GammaGateR: semi-automated marker gating for single-cell multiplexed imaging.

MOTIVATION: Multiplexed immunofluorescence (mIF) is an emerging assay for multichannel protein imaging that can decipher cell-level spatial features in tissues. However, existing automated cell phenotyping methods, such as clustering, face challenges in achieving consistency across experiments and often require subjective evaluation. As a result, mIF analyses often revert to marker gating based on manual thresholding of raw imaging data. RESULTS: To address the need for an evaluable semi-automated algorithm, we developed GammaGateR, an R package for interactive marker gating designed specifically for segmented cell-level data from mIF images. Based on a novel closed-form gamma mixture model, GammaGateR provides estimates of marker-positive cell proportions and soft clustering of marker-positive cells. The model incorporates user-specified constraints that provide a consistent but slide-specific model fit. We compared GammaGateR against the newest unsupervised approach for annotating mIF data, employing two colon datasets and one ovarian cancer dataset for the evaluation. We showed that GammaGateR produces highly similar results to a silver standard established through manual annotation. Furthermore, we demonstrated its effectiveness in identifying biological signals, achieved by mapping known spatial interactions between CD68 and MUC5AC cells in the colon and by accurately predicting survival in ovarian cancer patients using the phenotype probabilities as input for machine learning methods. GammaGateR is a highly efficient tool that can improve the replicability of marker gating results, while reducing the time of manual segmentation. AVAILABILITY AND IMPLEMENTATION: The R package is available at https://github.com/JiangmeiRubyXiong/GammaGateR.

Associations of neighborhood sociodemographic environment with mortality and circulating metabolites among low-income black and white adults living in the southeastern United States.

BACKGROUND: Residing in a disadvantaged neighborhood has been linked to increased mortality. However, the impact of residential segregation and social vulnerability on cause-specific mortality is understudied. Additionally, the circulating metabolic correlates of neighborhood sociodemographic environment remain unexplored. Therefore, we examined multiple neighborhood sociodemographic metrics, i.e., neighborhood deprivation index (NDI), residential segregation index (RSI), and social vulnerability index (SVI), with all-cause and cardiovascular disease (CVD) and cancer-specific mortality and circulating metabolites in the Southern Community Cohort Study (SCCS). METHODS: The SCCS is a prospective cohort of primarily low-income adults aged 40-79, enrolled from the southeastern United States during 2002-2009. This analysis included self-reported Black/African American or non-Hispanic White participants and excluded those who died or were lost to follow-up ≤ 1 year. Untargeted metabolite profiling was performed using baseline plasma samples in a subset of SCCS participants. RESULTS: Among 79,631 participants, 23,356 deaths (7214 from CVD and 5394 from cancer) were documented over a median 15-year follow-up. Higher NDI, RSI, and SVI were associated with increased all-cause, CVD, and cancer mortality, independent of standard clinical and sociodemographic risk factors and consistent between racial groups (standardized HRs among all participants were 1.07 to 1.20 in age/sex/race-adjusted model and 1.04 to 1.08 after comprehensive adjustment; all P < 0.05/3 except for cancer mortality after comprehensive adjustment). The standard risk factors explained < 40% of the variations in NDI/RSI/SVI and mediated < 70% of their associations with mortality. Among 1110 circulating metabolites measured in 1688 participants, 134 and 27 metabolites were associated with NDI and RSI (all FDR < 0.05) and mediated 61.7% and 21.2% of the NDI/RSI-mortality association, respectively. Adding those metabolites to standard risk factors increased the mediation proportion from 38.4 to 87.9% and 25.8 to 42.6% for the NDI/RSI-mortality association, respectively. CONCLUSIONS: Among low-income Black/African American adults and non-Hispanic White adults living in the southeastern United States, a disadvantaged neighborhood sociodemographic environment was associated with increased all-cause and CVD and cancer-specific mortality beyond standard risk factors. Circulating metabolites may unveil biological pathways underlying the health effect of neighborhood sociodemographic environment. More public health efforts should be devoted to reducing neighborhood environment-related health disparities, especially for low-income individuals.

The association between neighborhood obesogenic factors and prostate cancer risk and mortality: the Southern Community Cohort Study.

Background: Prostate cancer is one of the leading causes of cancer-related mortality among men in the United States. We examined the role of neighborhood obesogenic attributes on prostate cancer risk and mortality in the Southern Community Cohort Study (SCCS). Methods: From the total of 34,166 SCCS male participants, 28,356 were included in the analysis. We assessed the relationship between neighborhood obesogenic factors [neighborhood socioeconomic status (nSES) and neighborhood obesogenic environment indices including the restaurant environment index, the retail food environment index, parks, recreational facilities, and businesses] and prostate cancer risk and mortality by controlling for individual-level factors using a multivariable Cox proportional hazards model. We further stratified prostate cancer risk analysis by race and body mass index (BMI). Results: Median follow-up time was 133 months [interquartile range (IQR): 103, 152], and the mean age was 51.62 (SD: ± 8.42) years. There were 1,524 (5.37%) prostate cancer diagnoses and 98 (6.43%) prostate cancer deaths during follow-up. Compared to participants residing in the wealthiest quintile, those residing in the poorest quintile had a higher risk of prostate cancer (aHR = 1.32, 95% CI 1.12-1.57, p = 0.001), particularly among non-obese men with a BMI < 30 (aHR = 1.46, 95% CI 1.07-1.98, p = 0.016). The restaurant environment index was associated with a higher prostate cancer risk in overweight (BMI ≥ 25) White men (aHR = 3.37, 95% CI 1.04-10.94, p = 0.043, quintile 1 vs. None). Obese Black individuals without any neighborhood recreational facilities had a 42% higher risk (aHR = 1.42, 95% CI 1.04-1.94, p = 0.026) compared to those with any access. Compared to residents in the wealthiest quintile and most walkable area, those residing within the poorest quintile (aHR = 3.43, 95% CI 1.54-7.64, p = 0.003) or the least walkable area (aHR = 3.45, 95% CI 1.22-9.78, p = 0.020) had a higher risk of prostate cancer death. Conclusion: Living in a lower-nSES area was associated with a higher prostate cancer risk, particularly among Black men. Restaurant and retail food environment indices were also associated with a higher prostate cancer risk, with stronger associations within overweight White individuals. Finally, residing in a low-SES neighborhood or the least walkable areas were associated with a higher risk of prostate cancer mortality.

The association between neighborhood obesogenic factors and prostate cancer risk and mortality: the Southern Community Cohort Study.

Background: Prostate cancer is one of the leading causes of cancer-related mortality among men in the United States. We examined the role of neighborhood obesogenic attributes on prostate cancer risk and mortality in the Southern Community Cohort Study (SCCS). Methods: From the total of 34,166 SCCS male participants, 28,356 were included in the analysis. We assessed the relationship between neighborhood obesogenic factors [neighborhood socioeconomic status (nSES) and neighborhood obesogenic environment indices including the restaurant environment index, the retail food environment index, parks, recreational facilities, and businesses] and prostate cancer risk and mortality by controlling for individual-level factors using a multivariable Cox proportional hazards model. We further stratified prostate cancer risk analysis by race and body mass index (BMI). Results: Median follow-up time was 133 months [interquartile range (IQR): 103, 152], and the mean age was 51.62 (SD: ± 8.42) years. There were 1,524 (5.37%) prostate cancer diagnoses and 98 (6.43%) prostate cancer deaths during follow-up. Compared to participants residing in the wealthiest quintile, those residing in the poorest quintile had a higher risk of prostate cancer (aHR = 1.32, 95% CI 1.12-1.57, p = 0.001), particularly among non-obese men with a BMI < 30 (aHR = 1.46, 95% CI 1.07-1.98, p = 0.016). The restaurant environment index was associated with a higher prostate cancer risk in overweight (BMI ≥ 25) White men (aHR = 3.37, 95% CI 1.04-10.94, p = 0.043, quintile 1 vs. None). Obese Black individuals without any neighborhood recreational facilities had a 42% higher risk (aHR = 1.42, 95% CI 1.04-1.94, p = 0.026) compared to those with any access. Compared to residents in the wealthiest quintile and most walkable area, those residing within the poorest quintile (aHR = 3.43, 95% CI 1.54-7.64, p = 0.003) or the least walkable area (aHR = 3.45, 95% CI 1.22-9.78, p = 0.020) had a higher risk of prostate cancer death. Conclusion: Living in a lower-nSES area was associated with a higher prostate cancer risk, particularly among Black men. Restaurant and retail food environment indices were also associated with a higher prostate cancer risk, with stronger associations within overweight White individuals. Finally, residing in a low-SES neighborhood or the least walkable areas were associated with a higher risk of prostate cancer mortality.

The Hallmarks of Precancer.

Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.

Impacts of Poverty and Lifestyles on Mortality: A Cohort Study in Predominantly Low-Income Americans.

INTRODUCTION: Low socioeconomic status has been linked to increased mortality. However, the impacts of poverty, alone or combined with health behaviors, on mortality and life expectancy have not been adequately investigated. METHODS: Data from the Southern Community Cohort Study was used, including nearly 86,000 participants recruited during 2002-2009 across 12 US southeastern states. Analysis was conducted from February 2022 to January 2023. RESULTS: During a median follow-up of 12.1 years, 19,749 deaths were identified. A strong dose-response relationship was found between household incomes and mortality, with a 3.3-fold (95%CI=3.1-3.6) increased all-cause mortality observed for individuals in the lowest income group (<$15,000/year) compared with those in the highest group (≥$50,000/year). Within each income group, mortality monotonically increased with declining healthy lifestyle score. Risk was significantly lower among those in the lowest income but healthiest lifestyle group, compared to those with the highest income but unhealthiest lifestyle (HR=0.82, 95%CI=0.69-0.97). Poor White participants appeared to experience higher all-cause mortality than poor Black participants. Life expectancy was more than 10.0 years shorter for those in the lowest income group compared with those in the highest income group. CONCLUSIONS: Poverty is strongly associated with increased risk of death, but the risks could be modestly abated by a healthier lifestyle. These findings call for a comprehensive strategy for enhancing a healthy lifestyle and improving income equality to reduce death risks, particularly among those experiencing health disparities due to poverty.

Gut microbiome in association with chemotherapy-induced toxicities among patients with breast cancer.

BACKGROUND: Little research has focused on the relationship between gut microbiome and chemotherapy-induced toxicity. METHODS: This prospective study involves 301 patients with breast cancer who had prechemotherapy stool samples collected. Gut microbiome was sequenced by shotgun metagenomics; associations with chemotherapy-induced toxicities during first-line treatment by gut microbial diversity, composition, and metabolic pathways with severe (i.e., grade ≥3) hematological and gastrointestinal toxicities were evaluated via multivariable logistic regression. RESULTS: High prechemotherapy α-diversity was associated with a significantly reduced risk of both severe hematological toxicity (odds ratio [OR] = 0.94; 95% CI, 0.89-0.99; p = .048) and neutropenia (OR = 0.94; 95% CI, 0.89-0.99; p = .016). A high abundance of phylum Synergistota, class Synergistia, and order Synergistales were significantly associated with a reduced risk of severe neutropenia; conversely, enrichment of phylum Firmicutes C, class Negativicutes, phylum Firmicutes I, and class Bacilli A, order Paenibacillales were significantly associated with an increased risk of severe neutropenia (p range: 0.012-2.32 × 10-3; false discovery rate <0.1). Significant positive associations were also observed between severe nausea/vomiting and high Chao1 indexes, ß-diversity (p < .05), 20 species belonging to the family Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae (p value range: 6.14 × 10-3 to 1.33 × 10-5; false discovery rate <0.1), and three metabolic pathways involved in reductive tricarboxylic acid cycle I and cycle II, and an incomplete reductive tricarboxylic acid cycle (p < .01). Conversely, a high abundance of species Odoribacter laneus and the pathway related to the L-proline biosynthesis II were inversely associated with severe nausea/vomiting. CONCLUSIONS: Our study suggests that gut microbiota may be a potential preventive target to reduce chemotherapy-induced toxicity.

BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

Gut Microbiome of Patients With Breast Cancer in Vietnam.

PURPOSE: Gut microbiota play an important role in human health, including cancer. Cancer and its treatment, in turn, may alter the gut microbiome. To understand this complex relationship, we profiled the gut microbiome of 356 Vietnamese patients with breast cancer. MATERIALS AND METHODS: Stool samples were collected before chemotherapy, with 162 pre- and 194 postsurgery. The gut microbiome was measured by shotgun metagenomic sequencing. Associations of gut microbial diversity, taxa abundance, and gut microbiome health index (GMHI) with sociodemographic, clinical factors, and tumor characteristics were evaluated. RESULTS: Postsurgery samples were associated with significantly lower α- and ß-diversities (P < .001) and showed significant differences in the abundance of 15% of 2,864 investigated taxa (false discovery rate [FDR] <0.1) compared with presurgery samples. An unhealthy gut microbiome was prevalent among patients with breast cancer, with a mean GMHI of -0.79 and -2.81 in pre- and postsurgery stool samples, respectively. In an analysis of 162 presurgery stool samples, diagnosis delay was significantly associated with lower α-diversity, variation in ß-diversity, an increased abundance of species Enorma massiliensis, and a decreased abundance of Faecalicoccus pleomorphus. High intake of fiber was significantly associated with lower α-diversity and a higher abundance of species belonging to Bifidobacterium, Prevotella, and Bacteroides gena (FDR < 0.1). We did not find that cancer stage and subtype, menopausal status, comorbidity, antibiotic use during 3 months before stool collection, or physical activity was significantly associated with α- and ß-diversities or GMHI although a few significant differences were observed in taxa abundance. CONCLUSION: Our study revealed that diagnosis delay, high fiber intake, and breast cancer surgery, which is always followed by antibiotic prophylaxis in Vietnam, led to a less diverse and unhealthy gut microbiome among patients with breast cancer.

Dietary medium-chain fatty acids and risk of incident colorectal cancer in a predominantly low-income population: a report from the Southern Community Cohort Study.

BACKGROUND: No prospective observational study has specifically examined the associations between dietary intakes of medium-chain fatty acids and risk of colorectal cancer. OBJECTIVES: This study examined the association between dietary intakes of medium-chain fatty acids and colorectal cancer risk overall and by racial subgroups in a predominantly low-income United States population. METHODS: This prospective study included 71,599 eligible participants aged 40 to 79 who were enrolled in the Southern Community Cohort Study between 2002 and 2009 in 12 southeastern United States states. Incident colorectal cancer cases were ascertained via linkage to state cancer registries, which was completed through 31 December, 2016. The dietary intakes of medium-chain fatty acids were assessed using a validated 89-item food frequency questionnaire. Multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between intakes of medium-chain fatty acids and risk for incident colorectal cancer. RESULTS: Among 71,599 participants, 48,008 (67.3%) were Black individuals and 42,260 (59.0%) were female. A total of 868 incident colorectal cancer cases occurred during a median follow-up of 13.7 y. Comparing the highest to the lowest quartile, high intake of dodecanoic acid/lauric acid (C12:0) was associated with reduced risk of colorectal cancer among White participants (HR: 0.52; 95% CI: 0.30, 0.91; P-trend = 0.05), but not in Black individuals (HR: 0.92; 95% CI, 0.68, 1.24; P-trend = 0.80) in multivariable-adjusted models. No associations were found between intakes of hexanoic acid/caproic acid (C6:0), octanoic acid/caprylic acid (C8:0), or decanoic acid/capric acid (C10:0) and risk of incident colorectal cancer overall or within racial subgroups. CONCLUSIONS: In a predominantly low-income United States population, an increased dietary C12:0 intake was associated with a substantially reduced risk of colorectal cancer only among White individuals, but not in Black individuals.

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.

GammaGateR: semi-automated marker gating for single-cell multiplexed imaging.

Motivation: Multiplexed immunofluorescence (mIF) is an emerging assay for multichannel protein imaging that can decipher cell-level spatial features in tissues. However, existing automated cell phenotyping methods, such as clustering, face challenges in achieving consistency across experiments and often require subjective evaluation. As a result, mIF analyses often revert to marker gating based on manual thresholding of raw imaging data. Results: To address the need for an evaluable semi-automated algorithm, we developed GammaGateR, an R package for interactive marker gating designed specifically for segmented cell-level data from mIF images. Based on a novel closed-form gamma mixture model, GammaGateR provides estimates of marker-positive cell proportions and soft clustering of marker-positive cells. The model incorporates user-specified constraints that provide a consistent but slide-specific model fit. We compared GammaGateR against the newest unsupervised approach for annotating mIF data, employing two colon datasets and one ovarian cancer dataset for the evaluation. We showed that GammaGateR produces highly similar results to a silver standard established through manual annotation. Furthermore, we demonstrated its effectiveness in identifying biological signals, achieved by mapping known spatial interactions between CD68 and MUC5AC cells in the colon and by accurately predicting survival in ovarian cancer patients using the phenotype probabilities as input for machine learning methods. GammaGateR is a highly efficient tool that can improve the replicability of marker gating results, while reducing the time of manual segmentation. Availability and Implementation: The R package is available at https://github.com/JiangmeiRubyXiong/GammaGateR.

Dietary Inflammatory Potential and the Risk of Serrated and Adenomatous Colorectal Polyps.

Studies of dietary inflammation potential and risks of colorectal cancer precursors are limited, particularly for sessile serrated lesions (SSLs). This study examines the association using the energy-adjusted dietary inflammatory index (E-DIITM), a measure of anti- and/or pro-inflammatory diet, in a large US colonoscopy-based case-control study of 3246 controls, 1530 adenoma cases, 472 hyperplastic polyp cases, and 180 SSL cases. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models. Analyses were stratified by participant characteristics, and urinary prostaglandin E2 metabolite (PGE-M) and high-sensitivity plasma C-reactive protein (hs-CRP) levels, inflammation biomarkers. Highest E-DII™ intake was associated with significantly increased risks of colorectal adenomas (OR 1.36, 95% CI 1.11, 1.67), and hyperplastic polyps (OR 1.43, 95% CI 1.06, 1.98), compared with participants consuming the lowest E-DII™ quartile. A similar, but non-significant, increased risk was also observed for SSLs (OR 1.41, 95% CI 0.82, 2.41). The positive association was stronger in females (pinteraction <0.001), normal weight individuals (ptrend 0.01), and in individuals with lower inflammatory biomarkers (ptrend 0.02 and 0.01 for PGE-M and hs-CRP, respectively). A high E-DII™ is associated with colorectal polyp risk, therefore promoting an anti-inflammatory diet may aid in preventing colorectal polyps.

Associations of circulating saturated long-chain fatty acids with risk of mild cognitive impairment and Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

BACKGROUND: No study has examined the associations between peripheral saturated long-chain fatty acids (LCFAs) and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This study aimed to examine whether circulating saturated LCFAs are associated with both risks of incident MCI from cognitively normal (CN) participants and incident AD progressed from MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: We conducted analysis of data from older adults aged 55-90 years who were recruited at 63 sites across the USA and Canada. We examined associations between circulating saturated LCFAs (i.e., C14:0, C16:0, C18:0, C20:0) and risk for incident MCI in CN participants, and incident AD progressed from MCI. FINDINGS: 829 participants who were enrolled in ADNI-1 had data on plasma saturated LCFAs, of which 618 AD-free participants were included in our analysis (226 with normal cognition and 392 with MCI; 60.2% were men). Cox proportional-hazards models were used to account for time-to-event/censor with a 48-month follow-up period for the primary analysis. Other than C20:0, saturated LCFAs were associated with an increased risk for AD among participants with MCI at baseline (Hazard ratios (HRs) = 1.3 to 2.2, P = 0.0005 to 0.003 in fully-adjusted models). No association of C20:0 with risk of AD among participants with MCI was observed. No associations were observed between saturated LCFAs and risk for MCI among participants with normal cognition. INTERPRETATION: Saturated LCFAs are associated with increased risk of progressing from MCI to AD. This finding holds the potential to facilitate precision prevention of AD among patients with MCI. FUNDING: National Institutes of Health.

Consumption of ultra-processed foods and all-cause and cause-specific mortality in the Southern Community Cohort Study.

BACKGROUND & AIMS: Higher intake of ultra-processed foods (UPF) has been linked with higher risks of cancer, cardiovascular disease, and diabetes, as well as all-cause mortality. However, studies on UPF and cause-specific mortality remain limited, especially among disadvantaged populations. We aimed to examine associations of UPF intake with all-cause and cause-specific mortality among low-income Americans. METHODS: In the Southern Community Cohort Study (SCCS), a prospective cohort of mostly low-income Black and White Americans, we included 77,060 participants who completed a food frequency questionnaire (FFQ) at baseline (2002-2009) and had at least 1 year follow-up. All 89 items in the FFQ were categorized using the Nova classification. UPF intake was calculated as % of daily foods intake by weight (grams). Cox regression was used to estimate HR (95% CI) for the association of UPF intake (quartile or per 10% increase) with total and cause-specific mortality (cancer, coronary heart disease [CHD], stroke, and diabetes) after adjusting for sociodemographics, lifestyles, and disease history. RESULTS: Of 77,060 participants, 46,175 (59.9%) were women, 49,857 were Black (64.7%), and mean age was 52.4 (SD: 8.8) years at baseline. The mean intake of UPF was 41.0% (SD: 15.7%). UPF intake was inversely associated with Healthy Eating Index and intakes of fiber, minerals, and vitamins but positively associated with intakes of sugars and fats (all PFDR<0.0001). During an average follow-up of 12.2 years, we documented 17,895 total deaths, including 4267 from cancer, 2208 from CHD, 867 from stroke, and 997 from diabetes. In the fully adjusted model, higher UPF intake was not associated with all-cause, cancer, CHD, or stroke mortality but showed a significant association with increased diabetes mortality (HR [95% CI] = 1.32 [1.07, 1.62] for the highest versus lowest quartiles [>51.1% vs. <29.3%] and 1.09 [1.04, 1.15] per 10% increase). The adverse UPF-diabetes mortality association was noted regardless of sex, race, income, neighborhood deprivation, lifestyles, and cardiometabolic disease history, while particularly evident in participants with no more than high school education or a history of hypercholesterolemia (HR [95% CI] per 10% increase = 1.12 [1.05, 1.18] and 1.14 [1.07, 1.22], respectively; both Pinteraction<0.05). CONCLUSIONS: Among predominantly low-income Black and White American adults, UPF intake was associated with increased diabetes mortality, especially for individuals with limited education or hypercholesterolemia. Our findings suggest the potential impact of increasing access and intake of un/minimally processed food to replace UPF on reducing diabetes-related mortality among populations facing socioeconomic and health disparities.

Diet quality and lung cancer incidence in a low-income population in the United States.

BACKGROUND: Although tobacco smoking is the leading cause of lung cancer, interest in the relationship of diet quality on risk has been growing. METHODS: We examined the association between Healthy Eating Index-2010 (HEI-10) at enrollment and lung cancer incidence among 70,802 participants in a predominantly African American and low-income prospective cohort in the southern United States. Outcomes were ascertained through linkages with state cancer registries and the National Death Index (NDI). Hazard ratios by HEI-10 quartiles were assessed using Cox proportional hazard models adjusted for potential confounders. RESULTS: During ≤16 years of follow-up, 1454 incident lung cancers were identified. The lowest HEI-10 quartile compared to the highest was adversely associated with lung cancer risk (HR: 1.89, 95% CI 1.16-3.07) among male former smokers and female never smokers (HR: 2.58, 95% CI 1.06-6.28). CONCLUSIONS: Low-quality diet was associated with increased lung cancer risk among male former smokers and female never smokers but cautious interpretation of the findings should be taken due to the small number of lung cancers among never smokers and the possibility of residual confounding by smoking in ever smokers.

Association between Sleep Duration and Colorectal Adenomas: Findings from a Case-Control Study in Vietnam.

BACKGROUND: Colorectal cancer is one of the leading cancers worldwide and in Vietnam. Adenomas are important precursors of colorectal cancer. Study on the association between sleep duration and development of colorectal adenoma (CRA) is limited, particularly among Vietnamese population. METHODS: We conducted an individually matched case-control study of 870 CRA cases and 870 controls in a large-scale colorectal screening program involving 103,542 individuals ages ≥40 years old in Hanoi, Vietnam. Sleep duration was categorized in three groups: short: ≤6 hours/day, normal: 7 to 8 hours/day, and long: >8 hours/day. Conditional logistic regression was used to evaluate the association between sleep duration and adenomas risk after controlling for potential confounders. RESULTS: Overall, short-sleep duration was associated with increased risk of having CRA compared with normal duration [OR, 1.48; 95% confidence interval (CI), 1.12-1.97]. This pattern was present in both females (OR, 1.58; 95% CI, 1.14-2.18) and males (OR, 1.45; 95% CI, 1.08-1.93), with advanced adenomas (OR, 1.61; 95% CI, 1.09-2.38) and non-advanced adenomas (OR, 1.66; 95% CI, 1.19-2.32). Furthermore, the association between CRA development and short-sleep duration was more apparent among females who were nondrinker, nonobese, physically active, with proximal or both sided adenomas and with cardiometabolic disorder. Among males, the short-sleep duration was associated with CRA risk among never-smoking, cardiometabolic disorders, and obese. CONCLUSIONS: Short-sleep duration was associated with increased prevalence of both advanced and non-advanced CRAs among Vietnamese population. IMPACT: Findings from this study showed that maintaining an adequate sleep duration may have an important implication for colorectal adenoma prevention and control.

Supplement use and gastric cancer risk in the Southern Community Cohort Study.

PURPOSE: Gastric cancer remains a racial health disparity in the US, but few studies have examined supplements as a potential protective factor. We examined associations between regular supplement use and gastric cancer risk among the predominantly Black participants in the Southern Community Cohort Study (SCCS). METHODS: Of the 84,508 individuals recruited in the SCCS from 2002 to 2009, 81,884 responded to the baseline question: any vitamin or supplement taken at least once per month in the past year. Secondary analyses assessed specific supplement use. Associations with incident gastric cancer were examined using adjusted Cox proportional hazards models, stratified by histologic subtype and secondarily by healthy eating index (HEI). RESULTS: Approximately half of the participants (47%, n = 38,318) reported any regular supplement use. Among the 203 incident gastric cancers over the follow-up period (median, 7 years), 142 were non-cardia (NCGC), 31 cardia (CGC), and 30 unknown. Regular supplement use was associated with a 30% decreased risk of NCGC (hazards ratio (HR) 0.70; 95% confidence interval (CI) 0.49-0.99). Among participants below the HEI median, any regular supplement and multivitamin use were associated with a 52% and 70% decrease in risk of NCGC (HR 0.48; 95%CI 0.25-0.92 and HR 0.30; 95%CI 0.13-0.71), respectively. No associations were found for CGC. CONCLUSION: Regular supplement use, including multivitamins, was associated with a decreased risk of NCGC in the SCCS, particularly among participants with a lower quality diet. Inverse associations of supplement use and NCGC incidence provide support for clinical trials among high-risk populations in the US.

Associations between traditional Chinese medicine body constitution and obesity risk among US adults.

Background: Traditional Chinese medicine (TCM) body constitution (BC), primarily determined by physiological and clinical characteristics, is an important process for clinical diagnosis and treatment and play a critical role in precision medicine in TCM. The purpose of the study was to explore whether the distributions of BC types differed by obesity status. Methods: We conducted a study to evaluate BC type in US population during 2012-2016. A total of 191 White participants from Personalized Prevention of Colorectal Cancer Trial (PPCCT) completed a self-administered Traditional Chinese Medicine Questionnaire (TCMQ, English version). In this study, we further compared the distribution of major types of TCM BC in the PPCCT to those Chinese populations stratified by obesity status. Results: We found the Blood-stasis frequency was higher in US White adults, 22.6% for individuals with BMI <30 and 11.2% for obese individuals, compared to 1.4% and 1.8%, respectively, in Chinese populations. We also found the percentages Inherited-special and Qi-stagnation were higher in US White adults than those in Chinese populations regardless of obesity status. However, the proportions of Yang-deficiency were higher in Chinese populations than those in our study conducted in US White adults regardless of obesity status. Conclusions: These new findings indicate the difference in distribution of BC types we observed between US and Chinese populations cannot be explained by the differences in prevalence of obesity. Further studies are needed to confirm our findings and understand the potential mechanism including genetic background and/or environmental factors.

Temporal recording of mammalian development and precancer.

Key to understanding many biological phenomena is knowing the temporal ordering of cellular events, which often require continuous direct observations [1, 2]. An alternative solution involves the utilization of irreversible genetic changes, such as naturally occurring mutations, to create indelible markers that enables retrospective temporal ordering [3-8]. Using NSC-seq, a newly designed and validated multi-purpose single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo , while incorporating assigned cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during murine embryonic development and identified new intestinal epithelial progenitor states by their unique genetic histories. NSC-seq analysis of murine adenomas and single-cell multi-omic profiling of human precancers as part of the Human Tumor Atlas Network (HTAN), including 116 scRNA-seq datasets and clonal analysis of 418 human polyps, demonstrated the occurrence of polyancestral initiation in 15-30% of colonic precancers, revealing their origins from multiple normal founders. Thus, our multimodal framework augments existing single-cell analyses and lays the foundation for in vivo multimodal recording, enabling the tracking of lineage and temporal events during development and tumorigenesis.