Association between Circulating T Cells and the Gut Microbiome in Healthy Individuals: Findings from a Pilot Study.

Though the microbiome's impact on immune system homeostasis is well documented, the effect of circulating T cells on the gut microbiome remains unexamined. We analyzed data from 50 healthy volunteers in a pilot trial of aspirin, using immunophenotyping and 16S rRNA sequencing to evaluate the effect of baseline T cells on microbiome changes over 6 weeks. We employed an unsupervised sparse canonical correlation analysis (sCCA) and used multivariable linear regression models to evaluate the association between selected T cell subsets and selected bacterial genera after adjusting for covariates. In the cross-sectional analysis, percentages of naïve CD4+ T cells were positively associated with a relative abundance of Intestinimonas, and the percentage of activated CD8+ T cells was inversely associated with Cellulosibacter. In the longitudinal analysis, the baseline percentages of naïve CD4+ T cells and activated CD4+ T cells were inversely associated with a 6-week change in the relative abundance of Clostridium_XlVb and Anaerovorax, respectively. The baseline percentage of terminal effector CD4+ T cells was positively associated with the change in Flavonifractor. Notably, the microbiome taxa associated with T cell subsets exclusively belonged to the Bacillota phylum. These findings can guide future experimental studies focusing on the role of T cells in impacting gut microbiome homeostasis.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

Blood Pressure, Hypertension, and Antihypertensive Medication Use and Risk of Total and Fatal Prostate Cancer in Black and White Men in the Atherosclerosis Risk in Communities (ARIC) Study.

Black men are disproportionately burdened by hypertension and prostate cancer (PCa), and some cohorts suggest hypertension is associated with increased PCa risk. We investigated the association of hypertension and antihypertensive use with total (N = 889; 290 Black, 599 White) and fatal (N = 127; 42 Black, 85 White) PCa risk in 6658 (1578 Black, 5080 White) men in the Atherosclerosis Risk in Communities study. In adjusted Cox models, time-updated untreated stage 1 hypertension (systolic/diastolic blood pressure 130-139/80-89 mmHg) was associated with a higher risk of fatal PCa compared to untreated normal blood pressure (hazard ratio (HR) = 1.95; 95% confidence interval (CI) = 1.03-3.70). Compared to untreated normal/elevated blood pressure (combined given few events in those with untreated normal blood pressure), the association was significant in Black (HR = 3.35; 95% CI = 1.27-8.83), but not White (HR = 1.21; 95% CI = 0.58-2.55) men. Ever antihypertensive use was associated with a lower risk of fatal PCa compared to never use (HR = 0.52; 95% CI = 0.31-0.87), including short-term (< 10 years) and long-term (310 years) use (p-trend = 0.02) with similar inverse associations in Black and White men. Hypertension and antihypertensive use were not significantly associated with total PCa. The positive association of untreated stage 1 hypertension and fatal PCa warrants additional confirmation, especially in Black men, and characterization of the underlying mechanism.

Liver Fibrosis Scores and Prostate Cancer Risk and Mortality in the Atherosclerosis Risk in Communities Study.

Subclinical liver impairment due to fibrosis could influence the development and detectability of prostate cancer. To investigate the association between liver fibrosis and prostate cancer incidence and mortality, we included 5,284 men (mean age: 57.6 years, 20.1% Black) without cancer or liver disease at Visit 2 in the Atherosclerosis Risk in Communities study. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index, fibrosis 4 index (FIB-4), and nonalcoholic fatty liver disease fibrosis score (NFS). Over 25 years, 215 Black and 511 White men were diagnosed with prostate cancer, and 26 Black and 51 White men died from the disease. We estimated HRs for total and fatal prostate cancer using Cox regression. FIB-4 [quintile 5 vs. 1: HR = 0.47, 95% confidence interval (CI): 0.29-0.77, Ptrend = 0.004] and NFS (HR = 0.56, 95% CI: 0.33-0.97, Ptrend = 0.03) were inversely associated with prostate cancer risk in Black men. Compared with no abnormal score, men with ≥1 abnormal score had a lower prostate cancer risk if they were Black (HR = 0.46, 95% CI: 0.24-0.89), but not White (HR = 1.04, 95% CI: 0.69-1.58). Liver fibrosis scores did not appear to be associated with fatal prostate cancer in Black or White men. Among men without a clinical diagnosis of liver disease, higher liver fibrosis scores were associated with lower incidence of prostate cancer in Black men, but not in White men, and not with fatal prostate cancer in either race. Further research is needed to understand the influence of subclinical liver disease on prostate cancer development versus detectability and the racial differences observed. PREVENTION RELEVANCE: Investigating the link between liver fibrosis and prostate cancer risk and mortality, our study reveals the potential influence of liver health on prostate cancer development and on detection using PSA test, urging further research to understand the differential findings by race and to optimize prevention and intervention strategies.

Age-related Differences in T-cell Subsets and Markers of Subclinical Inflammation in Aging Are Independently Associated With Type 2 Diabetes in the Health and Retirement Study.

OBJECTIVES: Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T-cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS). METHODS: We measured 11 T-cell subsets, 5 pro-inflammatory markers, and 2 anti-inflammatory markers from the 2016 wave of the HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS, based on levels of blood glucose/glycated hemoglobin in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations. RESULTS: Among 8,540 participants (56 to 107 years of age), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index, and cytomegalovirus seropositivity, individuals with type 2 diabetes had lower naive T cells and higher memory and terminal effector T cells as compared with normoglycemic individuals. Among 3,230 normoglycemic participants in the 2016 survey, the incidence of diabetes was 1.8% over 4 years of follow-up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (hazard ratio [HR]=0.63, 95% confidence interval [CI] 0.49 to 0.80, p=0.0003) after adjustment for covariates. Baseline level of interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52, 95% CI 1.18 to 1.97, p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, although adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes. CONCLUSIONS: This study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, but CD4+ effector memory T-cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T-cell immunity affects diabetes risk.

Total-, LDL-, and HDL-cholesterol, apolipoproteins, and triglycerides with risk of total and fatal prostate cancer in Black and White men in the ARIC study.

BACKGROUND: Cholesterol reduction is considered a mechanism through which cholesterol-lowering drugs including statins are associated with a reduced aggressive prostate cancer risk. While prior cohort studies found positive associations between total cholesterol and more advanced stage and grade in White men, whether associations for total cholesterol, low (LDL)- and high (HDL)-density lipoprotein cholesterol, apolipoprotein B (LDL particle) and A1 (HDL particle), and triglycerides are similar for fatal prostate cancer and in Black men, who experience a disproportionate burden of total and fatal prostate cancer, is unknown. METHODS: We conducted a prospective study of 1553 Black and 5071 White cancer-free men attending visit 1 (1987-1989) of the Atherosclerosis Risk in Communities Study. A total of 885 incident prostate cancer cases were ascertained through 2015, and 128 prostate cancer deaths through 2018. We estimated multivariable-adjusted hazard ratios (HRs) of total and fatal prostate cancer per 1-standard deviation increments and for tertiles (T1-T3) of time-updated lipid biomarkers overall and in Black and White men. RESULTS: Greater total cholesterol concentration (HR per-1 SD = 1.25; 95% CI = 1.00-1.58) and LDL cholesterol (HR per-1 SD = 1.26; 95% CI = 0.99-1.60) were associated with higher fatal prostate cancer risk in White men only. Apolipoprotein B was nonlinearly associated with fatal prostate cancer overall (T2 vs. T1: HR = 1.66; 95% CI = 1.05-2.64) and in Black men (HR = 3.59; 95% CI = 1.53-8.40) but not White men (HR = 1.13; 95% CI = 0.65-1.97). Tests for interaction by race were not statistically significant. CONCLUSIONS: These findings may improve the understanding of lipid metabolism in prostate carcinogenesis by disease aggressiveness, and by race while emphasizing the importance of cholesterol control.

Associations between MICA and MICB Genetic Variants, Protein Levels, and Colorectal Cancer: Atherosclerosis Risk in Communities (ARIC).

BACKGROUND: The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development. METHODS: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of preselected SNPs with sMICA and sMICB levels and colorectal cancer risk (236 colorectal cancers, 8,609 participants) and of sMICA and sMICB levels with colorectal cancer risk (312 colorectal cancers, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed. RESULTS: Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males (HR = 0.68; 95% confidence interval, 0.49-0.96) but not in females (Pinteraction = 0.08). CONCLUSIONS: Rs2596542-T associated with lower sMICA levels was associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males. IMPACT: These findings support an importance of immunosurveillance in colorectal cancer.

Lower Expression of CFTR Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer.

Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral CFTR mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced CFTR expression in this population, we investigated association of tumoral CFTR expression with overall and disease-specific mortality in CRC patients. CFTR mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] CFTR expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased CFTR expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, CFTR expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57-0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47-0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and CFTR expression, (p-interaction: 0.06). The findings from these three datasets support the hypothesis that low CFTR expression is associated with increased CRC mortality.

Periodontal and Other Oral Bacteria and Risk of Lung Cancer in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Evidence suggests that periodontal disease is associated with increased lung cancer risk, but whether periodontal pathogens are explanatory is unknown. We prospectively studied associations of prediagnostic circulating antibodies with oral bacteria and of periodontal bacteria in subgingival plaque with lung cancer. METHODS: We included 4,263 cancer-free participants in the Atherosclerosis Risk in Communities study with previously measured serum IgG antibodies to 18 oral bacteria. In 1,287 participants for whom subgingival plaque was collected, counts for 8 periodontal bacteria were previously measured. Incident lung cancers (N = 118) were ascertained through 2015 (median follow-up = 17.5 years). We used Cox regression to estimate multivariable-adjusted associations, including for sums of antibodies to orange (C. rectus, F. nucleatum, P. intermedia, P. micra, and P. nigrescens) and red (P. gingivalis, T. forsythensis, and T. denticola) complex bacteria. RESULTS: Orange complex bacteria antibodies were positively associated with lung cancer [per IQR hazard ratios (HR) = 1.15; 95% confidence intervals (CI), 1.02-1.29], which was stronger in men (HR = 1.27, 95% CI 1.08-1.49), and explained by P. intermedia and P. nigrescens (HR = 1.15; 95% CI, 1.04-1.26). Suggestive positive associations with lung cancer (N = 40) were observed for F. nucleatum, A. actinomycetemcomitans, and P. gingivalis counts. Significant positive associations were found for the count to antibody ratio for P. intermedia and P. gingivalis. CONCLUSIONS: We identified positive associations with lung cancer for oral bacteria, especially orange complex that are moderately pathogenic for periodontal disease. IMPACT: This prospective study supports the need for more research on periodontal bacteria in lung cancer etiology. If associations are supported, this may inform novel lung cancer prevention strategies.

Sucrose Intakes and Incident Colorectal Cancer Risk among Women.

BACKGROUND: High sucrose intakes are hypothesized to increase colorectal cancer (CRC) risk by several mechanisms, and sucrose intakes have been consistently positively associated with CRC risk in case-control studies. However, all but one prospective study reported a null sucrose-CRC association. The only prospective study to report a positive association was the Iowa Women's Health Study (IWHS) of 35,221 cancer-free Iowa women, aged 55 - 69 years old at baseline in 1986, after four years of follow up. MATERIALS AND METHODS: To address the discrepant findings in the literature, after 26 years of follow up in the IWHS, we updated and expanded on our earlier reported analyses. During follow up through 2012, 1,731 women were diagnosed with CRC. Baseline dietary intakes were assessed with a Willett semiquantitative food frequency questionnaire. We used multivariable Cox proportional hazards regression models to estimate adjusted hazards ratios (HRs) and their 95% confidence intervals (CI). RESULTS: For those in the highest relative to the lowest intake quintiles, the adjusted HRs (95% CI) for CRC were 1.04 (0.87-1.23; Ptrend = 0.59) for sucrose, 1.00 (0.82-1.21; Ptrend = 0.67) for sucrose-containing foods, and 1.01, (0.83-1.22; Ptrend = 0.56) for nondairy sucrose-containing foods, respectively. These findings did not differ substantially by colorectal site or according to categories of selected participant characteristics. CONCLUSIONS: Our findings do not support that intakes of sucrose or sucrose-containing foods are substantially associated with CRC risk among older women.

Cross sectional association between cytomegalovirus seropositivity, inflammation and cognitive impairment in elderly cancer survivors.

PURPOSE: The higher prevalence of cognitive impairment/ dementia among cancer survivors is likely multifactorial. Since both exposures to cytomegalovirus (CMV) and inflammation are common among elderly cancer survivors, we evaluated their contribution towards dementia. METHODS: Data from 1387 cancer survivors and 7004 participants without cancer in the 2016 wave of the Health and Retirement Study (HRS) was used in this study. Two inflammatory biomarkers, C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR), were used to create an inflammation score. We used survey logistic regression adjusted for survey design parameters. RESULTS: CMV seropositivity was not associated with cognitive impairment among cancer survivors (p = 0.2). In addition, inflammation was associated with elevated odds of cognitive impairment (OR = 2.2, 95% CI [1.2, 4.2]). Cancer survivors who were both CMV seropositive and had increased inflammation had the highest odds of cognitive impairment compared to those who were CMV seronegative and had low inflammation (OR = 3.8, 95% CI [1.5, 9.4]). The stratified analysis among cancer survivors showed this association was seen only among cancer survivors in whom the cancer was diagnosed within three years of measurement of inflammation score and CMV serostatus (OR = 18.5; 95% CI [6.1, 56.1]). CONCLUSION: The CMV seropositivity and high inflammation was associated with higher cognitive impairment among cancer survivors. The stronger associations seen among cancer survivors diagnosed within the last three years suggest that strategies to reduce CMV activation and inflammation during or immediately after cancer treatment may be important in reducing the prevalence of cognitive impairment/ dementia among cancer survivors.

Lipid-Lowering Drug Use and Cancer Incidence and Mortality in the ARIC Study.

Background: Lipid-lowering drugs, particularly statins, are associated with reduced incidence of certain cancers in some studies. Associations with cancer mortality are not well studied, and whether associations are similar across race is unknown. Methods: We conducted a prospective analysis of 12 997 cancer-free participants in the Atherosclerosis Risk in Communities Study who were never users at visit 1 (1987-1989). Ever use, duration of use, and age at first use were modeled as time-dependent variables using Cox regression to estimate associations with total, obesity- and smoking-associated, bladder, breast, colorectal, lung, and prostate cancer incidence and mortality. Results: We ascertained 3869 cancer cases and 1661 cancer deaths in 237 999 or more person-years. At 6 years of follow-up, 70.8% of lipid-lowering drug use was a statin. Compared with never use, ever use was associated with lower total, obesity- and smoking-associated cancer mortality and with colorectal cancer mortality (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.32 to 0.79) and incidence (HR = 0.69, 95% CI = 0.53 to 0.92). Inverse associations were consistent by sex and race. Shorter-term use was associated with bladder cancer incidence in men (<10 years: HR = 1.67, 95% CI = 1.02 to 2.73). First use at age 60 years or older was inversely associated with: total mortality, obesity- and smoking-associated mortality, and colorectal cancer mortality; and total incidence, obesity- and smoking-associated incidence, and breast, colorectal, and prostate cancer incidence. Conclusions: This study provides additional evidence for inverse associations between lipid-lowering drug use and cancer incidence and mortality but a positive association with bladder cancer incidence in men. Evaluation of the impact of chemoprevention strategies that include lipid-lowering drugs on population-level cancer burden is needed.

Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts.

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

Efficacy and Adverse Events of Docetaxel for Metastatic, Hormone-sensitive Prostate Cancer Among Elderly Men: A Post Hoc Analysis of the CHAARTED Trial.

BACKGROUND: Combination therapy with docetaxel and androgen deprivation therapy (ADT) prolongs overall survival (OS) in men with metastatic hormone-sensitive prostate cancer. We assessed the benefits and adverse effects of docetaxel and ADT in relation to advancing age. METHODS: We performed a post hoc analysis of the CHAARTED trial comparing docetaxel and ADT vs. ADT alone (n = 773). Patients were stratified in age groups <60, 60-70, and >70 years old. Multivariable-adjusted progression-free survival (PFS) and OS were assessed using Kaplan-Meier curves and compared using multivariable Cox regressions with calculated interaction terms between age group and treatment arm. In the combination arm, the incidence of ≥1 adverse event (grade ≥3) and the number of adverse events per patient were compared for each age group using multivariable logistic and linear regressions, respectively. RESULTS: After adjusting for clinical variables, docetaxel's effect did not vary by age group for PFS and OS. There was no significant difference in the odds ratio of ≥1 adverse event (P > .1 for age groups 60-70 and >70 years old compared with <60 years old). However, men age >70 years old experienced +0.37 more adverse events per patient compared with men age <60 years old (95% CI, 0.11-0.64; P = .006). CONCLUSIONS: PFS and OS were similar across age groups for the combination of docetaxel and ADT compared with ADT. Older men experienced a modest increase in adverse events per patient, highlighting the importance of balancing treatment benefits and adverse effects in this age group.

Associations of dietary and lifestyle oxidative balance scores with mortality risk among older women: the Iowa Women's Health Study.

PURPOSE: Substantial basic science evidence suggests that oxidative stress may play a role in aging-related health outcomes, including cardiovascular diseases (CVD) and cancer, and oxidative stress markers were linked with all-cause and cause-specific mortality in epidemiologic studies. However, the associations of many individual dietary and lifestyle anti-/pro-oxidant exposures with mortality are inconsistent. Oxidative balance scores (OBS) that incorporated multiple dietary and lifestyle factors were previously developed and reported to reflect the collective oxidative effects of multiple exposures. METHODS: We investigated associations of 11-component dietary and 4-component (physical activity, adiposity, alcohol, and smoking) lifestyle OBS (higher scores were considered more anti-oxidative) with all-cause and cause-specific mortality among women 55-69 years of age at baseline in the prospective Iowa Women's Health Study (1986-2012). We assessed OBS-mortality associations using multivariable Cox proportional hazards regression. RESULTS: Of the 34,137 cancer-free women included in the analytic cohort, 18,058 died (4521 from cancer, and 6825 from CVD) during a mean/median 22.0/26.1 person-years of follow-up. Among participants in the highest relative to the lowest lifestyle OBS quintiles, the adjusted hazards ratios and their 95% confidence intervals for all-cause, all-cancer, and all-CVD mortality were 0.50 (0.48, 0.53), 0.47 (0.43, 0.52), and 0.54 (0.50, 0.58) (all Ptrend < 0.001), respectively. The associations of the dietary OBS with mortality were close to null. CONCLUSION: Our findings, combined with results from previous studies, suggest that a predominance of antioxidant over pro-oxidant lifestyle exposures may be associated with lower all-cause, all-CVD, and all-cancer mortality risk.

Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study.

Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.

Novel Dietary and Lifestyle Inflammation Scores Directly Associated with All-Cause, All-Cancer, and All-Cardiovascular Disease Mortality Risks Among Women.

BACKGROUND: Exogenous exposures collectively may contribute to chronic, low-grade inflammation and increase risks for major chronic diseases and mortality. We previously developed, validated, and reported a novel, FFQ-based and lifestyle questionnaire-based, inflammation biomarker panel-weighted, predominantly whole foods-based 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS; comprising physical activity, alcohol intake, BMI, and current smoking status). Both scores were more strongly associated with circulating biomarkers of inflammation in 3 populations than were previously reported dietary inflammation indices. Associations of the DIS and LIS with mortality risk have not been reported. OBJECTIVES: To investigate separate and joint associations of the DIS and LIS with all-cause, all-cancer, and cardiovascular disease (CVD) mortality risks in the prospective Iowa Women's Health Study (1986-2012; n = 33,155 women, ages 55-69 years, of whom 17,431 died during follow-up, including 4379 from cancer and 6574 from CVD). METHODS: We summed each study participant's scores' components, weighted by their published weights, to yield the participant's inflammation score; a higher score was considered more pro-inflammatory. We assessed DIS and LIS mortality associations using multivariable Cox proportional hazards regression. RESULTS: Among participants in the highest relative to the lowest DIS and LIS quintiles, the adjusted HRs for all-cause mortality were 1.11 (95% CI: 1.05-1.16) and 1.60 (95% CI: 1.53-1.68), respectively; for all-cancer mortality were 1.07 (95% CI: 0.97-1.17) and 1.51 (95% CI: 1.38-1.66), respectively; and for CVD mortality were 1.12 (95% CI: 1.03-1.21) and 1.79 (95% CI: 1.66-1.94), respectively (all Ptrend values < 0.01). Among those in the highest relative to the lowest joint LIS/DIS quintiles, the HRs for all-cause, all-cancer, and all-CVD mortality were 1.88 (95% CI: 1.71-2.08), 1.82 (95% CI: 1.50-2.20), and 1.92 (95% CI: 1.64-2.24), respectively. CONCLUSIONS: More pro-inflammatory diets and lifestyles, separately but especially jointly, may be associated with higher all-cause, all-cancer, and all-CVD mortality risks among women.

Dietary and Lifestyle Oxidative Balance Scores and Incident Colorectal Cancer Risk among Older Women; the Iowa Women's Health Study.

BACKGROUND: Basic science literature strongly supports a role of oxidative stress in colorectal cancer (CRC) etiology, but in epidemiologic studies, associations of most individual exposures with CRC have been weak or inconsistent. However, recent epidemiologic evidence suggests that the collective effects of these exposures on oxidative balance and CRC risk may be substantial. METHODS: Using food frequency and lifestyle questionnaire data from the prospective Iowa Women's Health Study (1986-2012), we investigated associations of 11-component dietary and 4-component lifestyle oxidative balance scores (OBS) with incident CRC using multivariable Cox proportional hazards regression. RESULTS: Of the 33,736 cancer-free women aged 55-69 years at baseline, 1,632 developed CRC during follow-up. Among participants in the highest relative to the lowest dietary and lifestyle OBS quintiles (higher anti-oxidant relative to pro-oxidant exposures), the adjusted hazard ratios (HRs) and their 95% confidence intervals (CI) were, respectively, 0.77 (0.63, 0.94) (Ptrend=0.02) and 0.61 (0.52, 0.71) (Ptrend<0.0001). Among those in the highest relative to the lowest joint lifestyle/dietary OBS quintile, the HR was 0.45 (95% CI 0.26, 0.77). CONCLUSIONS: Our findings suggest that a predominance of antioxidant over pro-oxidant dietary and lifestyle exposures-separately and especially jointly-may be inversely associated with CRC risk among older women.

Associations between tissue-based CD3+ T-lymphocyte count and colorectal cancer survival in a prospective cohort of older women.

Tumor-infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T-lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T-cells in colorectal tumor and histologically normal tissues with CRC-specific and all-cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin-embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55-69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow-up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC-specific and all-cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38-0.89) for CRC-specific mortality and 0.82 (0.63-1.05) for all-cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19-1.17) and 0.50 (0.27-0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC-specific and all-cause mortality. Although the association between tumor CD3+ score and all-cause mortality was not significant, both higher CD3+ T-lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC-specific and all-cause mortality.

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.