Trends in Mortality From Poisonings, Firearms, and All Other Injuries by Intent in the US, 1999-2020.

Importance: Although deaths due to external causes are a leading cause of mortality in the US, trends over time by intent and demographic characteristics remain poorly understood. Objective: To examine national trends in mortality rates due to external causes from 1999 to 2020 by intent (homicide, suicide, unintentional, and undetermined) and demographic characteristics. External causes were defined as poisonings (eg, drug overdose), firearms, and all other injuries, including motor vehicle injuries and falls. Given the repercussions of the COVID-19 pandemic, US death rates for 2019 and 2020 were also compared. Design, Setting, and Participants: Serial cross-sectional study using national death certificate data obtained from the National Center for Health Statistics and including all external causes of 3 813 894 deaths among individuals aged 20 years or older from January 1, 1999, to December 31, 2020. Data analysis was conducted from January 20, 2022, to February 5, 2023. Exposures: Age, sex, and race and ethnicity. Main Outcomes and Measures: Trends in age-standardized mortality rates and average annual percentage change (AAPC) in rates calculated by intent (suicide, homicide, unintentional, and undetermined), age, sex, and race and ethnicity for each external cause. Results: Between 1999 and 2020, there were 3 813 894 deaths due to external causes in the US. From 1999 to 2020, poisoning death rates increased annually (AAPC, 7.0%; 95% CI, 5.4%-8.7%). From 2014 to 2020, poisoning death rates increased the most among men (APC, 10.8%; 95% CI, 7.7%-14.0%). During the study period, poisoning death rates increased in all the racial and ethnic groups examined; the most rapid increase was among American Indian and Alaska Native individuals (AAPC, 9.2%; 95% CI, 7.4%-10.9%). During the study period, death rates for unintentional poisoning had the most rapid rate of increase (AAPC, 8.1%; 95% CI, 7.4%-8.9%). From 1999 to 2020, firearm death rates increased (AAPC, 1.1%; 95% CI, 0.7%-1.5%). From 2013 to 2020, firearm mortality increased by an average of 4.7% annually (95% CI, 2.9%-6.5%) among individuals aged 20 to 39 years. From 2014 to 2020, mortality from firearm homicides increased by an average of 6.9% annually (95% CI, 3.5%-10.4%). From 2019 to 2020, mortality rates from external causes accelerated further, largely from increases in unintentional poisoning, and homicide due to firearms and all other injuries. Conclusions and Relevance: Results of this cross-sectional study suggest that from 1999 to 2020, death rates due to poisonings, firearms, and all other injuries increased substantially in the US. The rapid increase in deaths due to unintentional poisonings and firearm homicides is a national emergency that requires urgent public health interventions at the local and national levels.

Circulating trans fatty acids are associated with prostate cancer in Ghanaian and American men.

The association between fatty acids and prostate cancer remains poorly explored in African-descent populations. Here, we analyze 24 circulating fatty acids in 2934 men, including 1431 prostate cancer cases and 1503 population controls from Ghana and the United States, using CLIA-certified mass spectrometry-based assays. We investigate their associations with population groups (Ghanaian, African American, European American men), lifestyle factors, the fatty acid desaturase (FADS) genetic locus, and prostate cancer. Blood levels of circulating fatty acids vary significantly between the three population groups, particularly trans, omega-3 and omega-6 fatty acids. FADS1/2 germline genetic variants and lifestyle factors explain some of the variation in fatty acid levels, with the FADS1/2 locus showing population-specific associations, suggesting differences in their control by germline genetic factors. All trans fatty acids, namely elaidic, palmitelaidic, and linoelaidic acids, associated with an increase in the odds of developing prostate cancer, independent of ancestry, geographic location, or potential confounders.

Immune Profile of Exosomes in African American Breast Cancer Patients Is Mediated by Kaiso/THBS1/CD47 Signaling.

African American (AA) women with breast cancer are more likely to have higher inflammation and a stronger overall immune response, which correlate with poorer outcomes. In this report, we applied the nanostring immune panel to identify differences in inflammatory and immune gene expression by race. We observed a higher expression of multiple cytokines in AA patients compared to EA patients, with high expression of CD47, TGFB1, and NFKB1 associated with the transcriptional repressor Kaiso. To investigate the mechanism associated with this expression pattern, we observed that Kaiso depletion results in decreased expression of CD47, and its ligand SIRPA. Furthermore, Kaiso appears to directly bind to the methylated sequences of the THBS1 promotor and repress gene expression. Similarly, Kaiso depletion attenuated tumor formation in athymic nude mice, and these Kaiso-depleted xenograft tissues showed significantly higher phagocytosis and increased infiltration of M1 macrophages. In vitro validation using MCF7 and THP1 macrophages treated with Kaiso-depleted exosomes showed a reduced expression of immune-related markers (CD47 and SIRPA) and macrophage polarization towards the M1 phenotype compared to MCF7 cells treated with exosomes isolated from high-Kaiso cells. Lastly, analysis of TCGA breast cancer patient data demonstrates that this gene signature is most prominent in the basal-like subtype, which is more frequently observed in AA breast cancer patients.

The impact of social and environmental factors on cancer biology in Black Americans.

Low socioeconomic status (SES) is associated with early onset of chronic diseases and reduced life expectancy. The involvement of neighborhood-level factors in defining cancer risk and outcomes for marginalized communities has been an active area of research for decades. Yet, the biological processes that underlie the impact of SES on chronic health conditions, such as cancer, remain poorly understood. To date, limited studies have shown that chronic life stress is more prevalent in low SES communities and can affect important molecular processes implicated in tumor biology such as DNA methylation, inflammation, and immune response. Further efforts to elucidate how neighborhood-level factors function physiologically to worsen cancer outcomes for disadvantaged communities are underway. This review provides an overview of the current literature on how socioenvironmental factors within neighborhoods contribute to more aggressive tumor biology, specifically in Black U.S. women and men, including the impact of environmental pollutants, neighborhood deprivation, social isolation, structural racism, and discrimination. We also summarize commonly used methods to measure deprivation, discrimination, and structural racism at the neighborhood-level in cancer health disparities research. Finally, we offer recommendations to adopt a multi-faceted intersectional approach to reduce cancer health disparities and develop effective interventions to promote health equity.

Associations between quantitative measures of TDLU involution and breast tumor molecular subtypes among breast cancer cases in the Black Women's Health Study: a case-case analysis.

BACKGROUND: Terminal duct lobular units (TDLUs) are the structures in the breast that give rise to most breast cancers. Previous work has shown that TDLU involution is inversely associated with TDLU metrics, such as TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU, and that these metrics may be elevated in the normal breast tissue of women diagnosed with triple-negative (TN) compared with luminal A breast tumors. It is unknown whether this relationship exists in Black women, who have the highest incidence of TN breast cancer and the highest overall breast cancer mortality rate. We examined relationships between TDLU metrics and breast cancer molecular subtype among breast cancer cases in the Black Women's Health Study (BWHS). METHODS: We assessed quantitative TDLU metrics (TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU) in digitized 247 hematoxylin and eosin-stained adjacent normal tissue sections from 223 BWHS breast cancer cases, including 65 triple negative (TN) cancers (estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor-2 (HER2) negative) and 158 luminal A cancers (ER positive, HER2 negative). We evaluated associations of least square mean TDLU metrics adjusted for age and body mass index (BMI) with patient and clinical characteristics. In logistic regression models, we evaluated associations between TDLU metrics and breast cancer subtype, adjusting for age, BMI, and tumor size. RESULTS: Older age and higher BMI were associated with lower TDLU metrics and larger tumor size and lymph node invasion with higher TDLU metrics. The odds of TN compared with luminal A breast cancer increased with increasing tertiles of TDLU metrics, with odds ratios (95% confidence intervals) for tertile 3 versus tertile 1 of 2.18 (0.99, 4.79), 2.77 (1.07, 7.16), and 1.77 (0.79, 3.98) for TDLU count, TDLU span, and acini count/TDLU, respectively. CONCLUSION: Associations of TDLU metrics with breast cancer subtypes in the BWHS are consistent with previous studies of White and Asian women, demonstrating reduced TDLU involution in TN compared with luminal A breast cancers. Further investigation is needed to understand the factors that influence TDLU involution and the mechanisms that mediate TDLU involution and breast cancer subtype.

African Ancestry-Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent.

Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent. SIGNIFICANCE: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race-group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483.

Understanding how genetic ancestry may influence cancer development.

Of the multifactorial determinants that lead to cancer health disparities among race groups, quantified genetic ancestry has begun to expand our knowledge beyond self-reported race. However, it is essential to study these biological determinants in the context of social determinants to truly improve clinical tools and achieve equitable survival outcomes.

Immune response and inflammation in cancer health disparities.

Cancer death rates vary among population groups. Underserved populations continue to experience an excessive burden of lethal cancers that is largely explained by health-care disparities. However, the prominent role of advanced-stage disease as a driver of cancer survival disparities may indicate that some cancers are more aggressive in certain population groups than others. The tumor mutational burden can show large differences among patients with similar-stage disease but differences in race/ethnicity or residence. These dissimilarities may result from environmental or chronic inflammatory exposures, altering tumor biology and the immune response. We discuss the evidence that inflammation and immune response dissimilarities among population groups contribute to cancer disparities and how they can be targeted to reduce these disparities.