Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men.

Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.

Commentary: Some water in the data desert: the Cancer Intervention and Surveillance Modeling Network's capacity to guide mitigation of cancer health disparities.

Despite significant progress in cancer research and treatment, a persistent knowledge gap exists in understanding and addressing cancer care disparities, particularly among populations that are marginalized. This knowledge deficit has led to a "data divide," where certain groups lack adequate representation in cancer-related data, hindering their access to personalized and data-driven cancer care. This divide disproportionately affects marginalized and minoritized communities such as the U.S. Black population. We explore the concept of "data deserts," wherein entire populations, often based on race, ethnicity, gender, disability, or geography, lack comprehensive and high-quality health data. Several factors contribute to data deserts, including underrepresentation in clinical trials, poor data quality, and limited access to digital technologies, particularly in rural and lower-socioeconomic communities.The consequences of data divides and data deserts are far-reaching, impeding equitable access to precision medicine and perpetuating health disparities. To bridge this divide, we highlight the role of the Cancer Intervention and Surveillance Modeling Network (CISNET), which employs population simulation modeling to quantify cancer care disparities, particularly among the U.S. Black population. We emphasize the importance of collecting quality data from various sources to improve model accuracy. CISNET's collaborative approach, utilizing multiple independent models, offers consistent results and identifies gaps in knowledge. It demonstrates the impact of systemic racism on cancer incidence and mortality, paving the way for evidence-based policies and interventions to eliminate health disparities. We suggest the potential use of voting districts/precincts as a unit of aggregation for future CISNET modeling, enabling targeted interventions and informed policy decisions.

Wnt7a deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterised by loss of microvessels. The Wnt pathways control pulmonary angiogenesis but their role in PAH is incompletely understood. We hypothesised that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH. METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a -/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx). RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with the formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced vascular endothelial growth factor (VEGF)-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signalling by facilitating Y1175 tyrosine phosphorylation in vascular endothelial growth factor receptor 2 (VEGFR2) through receptor tyrosine kinase-like orphan receptor 2 (ROR2), a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a -/- mice under either chronic hypoxia or SuHx, global Wnt7a +/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodelling. Similar to PAH, Wnt7a +/- PMVECs exhibited an insufficient angiogenic response to VEGF-A that improved with Wnt7a. CONCLUSIONS: Wnt7a promotes VEGF signalling in lung PMVECs and its loss is associated with an insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.

Associations in Cigarette Smoking and Health Conditions by Race/Ethnicity Among a Diverse Sample of Patients Receiving Treatment in a Federally Qualified Health Care Setting in Chicago.

Purpose: To examine the association of cigarette use and smoking-related health conditions by race/ethnicity among diverse and low-income patients at a federally qualified health center (FQHC). Methods: Demographics, smoking status, health conditions, death, and health service use were extracted from electronic medical data for patients seen between September 1, 2018, and August 31, 2020 (n=51,670). Smoking categories included everyday/heavy smoker, someday/light smoker, former smoker, or never smoker. Results: Current and former smoking rates were 20.1% and 15.2%, respectively. Males, Black, White, non-partnered, older, and Medicaid/Medicare patients were more likely to smoke. Compared with never smokers, former and heavy smokers had higher odds for all health conditions except respiratory failure, and light smokers had higher odds of asthma, chronic obstructive pulmonary disease, emphysema, and peripheral vascular disease. All smoking categories had more emergency department visits and hospitalizations than never smokers. The associations between smoking status and health conditions differed by race/ethnicity. White patients who smoked had a greater increase in odds of stroke and other cardiovascular diseases compared with Hispanic and Black patients. Black patients who smoked had a greater increase in odds of emphysema and respiratory failure compared with Hispanic patients. Black and Hispanic patients who smoked had a greater increase in emergency care use compared with White patients. Conclusion: Smoking was associated with disease burden and emergency care and differed by race/ethnicity. Health Equity Implications: Resources to document smoking status and offer cessation services should be increased in FQHCs to promote health equity for lower income populations.

Does the Vaginal Microbiome Operate Differently by Race to Influence Risk of Precervical Cancer?

Background: The vaginal microbiome (VMB) plays an important role in the persistence of human papillomavirus (HPV) infection and differs by race and among women with cervical intraepithelial neoplasia (CIN). Materials and Methods: We explored these relationships using 16S rRNA VMB taxonomic profiles of 3050 predominantly Black women. VMB profiles were assigned to three subgroups based on taxonomic markers indicative of vaginal wellness: optimal (Lactobacillus crispatus, L. gasseri, and L. jensenii), moderate (L. iners), and suboptimal (Gardnerella vaginalis, Atopobium vaginae, Ca. Lachnocurva vaginae, and others). Multivariable Firth logistic regression models were adjusted for age, smoking, VMB, HPV, and pregnancy status. Results: VMB prevalence by subgroup was 18%, 30%, and 51% for the optimal, moderate, and suboptimal groups, respectively. In fully adjusted models, the risk of CIN grade 3 (CIN3) among non-Latina (nL) Blacks was twice that of nL Whites (odds ratio [OR] = 2.0, 95% confidence interval [CI]: 1.1, 3.9, p = 0.02). The VMB modified this association (p = 0.04) such that the risk of CIN3 was significantly higher for nL Blacks than for nL Whites only among women with optimal VMBs (OR = 7.8, 95% CI: 1.7, 74.5, p = 0.007). Within racial groups, the risk of CIN3 was only elevated among nL White women with suboptimal VMBs (OR = 6.0, 95% CI: 1.3, 56.9, p = 0.02) compared with their racial counterparts with optimal VMBs. Conclusions: Our findings suggest that race is a modifier of the VMB in HPV carcinogenesis. An optimal VMB does not appear to be protective for nL Black women compared with nL White women.

Advancing More Equitable Care Through the Development of a Health Equity Report Card.

The root causes of racial disparities in access to optimal cancer care and related cancer outcomes are complex, multifactorial, and not rooted in biology. Contributing factors to racial disparities in care delivery include implicit and explicit bias, lack of representation of people of color in the oncology care and research workforce, and homogenous research participants that are not representative of the larger community. Systemic and structural barriers include policies leading to lack of insurance and underinsurance, costs of cancer treatment and associated ancillary costs of care, disparate access to clinical trials, and social determinants of health, including exposure to environmental hazards, access to housing, childcare, and economic injustices. To address these issues, ACS CAN, NCCN, and NMQF convened the Elevating Cancer Equity (ECE) initiative. The ECE Working Group developed the Health Equity Report Card (HERC). In this manuscript, we describe the process taken by the ECE Working Group to develop the HERC recommendations, the strategies employed by NCCN to develop an implementation plan and scoring methodology for the HERC, and next steps to pilot the HERC tool in practice settings.

Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10.

Targeting KRAS-mutated non-small-cell lung cancer (NSCLC) remains clinically challenging. Here we show that loss of function of Miz1 inhibits lung tumorigenesis in a mouse model of oncogenic KRAS-driven lung cancer. In vitro, knockout or silencing of Miz1 decreases cell proliferation, clonogenicity, migration, invasion, or anchorage-independent growth in mutant (MT) KRAS murine or human NSCLC cells but has unremarkable impact on non-tumorigenic cells or wild-type (WT) KRAS human NSCLC cells. RNA-sequencing reveals Protocadherin-10 (Pcdh10) as the top upregulated gene by Miz1 knockout in MT KRAS murine lung tumor cells. Chromatin immunoprecipitation shows Miz1 binding on the Pcdh10 promoter in MT KRAS lung tumor cells but not non-tumorigenic cells. Importantly, silencing of Pcdh10 rescues cell proliferation and clonogenicity in Miz1 knockout/knockdown MT KRAS murine or human tumor cells, and rescues allograft tumor growth of Miz1 knockout tumor cells in vivo. Miz1 is upregulated in MT KRAS lung tumor tissues compared with adjacent non-involved tissues in mice. Consistent with this, Miz1 is upregulated while Pcdh10 is downregulated in human lung adenocarcinomas (LUAD) compared with normal tissues, and high Miz1 levels or low Pcdh10 levels are associated with poor survival in lung cancer patients. Furthermore, the Miz1 signature is associated with worse survival in MT but not WT KRAS LUAD, and Pcdh10 is downregulated in MT compared to WT KRAS LUAD. Taken together, our studies implicate the Miz1/Pcdh10 axis in oncogenic KRAS-driven lung tumorigenesis.

KCNF1 promotes lung cancer by modulating ITGB4 expression.

Lung cancer continues to be the leading cause of cancer death in the United States. Despite recent advances, the five-year survival rate for lung cancer compared to other cancers still remains fairly low. The discovery of molecular targets for lung cancer is key to the development of new approaches and therapies. Electrically silent voltage-gated potassium channel (KvS) subfamilies, which are unable to form functional homotetramers, are implicated in cell-cycle progression, cell proliferation and tumorigenesis. Here, we analyzed the expression of KvS subfamilies in human lung tumors and identified that potassium voltage-gated channel subfamily F member 1 (KCNF1) was up-regulated in non-small cell lung cancer (NSCLC). Silencing of KCNF1 in NSCLC cell lines reduced cell proliferation and tumor progression in mouse xenografts, re-established the integrity of the basement membrane, and enhanced cisplatin sensitivity. KCNF1 was predominately localized in the nucleoplasm and likely mediated its functions in an ion-independent manner. We identified integrin ß4 subunit (ITGB4) as a downstream target for KCNF1. Our findings suggest that KCNF1 promotes lung cancer by enhancing ITGB4 signaling and implicate KCNF1 as a novel therapeutic target for lung cancer.

Cell Competition in Carcinogenesis.

The majority of human cancers evolve over time through the stepwise accumulation of somatic mutations followed by clonal selection akin to Darwinian evolution. However, the in-depth mechanisms that govern clonal dynamics and selection remain elusive, particularly during the earliest stages of tissue transformation. Cell competition (CC), often referred to as 'survival of the fittest' at the cellular level, results in the elimination of less fit cells by their more fit neighbors supporting optimal organism health and function. Alternatively, CC may allow an uncontrolled expansion of super-fit cancer cells to outcompete their less fit neighbors thereby fueling tumorigenesis. Recent research discussed herein highlights the various non-cell-autonomous principles, including interclonal competition and cancer microenvironment competition supporting the ability of a tumor to progress from the initial stages to tissue colonization. In addition, we extend current insights from CC-mediated clonal interactions and selection in normal tissues to better comprehend those factors that contribute to cancer development.

Enrollment Matters: The Reality of Disparity and Pursuit of Equity in Clinical Trials.

SUMMARY: Disparities in clinical trial enrollment persist, fortified by the foundation and historical ideologies undergirding clinical cancer research. The scientific community has an ethical responsibility to seize the current moment to deconstruct and reconstruct these paradigms for more equitable research.

Impact of Federal, State, and Local Housing Policies on Disparities in Cardiovascular Disease in Black/African American Men and Women: From Policy to Pathways to Biology.

Racist and discriminatory federal, state, and local housing policies significantly contribute to disparities in cardiovascular disease incidence and mortality for individuals that self-identify as Black or African American. Here we highlight three key housing policies - "redlining," zoning, and the construction of highways - which have wrought a powerful, sustained, and destructive impact on cardiovascular health in Black/African American communities. Redlining and highway construction policies have restricted access to quality health care, increased exposure to carcinogens such as PM2.5, and increased exposure to extreme heat. At the root of these policy decisions are longstanding, toxic societal factors including racism, segregation, and discrimination, which also serve to perpetuate racial inequities in cardiovascular health. Here, we review these societal and structural factors and then link them with biological processes such as telomere shortening, allostatic load, oxidative stress, and tissue inflammation. Lastly, we focus on the impact of inflammation on the immune system and the molecular mechanisms by which the inflamed immune microenvironment promotes the formation of atherosclerotic plaques. We propose that racial residential segregation and discrimination increases tissue inflammation and cytokine production, resulting in dysregulated immune signaling, which promotes plaque formation and cardiovascular disease. This framework has the power to link structural racism not only to cardiovascular disease, but also to cancer.

The National Heart Lung and Blood Institute Disparities Elimination through Coordinated Interventions to Prevent and Control Heart and Lung Disease Alliance.

OBJECTIVE: To describe the National Heart Lung and Blood Institute (NHLBI) sponsored Disparities Elimination through Coordinated Interventions to Prevent and Control Heart and Lung Disease (DECIPHeR) Alliance to support late-stage implementation research aimed at reducing disparities in communities with high burdens of cardiovascular and/or pulmonary disease. STUDY SETTING: NHBLI funded seven DECIPHeR studies and a Coordinating Center. Projects target high-risk diverse populations including racial and ethnic minorities, urban, rural, and low-income communities, disadvantaged children, and persons with serious mental illness. Two projects address multiple cardiovascular risk factors, three focus on hypertension, one on tobacco use, and one on pediatric asthma. STUDY DESIGN: The initial phase supports planning activities for sustainable uptake of evidence-based interventions in targeted communities. The second phase tests late-stage evidence-based implementation strategies. DATA COLLECTION/EXTRACTION METHODS: Not applicable. PRINCIPAL FINDINGS: We provide an overview of the DECIPHeR Alliance and individual study designs, populations, and settings, implementation strategies, interventions, and outcomes. We describe the Alliance's organizational structure, designed to promote cross-center partnership and collaboration. CONCLUSIONS: The DECIPHeR Alliance represents an ambitious national effort to develop sustainable implementation of interventions to achieve cardiovascular and pulmonary health equity.

Improving Equity in Cancer Care in the Face of a Public Health Emergency.

ABSTRACT: Cancer health disparities have been well documented among different populations in the United States for decades. While the cause of these disparities is multifactorial, the COVID-19 pandemic has highlighted the structural barriers to health and health care and the gaps in public health infrastructure within the United States. The most long-standing inequities are rooted in discriminatory practices, current and historical, which have excluded and disenfranchised many of the most vulnerable populations in the nation. These systemic barriers are themselves a public health crisis, resulting in increased mortality rates in communities of color from both COVID-19 and cancer. While implementing programs to temporarily improve cancer equity locally or regionally is laudable, it is imperative to develop a public health strategy focused on alleviating the root causes of health inequities to improve the health and well-being of every citizen and ensure readiness for the next public health emergency.

Disparate groups share cancer disparities.

Due to historical and structural factors, underserved rural and racial/ethnic minorities suffer a disproportionate cancer burden based in part on common disparities they share. The time is ripe for cancer researchers to engage with these underserved populations to build trust in science and improve care for those they serve.

Cancer statistics for African American/Black People 2022.

African American/Black individuals have a disproportionate cancer burden, including the highest mortality and the lowest survival of any racial/ethnic group for most cancers. Every 3 years, the American Cancer Society estimates the number of new cancer cases and deaths for Black people in the United States and compiles the most recent data on cancer incidence (herein through 2018), mortality (through 2019), survival, screening, and risk factors using population-based data from the National Cancer Institute and the Centers for Disease Control and Prevention. In 2022, there will be approximately 224,080 new cancer cases and 73,680 cancer deaths among Black people in the United States. During the most recent 5-year period, Black men had a 6% higher incidence rate but 19% higher mortality than White men overall, including an approximately 2-fold higher risk of death from myeloma, stomach cancer, and prostate cancer. The overall cancer mortality disparity is narrowing between Black and White men because of a steeper drop in Black men for lung and prostate cancers. However, the decline in prostate cancer mortality in Black men slowed from 5% annually during 2010 through 2014 to 1.3% during 2015 through 2019, likely reflecting the 5% annual increase in advanced-stage diagnoses since 2012. Black women have an 8% lower incidence rate than White women but a 12% higher mortality; further, mortality rates are 2-fold higher for endometrial cancer and 41% higher for breast cancer despite similar or lower incidence rates. The wide breast cancer disparity reflects both later stage diagnosis (57% localized stage vs 67% in White women) and lower 5-year survival overall (82% vs 92%, respectively) and for every stage of disease (eg, 20% vs 30%, respectively, for distant stage). Breast cancer surpassed lung cancer as the leading cause of cancer death among Black women in 2019. Targeted interventions are needed to reduce stark cancer inequalities in the Black community.

Project COALESCE-An Example of Academic Institutions as Conveners of Community-Clinic Partnerships to Improve Cancer Screening Access.

In Virginia, 56% of colorectal cancers (CRC) are diagnosed late, making it one of three enduring CRC mortality hotspots in the US. Cervical cancer (CCa) exhibits a similar pattern, with 48% late-stage diagnosis. Mortality for these cancers is worse for non-Latinx/e(nL)-Black people relative to nL-White people in Virginia, but preventable with equitable screening access and timely diagnostic follow-up. However, structural barriers, such as fractured referral systems and extended time between medical visits, remain. Because Federally Qualified Health Centers (FQHCs) care for a large proportion of racial and ethnic minorities, and underserved communities, regardless of ability to pay, they are ideal partners to tackle structural barriers to cancer screenings. We piloted a quality improvement initiative at five FQHCs in southcentral Virginia to identify and address structural, race-related barriers to CRC, as well as CCa screening and diagnostic follow-up using evidence-based approaches. Uniquely, FQHCs were paired with local community organizations in a didactic partnership, to elevate the community's voice while together, increase support, acceptance, uptake, and intervention sustainability. We report on project development, and share preliminary data within the context of project goals, namely, to increase cancer screenings by 5-10%, improve knowledge and diagnostic follow-up processes, and build longitudinal partnerships.

American Cancer Society's report on the status of cancer disparities in the United States, 2021.

In this report, the authors provide comprehensive and up-to-date US data on disparities in cancer occurrence, major risk factors, and access to and utilization of preventive measures and screening by sociodemographic characteristics. They also review programs and resources that have reduced cancer disparities and provide policy recommendations to further mitigate these inequalities. The overall cancer death rate is 19% higher among Black males than among White males. Black females also have a 12% higher overall cancer death rate than their White counterparts despite having an 8% lower incidence rate. There are also substantial variations in death rates for specific cancer types and in stage at diagnosis, survival, exposure to risk factors, and receipt of preventive measures and screening by race/ethnicity, socioeconomic status, and geographic location. For example, kidney cancer death rates by sex among American Indian/Alaska Native people are ≥64% higher than the corresponding rates in each of the other racial/ethnic groups, and the 5-year relative survival for all cancers combined is 14% lower among residents of poorer counties than among residents of more affluent counties. Broad and equitable implementation of evidence-based interventions, such as increasing health insurance coverage through Medicaid expansion or other initiatives, could substantially reduce cancer disparities. However, progress will require not only equitable local, state, and federal policies but also broad interdisciplinary engagement to elevate and address fundamental social inequities and longstanding systemic racism.