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ObjectiveTo prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers.Design and settingA nested case–control study within two prospective cohort studies, the Shanghai Women’s Health Study (n=74 941) and the Shanghai Men’s Health Study (n=61 480).ParticipantsLifetime never-smokers who had no cancer at baseline. Cases were subjects who were diagnosed with incident lung cancer (n=114) and were matched 1:1 with controls on sex, age (≤2 years), date (≤30 days) and time (morning/afternoon) of sample collection, antibiotic use during the week before sample collection (yes/no) and menopausal status (for women).Main outcomes and measuresMetagenomic shotgun sequencing was used to measure the community structure and abundance of the oral microbiome in pre-diagnostic oral rinse samples of each case and control. Multivariable logistic regression models were used to estimate the association of lung cancer risk with alpha diversity metrics and relative abundance of taxa. The Microbiome Regression-Based Kernel Association Test (MiRKAT) evaluated the association between risk and the microbiome beta diversity.ResultsSubjects with lower microbiota alpha diversity had an increased risk of lung cancer compared with those with higher microbial alpha diversity (Shannon: ptrend=0.05; Simpson: ptrend=0.04; Observed Species: ptrend=0.64). No case–control differences were apparent for beta diversity (pMiRKAT=0.30). After accounting for multiple comparisons, a greater abundance of Spirochaetia (ORlow 1.00 (reference), ORmedium 0.61 (95% CI 0.32 to 1.18), ORhigh 0.42 (95% CI 0.21 to 0.85)) and Bacteroidetes (ORlow 1.00 (reference), ORmedium 0.66 (95% CI 0.35 to 1.25), ORhigh 0.31 (95% CI 0.15 to 0.64)) was associated with a decreased risk of lung cancer, while a greater abundance of the Bacilli class (ORlow 1.00 (reference), ORmedium 1.49 (95% CI 0.73 to 3.08), ORhigh 2.40 (95% CI 1.18 to 4.87)) and Lactobacillales order (ORlow 1.00 (reference), ORmedium 2.15 (95% CI 1.03 to 4.47), ORhigh 3.26 (95% CI 1.58 to 6.70)) was associated with an increased risk of lung cancer.ConclusionsOur prospective study of never-smokers suggests that lower alpha diversity was associated with a greater risk of lung cancer and the abundance of certain specific taxa was associated with altered risk, providing further insight into the aetiology of lung cancer in the absence of active tobacco smoking.

Transcriptome-wide association studies (TWAS) have successfully discovered many putative disease susceptibility genes. However, TWAS may suffer from inaccuracy of gene expression predictions due to inclusion of non-regulatory variants. By integrating prior knowledge of susceptible transcription factor occupied elements, we develop sTF-TWAS and demonstrate that it outperforms existing TWAS approaches in both simulation and real data analyses. Under the sTF-TWAS framework, we build genetic models to predict alternative splicing and gene expression in normal breast, prostate and lung tissues from the Genotype-Tissue Expression project and apply these models to data from large genome-wide association studies (GWAS) conducted among European-ancestry populations. At Bonferroni-corrected P  < 0.05, we identify 354 putative susceptibility genes for these cancers, including 189 previously unreported in GWAS loci and 45 in loci unreported by GWAS. These findings provide additional insight into the genetic susceptibility of human cancers. Additionally, we show the generalizability of the sTF-TWAS on non-cancer diseases. Transcriptome-wide association studies can uncover genes involved in disease. Here, the authors extend the framework with a transcriptome-wide association study approach which incorporates transcription factor occupancy, adding tissue-specific mechanistic support to associations.

Gut microbial stability typically decreases with physiological aging. This decline may vary between sexes and can potentially be mitigated by adopting a healthy lifestyle. Microbial guilds, defined as functionally coherent groups of bacteria, may serve as meaningful ecological indicators of aging. This study included 2944 participants aged 51–89 years from the Shanghai Men's and Women's Health Studies. Using 16S rRNA gene sequencing and a guild‐based approach, we evaluated the associations between gut microbiota and age in 1353 relatively healthy individuals. We found that women demonstrated a decline in the Chao1 index, an increase in Pielou evenness, and a remarkable shift in Bray–Curtis distance, whereas men exhibited an increase in Bray–Curtis uniqueness. Of the 45 age‐related guilds identified, 16 (8 in men and 10 in women) were considered potential aging biomarkers (pFDR < 0.05), with Guild_6 (Bifidobacterium sp. dominated) and Guild_118 (Veillonella dispar dominated) being common to both sexes. These guilds were associated with consistent predicted functions, particularly 1,4‐dihydroxy‐2‐naphthoate biosynthesis. We estimated sex‐specific microbial age using random forest models and found that women and individuals with major chronic diseases had higher microbial ages. Prospective analysis revealed that an “old” microbial age was associated with a higher risk of type 2 diabetes (HR = 2.0, 95% CI: 1.1, 3.7). Individuals with healthier lifestyles had a 0.43‐year lower microbial age (95% CI: −0.85, −0.01). Our findings elucidate the sex‐differentiated aging patterns of gut microbiota in Chinese adults and imply the potential benefits of healthy lifestyle behaviors in slowing down microbiome aging. This study employed a guild‐based approach to identify sex‐specific age‐related gut microbiota in two large cohorts of Chinese adults. The microbial age, derived from the significant guilds identified, was higher in women and less healthy individuals, was associated with an increased risk of type 2 diabetes, and could be slowed by healthy lifestyles. These findings highlight the role of multiple major noncommunicable diseases in accelerating aging and underscore the importance of a healthy lifestyle in promoting healthy aging.

Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility. The identification of transcription factors (TFs) whose binding sites are affected by risk genetic variants remains crucial. Here, the authors develop a statistical framework to analyse ChIP-seq and GWAS data, identify 22 breast cancer risk-associated TFs and a core TF-transcriptional network for FOXA1 and co-factors.

Purpose Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk. Methods We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk. Results No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV] , Peptostreptococcaceae_[XI] , and Erysipelotrichaceae and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59–0.98), 0.80 (0.66–0.97), 0.81 (0.67–0.99), and 0.83 (0.71–0.98), respectively (all p  < 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus Bacteroidetes_[G-5] and species Alloprevotella sp._oral_taxon_912 , Capnocytophaga sputigena , Lactococcus lactis , Peptoniphilaceae_[G-1] sp._oral_taxon_113 , Leptotrichia sp._oral_taxon_225 , and Fretibacterium fastidiosum was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30–1.00), 0.36 (0.17–0.73), 0.53 (0.31–0.92), 0.43 (0.21–0.88), 0.43 (0.19–0.94), 0.57 (0.34–0.99), and 0.54 (0.31–0.94), respectively (all p  < 0.05). Species L. sp._oral_taxon_225 was significantly associated with decreased lung cancer risk in African Americans (OR [95% CIs] 0.28 [0.12–0.66]; p  = 0.00012). Conclusion Results from this study suggest that oral microbiota may play a role in the development of lung cancer.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic disease worldwide. The prevalence of T2DM is increasing rapidly in China. Understanding the contribution of modifiable lifestyle factors on T2DM risk is imperative to prevent the development of T2DM in China. We examined associations between lifestyle factors including physical activity, smoking and alcohol consumption with incidence of T2DM among middle-aged and elderly men in urban Shanghai. Information on socio-demographics, lifestyle habits, dietary habits, and disease history was collected via in-person interviews. Anthropometric measurements were taken. A total of 51 464 Chinese men aged 40-74 years free of T2DM, coronary heart disease (CHD), and stroke at baseline were included in the current study. Incident T2DM was identified through follow-up surveys conducted every 2-3 years. Cox proportional hazard analyses were conducted to evaluate associations between lifestyle risk factors and incidence of T2DM. We documented 1304 new cases of T2DM during 276 929 person-years of follow-up (average: 5.4 years). Physical activity was inversely associated with T2DM risk. Daily living, commuting, and total physical activity METs had inverse negative dose-response relationships with T2DM (P-trend = 0.0033, 0.0022, and <0.0001, respectively). Regular participation in exercise or sports reduced T2DM risk (HR = 0.86, 95%CI: 0.76-0.98). Moderate alcohol intake (1-3 drinks/day) was inversely related to T2DM risk (HR = 0.80, 95%CI: 0.67-0.94). Cigarette smoking, on the other hand, was associated with increased T2DM risk; HRs were 1.25 (95%CI: 1.00-1.56) for smoking more than 20 cigarettes per day and 1.28 (95%CI: 1.04-1.57) for smoking more than 40 pack-years. Physical activity and moderate alcohol intake are inversely associated with T2DM risk, whereas smoking was positively associated with T2DM risk among middle-age and elderly Chinese men. Preventive measures should be developed to focus on these modifiable lifestyle habits to reduce the upward trend of T2DM.

To evaluate associations of premature ovarian failure (POF) with mortality and morbidity in Asian populations. We identified 1,003 cases of POF among 36,402 postmenopausal women who participated in the Shanghai Women's Health Study, a population-based cohort study. Cox regression and logistic regression models were applied in data analysis. After adjustment for potential confounding factors, we found that POF increased the risk of total and cancer-specific mortality (HR (95%CIs): 1.29 (1.08-1.54) and 1.38 (1.05-1.81), respectively). POF was also associated with high prevalence of autoimmune disease (OR (95%CI): 1.56 (1.04-2.35)) but decreased incidence of breast cancer (OR (95%CI): 0.59 (0.38-0.91)). Similar results were observed when hormone replacement therapy users were excluded from the analysis. POF is associated with high waist-to-hip ratio. Our results suggest that women with POF experience increased mortality and that these women may benefit from heightened surveillance and appropriate interventions.

Purpose To prospectively investigate accelerated aging and its association with total mortality and breast cancer-specific mortality/recurrence among breast cancer survivors. Methods This study included 4218 female breast cancer patients enrolled into a population-based cohort study approximately 6-month post-diagnosis. Information on aging-related symptoms (i.e., self-rated overall health condition, energy level, depression, sleep difficulty, and quality) was collected at 18- and 36-month post-diagnosis surveys. Information on overall health, daily function impairments, survival status, and recurrence was collected at 10-year post-diagnosis survey. Record linkages with vital statistics were conducted to collect mortality information. Cox proportional hazards model was applied. Results Among 3041 10-year survivors with a mean age of 63.7 ± 9.7 years, respectively, 52.3%, 19.0%, and 27.6% reported poor health, limitation in daily activity, and climbing floors. Age-specific prevalence revealed that breast cancer survivors reached similar prevalence of the functional limitations 5–10 years earlier than cancer-free women. At the 18-month post-diagnosis survey, respectively, 47.0%, 72.5%, and 25.1% of survivors reported unsatisfied overall health condition, reduced energy level, and depression symptoms. After a median follow-up of 10.9 years, low self-rated overall health, low energy level, and depression were significantly associated with increased total mortality, with hazard ratios (HRs; 95% confidence intervals [CI]) of 3.14 (2.43, 4.06), 1.49 (1.20, 1.84), and 1.59 (1.21, 2.09), respectively. Low self-rated health was associated with breast cancer-specific mortality/recurrence (HR  1.85, 95% CI 1.30, 2.65). No significant association was found for sleep difficulty and quality. Conclusion Aging-related physical changes/symptoms are commonly presented at 18 months after breast cancer diagnosis and are associated with worse prognosis. Impact Our findings highlight the concern of accelerated aging among breast cancer survivors.

Obesity is known to be a major risk factor for diabetes, but the magnitude of risk and variation between blacks and whites are less well documented in populations heavily affected by obesity. Herein we assess rates and risks of incident diabetes in a diverse southern population where obesity is common. A total of 24,000 black and 14,064 white adults aged 40-79 in the Southern Community Cohort Study with no self-reported diabetes at study enrollment during 2002-2009 was followed for up to 10 (median 4.5) years. Incidence rates, odds ratios (OR) and accompanying 95% confidence intervals (CI) for medication-treated incident diabetes were determined according to body mass index (BMI) and other characteristics, including tobacco and alcohol consumption, healthy eating and physical activity indices, and socioeconomic status (SES). Risk of incident diabetes rose monotonically with increasing BMI, but the trends differed between blacks and whites (pinteraction < .0001). Adjusted ORs (CIs) for diabetes among those with BMI≥40 vs 20-25 kg/m2 were 11.9 (8.4-16.8) for whites and 4.0 (3.3-4.8) for blacks. Diabetes incidence was more than twice as high among blacks than whites of normal BMI, but the racial difference became attenuated as BMI rose, with estimated 5-year probabilities of developing diabetes approaching 20% for both blacks and whites with BMI≥40 kg/m2. Diabetes risk was also associated with low SES, significantly (pinteraction≤.02) more so for whites, current cigarette smoking, and lower healthy eating and physical activity indices, although high BMI remained the predominant risk factor among both blacks and whites. From baseline prevalence and 20-year projections of the incidence trends, we estimate that the large majority of surviving cohort participants with BMI≥40 kg/m2 will be diagnosed with diabetes. Even using conservative criteria to ascertain diabetes incidence (i.e., requiring diabetes medication use and ignoring undiagnosed cases), rates of obesity-associated diabetes were exceptionally high in this low-income adult population. The findings indicate that effective strategies to halt the rising prevalence of obesity are needed to avoid substantial increases in diabetes in coming years.

Background Large social networks have been associated with better overall survival after a breast cancer diagnosis in some but not all study populations. This study evaluated associations of social support and religiosity/spirituality with survival among Black and White women with breast cancer of largely low socioeconomic status in the United States (US). Methods The study used data from the prospective Southern Community Cohort Study, which enrolled approximately 86,000 adults in the southeastern US during 2002–2009. A total of 1,347 Black and White women with incident breast cancer were identified in the cohort and followed through December 2020 for mortality via linkage with the National Death Index. Exposures of interest were social support and religiosity obtained via baseline questionnaire, including number of close friends/relatives who can provide instrumental and emotional support, and frequency of attendance at religious services. Multivariable Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality in association with social support and religiosity. The models were tested for proportional hazards assumption using Schoenfeld residuals. Results Among the 1,347 women with breast cancer, 365 (27.1%) died during follow up. The participants were followed up for 17 years with a median follow-up time of 5 years. In all-cause mortality analyses, women who reported having 2 + relatives/friends for emotional support had a 20% reduced hazard of death compared to women with ≤  1 relative/friend (HR = 0.80, 95% CI: 0.67–0.96) after adjusting for age at breast cancer diagnosis, race, time from cohort enrollment to diagnosis, income, education, marital status, insurance, and tumor hormone receptor status. Similarly, women reporting having 2 + people able to provide instrumental support (render assistance in an emergency or lend money) had a 25% (HR = 0.75, 95% CI: 0.59–0.95) reduced hazard of death compared to those who had  ≤  1. Frequent attendance at religious services/meetings was associated with reduced hazard of death compared to those who did not attend (HR = 0.60, CI: 0.41–0.89); addition of cancer stage in the models attenuated this association. Conclusions A large social support network and regular attendance at faith-based services were associated with better survival among women with breast cancer. This calls for incorporating appropriate interventions to cancer care such as social support groups to improve survival.