drinks/d vs 0 or occasional drinks) with the incidence of CRC and an inverse association of higher vs lower intakes of dietary fiber, calcium, and yogurt with CRC risk. The evidence for convincing associations remained robust following sensitivity analyses. Conclusions and Relevance: This umbrella review found convincing evidence of an association between lower CRC risk and higher intakes of dietary fiber, dietary calcium, and yogurt and lower intakes of alcohol and red meat. More research is needed on specific foods for which evidence remains suggestive, including other dairy products, whole grains, processed meat, and specific dietary patterns.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33531435

RESUMO

BACKGROUND: Type 2 diabetes increases risk of developing colorectal cancer (CRC), but the association of pre-existing diabetes with CRC survival remains unclear. METHODS: We analyzed survival by diabetes status at cancer diagnosis among 4038 patients with CRC from two prospective U.S. cohorts. Cox proportional hazards regression was used to calculate HRs and 95% confidence intervals (CIs) for overall and cause-specific mortality, with adjustment for tumor characteristics and lifestyle factors. RESULTS: In the first 5 years after CRC diagnosis, diabetes was associated with a modest increase in overall mortality in women (HR, 1.22; 95% CI, 1.00-1.49), but not in men (HR, 0.83; 95% CI, 0.62-1.12; P heterogeneity by sex = 0.04). Beyond 5 years, diabetes was associated with substantially increased overall mortality with no evidence of sex heterogeneity; in women and men combined, the HRs were 1.45 (95% CI, 1.09-1.93) during >5 to 10 years and 2.58 (95% CI, 1.91-3.50) during >10 years. Compared with those without diabetes, CRC patients with diabetes had increased mortality from other malignancies (HR, 1.78; 95% CI, 1.18-2.67) and cardiovascular disease (HR, 1.93; 95% CI, 1.29-2.91). Only women with diabetes for more than 10 years had increased mortality from CRC (HR, 1.33; 95% CI, 1.01-1.76). CONCLUSIONS: Among patients with CRC, pre-existing diabetes was associated with increased risk of long-term mortality, particularly from other malignancies and cardiovascular disease. IMPACT: Our findings highlight the importance of cardioprotection and cancer prevention to CRC survivors with diabetes.

10.
JAMA Oncol ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33475710

RESUMO

Importance: Although aspirin is recommended for the prevention of colorectal cancer (CRC) among adults aged 50 to 59 years, recent data from a randomized clinical trial suggest a lack of benefit and even possible harm among older adults. Objective: To examine the association between aspirin use and the risk of incident CRC among older adults. Design, Setting, and Participants: A pooled analysis was conducted of 2 large US cohort studies, the Nurses' Health Study (June 1, 1980-June 30, 2014) and Health Professionals Follow-up Study (January 1, 1986-January 31, 2014). A total of 94 540 participants aged 70 years or older were included and followed up to June 30, 2014, for women or January 31, 2014, for men. Participants with a diagnosis of any cancer, except nonmelanoma skin cancer, or inflammatory bowel disease were excluded. Statistical analyses were conducted from December 2019 to October 2020. Main Outcomes and Measures: Cox proportional hazards models were used to calculate multivariable adjusted hazard ratios (HRs) and 95% CIs for incident CRC. Results: Among the 94 540 participants (mean [SD] age, 76.4 [4.9] years for women, 77.7 [5.6] years for men; 67 223 women [71.1%]; 65 259 White women [97.1%], 24 915 White men [96.0%]) aged 70 years or older, 1431 incident cases of CRC were documented over 996 463 person-years of follow-up. After adjustment for other risk factors, regular use of aspirin was associated with a significantly lower risk of CRC at or after age 70 years compared with nonregular use (HR, 0.80; 95% CI, 0.72-0.90). However, the inverse association was evident only among aspirin users who initiated aspirin use before age 70 years (HR, 0.80; 95% CI, 0.67-0.95). In contrast, initiating aspirin use at or after 70 years was not significantly associated with a lower risk of CRC (HR, 0.92; 95% CI, 0.76-1.11). Conclusions and Relevance: Initiating aspirin at an older age was not associated with a lower risk of CRC in this pooled analysis of 2 cohort studies. In contrast, those who used aspirin before age 70 years and continued into their 70s or later had a reduced risk of CRC.

11.
Eur J Epidemiol ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33428024

RESUMO

Most cohort studies have only a single physical activity (PA) measure and are thus susceptible to reverse causation and measurement error. Few studies have examined the impact of these potential biases on the association between PA and mortality. A total of 133,819 participants from Nurses' Health Study and Health Professionals Follow-up Study (1986-2014) reported PA through biennial questionnaires. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for PA and mortality using different analytic approaches comparing single (baseline, simple update = most recent) versus repeated (cumulative average) measures of PA and applying various lag times separating PA measurement and time at risk. Over 3.2 million person-years, we documented 47,273 deaths. The pooled multivariable-adjusted HR (95% CI) of all-cause mortality per 10 MET-hour/week was 0.95 (0.94-0.96) for baseline PA, 0.78 (0.77-0.79) for simple updated PA and 0.87 (0.86-0.88) for cumulative average PA in the range of 0-50 MET-hour/week. Simple updated PA showed the strongest inverse association, suggesting larger impact of reverse causation. Application of 2-year lag substantially reduced the apparent reverse causation (0.85 (0.84-0.86) for simple updated PA and 0.90 (0.89-0.91) for cumulative average PA), and 4-12-year lags had minimal additional effects. In the dose-response analysis, baseline or simple updated PA showed a J or U-shaped association with all-cause mortality while cumulative average PA showed an inverse association across a wide range of PA (0-150 MET-hour/week). Similar findings were observed for different specific mortality causes. In conclusion, PA measured at baseline or with short lag time was prone to bias. Cumulative average PA showed robust evidence that PA is inversely associated with mortality in a dose-response manner.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33514605

RESUMO

BACKGROUND: We prospectively examined the extent to which greater inflammatory and insulinemic potential of diet and lifestyle are associated with the risk of developing hepatocellular carcinoma (HCC) in two nationwide cohorts. METHODS: Five kinds of pattern scores including the empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH) and insulin resistance (EDIR), empirical lifestyle pattern score for hyperinsulinemia (ELIH) and insulin resistance (ELIR) were calculated. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS: After an average follow-up of 25.6 years among 119,316 participants, 142 incident HCC cases were documented. Higher adherence to EDIP (HR by comparing extreme tertiles: 2.03, 95% CI: 1.31-3.16, Ptrend= 0.001), EDIH (HR=1.61, 95% CI: 1.06-2.43, Ptrend= 0.02), and EDIR (HR=1.62, 95% CI: 1.08-2.42, Ptrend= 0.02) were associated with increased risk of HCC. Likewise, participants with higher scores of ELIH (HR=1.89, 95% CI: 1.25-2.87, Ptrend= 0.001) and ELIR (HR=2.05, 95% CI: 1.34-3.14, Ptrend= 0.0004) had higher risk of developing HCC. Additional adjustment for diabetes mellitus and/or body mass index attenuated the magnitude of the associations, indicating that diabetes and/or adiposity may partly mediate the association of these patterns with HCC risk. CONCLUSIONS: Our findings suggest that inflammation and insulin resistance/hyperinsulinemia are potential mechanisms linking dietary or lifestyle factors and HCC development. IMPACT: Inflammation and insulin resistance/hyperinsulinemia may partly mediate the association of diet and other lifestyles with HCC development, and interventions to reduce the adverse effect of pro-inflammatory and hyperinsulinemic diet and lifestyle may reduce HCC risk.

13.
BMC Med ; 19(1): 18, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33504335

RESUMO

BACKGROUND: Sex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown. METHODS: We retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses' Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P < 0.005 was considered statistically significant. RESULTS: During 20 years of follow-up, we documented 535 conventional adenoma cases and 402 serrated polyp cases. Higher concentrations of SHBG were associated with lower risk of conventional adenomas, particularly advanced adenomas (multivariable OR comparing the highest to the lowest quartile, 0.40, 95% CI 0.24-0.67, P for trend < 0.0001). A nominally significant association was found for SHBG with lower risk of large serrated polyps (≥ 10 mm) (OR, 0.47, 95% CI 0.17-1.35, P for trend = 0.02) as well as free estradiol and free testosterone with higher risk of conventional adenomas (OR, 1.54, 95% CI 1.02-2.31, P for trend = 0.03 and OR, 1.33, 95% CI 0.99-1.78, P for trend = 0.03, respectively). CONCLUSIONS: The findings suggest a potential role of sex hormones, particularly SHBG, in early colorectal carcinogenesis.

14.
Eur Urol ; 79(3): 405-412, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33422354

RESUMO

BACKGROUND: Hyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk. OBJECTIVE: To determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: We prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986-2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Total, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns-empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern-and prostate cancer risk estimated using Cox proportional hazard regression. RESULTS AND LIMITATIONS: During 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01-1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00-1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06-1.35) for advanced, 1.22 (1.04-1.42) for fatal, and 1.20 (1.04-1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00-1.35). CONCLUSIONS: Hyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease. PATIENT SUMMARY: Avoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33500320

RESUMO

BACKGROUND: Men engaged in high physical activity have lower risks of advanced and fatal prostate cancer. Mechanisms underlying this association are not well understood but may include systemic and tumor-specific effects. We investigated potential mechanisms linking physical activity and gene expression in prostate tissue from men with prostate cancer. METHODS: We included a subset of 118 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 1986-2005 with whole transcriptome gene expression profiling on tumor and adjacent normal prostate tissue and physical activity data. Long-term vigorous physical activity was self-reported as the average time spent engaged in various forms of recreational physical activity at baseline and biennially until prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and Hallmark gene sets to identify pathways with differential expression based on vigorous physical activity. RESULTS: In adjacent normal tissue, we identified 25 KEGG gene sets enriched (down-regulated) in the highest compared to lowest quintile of vigorous physical activity at a false-discovery rate <0.10, including a number of cancer- and immune-related pathways. While no gene sets reached statistical significance in tumor tissue, top gene sets differentially expressed included TGF beta, apoptosis, and p53 signaling pathways. CONCLUSIONS: These findings suggest that physical activity may influence the tumor microenvironment. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to lethal prostate cancer. IMPACT: Identification of gene expression alterations in the prostate associated with physical activity can improve our understanding of prostate cancer etiology.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33418132

RESUMO

BACKGROUND & AIMS: Obesity, type 2 diabetes, and lifestyle factors (cigarette smoking, alcohol drinking, and coffee consumption) have been associated with the risk of developing gallstone disease in observational studies, but whether these associations are causal is undetermined. We conducted a Mendelian randomization study to assess these associations. METHODS: Genetic instruments associated with the exposures at the genome-wide significance (p < 5×10-8) level were selected from corresponding genome-wide associations studies (n=224 459 to 1 232 091 individuals). Summary-level data for gallstone disease were obtained from the UK Biobank (10 520 cases and 350 674 non-cases) and FinnGen consortium (11 675 cases and 121 348 non-cases). Univariable and multivariable Mendelian randomization analyses were conducted. Results from UK Biobank and FinnGen were combined using fixed-effects meta-analysis. RESULTS: The odds ratios were 1.63 (95% confidence interval (CI), 1.49, 1.79) for one standard deviation (SD) increase in body mass index, 1.81 (95% CI, 1.60, 2.05) for one SD increase in waist circumference, 1.13 (95% CI, 1.09, 1.17) for one unit increase in the log-odds ratio of type 2 diabetes and 1.25 (95% CI, 1.16, 1.34) for one SD increase in prevalence of smoking initiation. The associations for body mass index and type 2 diabetes persisted after mutual adjustment. Genetically predicted coffee consumption was inversely associated with gallstone disease after adjustment for body mass index and smoking (odds ratio per 50% increase 0.44, 95% CI, 0.21, 0.91). There was no association with alcohol consumption. CONCLUSIONS: This study supports independent causal roles of obesity, type 2 diabetes, and smoking in gallstone disease.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33418133

RESUMO

OBJECTIVE: The etiology of diverticulitis is poorly understood. The long-held belief that constipation and low-fiber diet are risk factors for diverticulosis has recently been challenged by studies that suggest that more frequent bowel movements predispose to diverticulosis. We aim to prospectively explore the association between bowel movement frequency and incident diverticulitis. DESIGN: We studied participants of the Nurses' Health Study (NHS) and Health Professional Follow-up Study (HPFS). Participants' medical history, lifestyle factors and diet were used in Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios(HRs) and 95% confidence intervals(CI). RESULTS: In the NHS during over 24 years of follow-up encompassing 1,299,922 person-years, we documented 5,214 incident cases of diverticulitis, and in the HPFS over 14 years encompassing 368,661 person-years of follow-up, we documented 390 incident cases of diverticulitis. We observed an inverse association between the frequency of bowel movements and risk of diverticulitis. In the NHS, compared with women who had daily bowel movements, those with more than once daily bowel movements had a HR of 1.30 (95% CI, 1.19, 1.42) and those with less frequent bowel movements had a HR of 0.89 (95% CI, 0.82, 0.95; p-trend < 0.0001). In the HPFS, the corresponding HRs were 1.29 (95% CI, 1.04, 1.59) and 0.61 (95% CI, 0.36, 1.03; p-trend = 0.003). The association between bowel movements and diverticulitis was not modified by categories of age, BMI, physical activity, laxative use or fiber intake. CONCLUSION: More frequent bowel movements appear to be a risk factor for subsequent diverticulitis both in men and women. Further studies are needed to understand the potential mechanisms that may underlie this association.

20.
J Am Coll Cardiol ; 77(4): 423-436, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33509399

RESUMO

This is an update of the previous 2018 systematic review and meta-analysis of vitamin and mineral supplementation on cardiovascular disease outcomes and all-cause mortality. New randomized controlled trials and meta-analyses were identified by searching the Cochrane library, Medline, and Embase, and data were analyzed using random effects models and classified by the Grading of Recommendations Assessment Development and Evaluation approach. This updated review shows similar findings to the previous report for preventive benefits from both folic acid and B vitamins for stroke and has been graded with moderate quality. No effect was seen for the commonly used multivitamins, vitamin D, calcium, and vitamin C, and an increased risk was seen with niacin (with statin) for all-cause mortality. Conclusive evidence for the benefit of supplements across different dietary backgrounds, when the nutrient is sufficient, has not been demonstrated.

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