Oral Microbiome and Subsequent Risk of Head and Neck Squamous Cell Cancer.

Importance: The oral microbiota may be involved in development of head and neck squamous cell cancer (HNSCC), yet current evidence is largely limited to bacterial 16S amplicon sequencing or small retrospective case-control studies. Objective: To test whether oral bacterial and fungal microbiomes are associated with subsequent risk of HNSCC development. Design, Setting, and Participants: Prospective nested case-control study among participants providing oral samples in 3 epidemiological cohorts, the American Cancer Society Cancer Prevention Study II Nutrition Cohort, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and the Southern Community Cohort Study. Two hundred thirty-six patients who prospectively developed HNSCC were identified during a mean (SD) of 5.1 (3.6) years of follow-up. Control participants who remained HNSCC free were selected by 2:1 frequency matching on cohort, age, sex, race and ethnicity, and time since oral sample collection. Data analysis was conducted in 2023. Exposures: Characterization of the oral bacterial microbiome using whole-genome shotgun sequencing and the oral fungal microbiome using internal transcribed spacer sequencing. Association of bacterial and fungal taxa with HNSCC was assessed by analysis of compositions of microbiomes with bias correction. Association with red and orange oral pathogen complexes was tested by logistic regression. A microbial risk score for HNSCC risk was calculated from risk-associated microbiota. Main Outcomes and Measures: The primary outcome was HNSCC incidence. Results: The study included 236 HNSCC case participants with a mean (SD) age of 60.9 (9.5) years and 24.6% women during a mean of 5.1 (3.6) years of follow-up, and 485 matched control participants. Overall microbiome diversity at baseline was not related to subsequent HNSCC risk; however 13 oral bacterial species were found to be differentially associated with development of HNSCC. The species included the newly identified Prevotella salivae, Streptococcus sanguinis, and Leptotrichia species, as well as several species belonging to beta and gamma Proteobacteria. The red/orange periodontal pathogen complex was moderately associated with HNSCC risk (odds ratio, 1.06 per 1 SD; 95% CI, 1.00-1.12). A 1-SD increase in microbial risk score (created based on 22 bacteria) was associated with a 50% increase in HNSCC risk (multivariate odds ratio, 1.50; 95% CI, 1.21-1.85). No fungal taxa associated with HNSCC risk were identified. Conclusions and Relevance: This case-control study yielded compelling evidence that oral bacteria are a risk factor for HNSCC development. The identified bacteria and bacterial complexes hold promise, along with other risk factors, to identify high-risk individuals for personalized prevention of HNSCC.

Ultra-processed products and risk of liver cancer: A prospective cohort study.

BACKGROUND & AIMS: Several studies have shown positive associations between ultra-processed foods and drinks and cancer risk. However, evidence remains limited for liver cancer. We aimed to evaluate the associations between ultra-processed foods and drinks and liver cancer risk. METHODS: We included 73,119 participants (22,431 Whites, 47,837 Blacks, 2851 other race) from the Southern Community Cohort Study. Ultra-processed products were defined based on the Nova classification using data from a validated food frequency questionnaire and calculated as percentage of daily foods by weight. Incident liver cancer and vital status were ascertained via linkages to state cancer registries and the National Death Index as of December 31, 2019. RESULTS: With a median of 13.9 year's follow-up, we documented 453 incident liver cancer cases. Participants with higher intake of ultra-processed foods had an elevated risk of liver cancer (hazard ratios [HR] Tertile 3 vs. tertile 1 1.69, 95% confidence intervals [CI]: 1.28-2.22; Ptrend<0.001). The subclasses of ultra-processed foods, such as ultra-processed grains and fried potatoes (HR T3 vs. T1 1.29, 95% CI: 1.01-1.65; Ptrend = 0.03), processed protein foods (HR T3 vs. T1 1.49, 95% CI: 1.14-1.94; Ptrend = 0.007) and mixed dishes (HR T3 vs. T1 1.39, 95% CI: 1.09-1.77; Ptrend = 0.01), were positively associated with liver cancer risk. No significant association was found for ultra-processed drinks (HR T3 vs. T1 0.85, 95% CI: 0.67-1.07; Ptrend = 0.16). DISCUSSION: In a prospective cohort with predominantly low-income Southern US adults, we found certain ultra-processed foods were associated with a higher risk of liver cancer. Further studies are needed to confirm our findings.

Sitting Time, Physical Activity and Mortality: A Cohort Study In Low-Income Older Americans.

INTRODUCTION: Physical inactivity and sedentary behavior are recognized as independent risk factors for many diseases. However, studies investigating their associations with total and cause-specific mortality in low-income and Black populations are limited, particularly among older adults. METHODS: A prospective cohort study was conducted among 8,337 predominantly low-income and Black Americans aged ≥65 years residing in the southern United States. Participants reported their daily sitting time and leisure-time physical activity (LTPA) at baseline (2002-2009), and mortality data were collected through 2019. Analysis was conducted from September 2022 to October 2023. RESULTS: During a median follow-up of 12.25 years, nearly 50% (n=4,111) were deceased. A prolonged sitting time (>10 hours/day versus <4 hours/day) was associated with elevated all-cause mortality (hazard ratios [HR], 1.15; 95% confidence intervals [CI], 1.04-1.27) after adjusting for LTPA and other potential confounders. LTPA was associated with a reduced risk of all-cause mortality, with an adjusted HR of 0.75 (95% CI 0.64, 0.88) associated with 150-300 minutes per week of moderate-intensity physical activity. Individuals who were physically inactive and had a sitting time of >10 hours/day had the highest mortality risk (HR, 1.48; 95% CI, 1.23-1.78), compared with those who were physically active and had low sitting time. These associations were more pronounced for mortality due to cardiovascular diseases. CONCLUSIONS: High sitting time is an independent risk factor for all-cause and cardiovascular disease mortality, and LTPA could partially attenuate the adverse association of prolonged sitting time with mortality.

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.

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.

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.

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.

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.

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.

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.

Association of cardiometabolic comorbidities with mortality among low-income Black and White Americans.

METHODS: Investigated the association of multiple cardiometabolic comorbidities with total/major cause-specific mortality and evaluate if this association might be modified by race among predominantly low-income Black and White participants. METHODS: The Southern Community Cohort Study, prospective cohort study. Participants (40-79 years) recruited predominantly from community health centers across 12 states in southeastern United States. Enrollment began in 2002 and concluded in 2009, follow-up until 2020. Cardiometabolic comorbidities (diabetes, hypertension, myocardial infarction, stroke) ascertained at the baseline survey. Cox proportional hazard models used. RESULTS: Study included 76,721 participants; 16,197, 41,944, 5,247, and 4,919 participants with prior diagnosis of diabetes, hypertension, myocardial infarction, and stroke, respectively at baseline. Compared to individuals with no comorbidity, individuals with any single comorbidity experienced a significantly 30 to 90% increased rate of death due to any causes. The increase in mortality was elevated with an increasing number of comorbidities, with HR of 3.81 (95% CI: 3.26-4.46) and a cumulative risk of 62.5% at age 75 years for total mortality for those with four comorbidities. The risk was high for death due to cardiovascular diseases (HR: 6.18, 95% CI: 5.12-7.47). These associations were stronger among Blacks than Whites. Individuals with four comorbidities at age 40 years were estimated to have a 16-year loss in life expectancy compared with those without any comorbidity. CONCLUSION: Cardiometabolic comorbidities were associated with increases in all-cause and major cause-specific mortality, particularly Black Americans. This study calls for effective measures to prevent cardiometabolic comorbidities to reduce premature deaths in underserved Americans.

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.