Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencingin aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas

Hypertension and contraceptive use among women of child-bearing age in the United States from 2001 to 2018

BACKGROUND: Hypertension (HTN) in pregnancy is a leading cause of maternal mortality in the United States. Contraception is widely used, and estrogen-based combined hormonal forms are known to increase blood pressure (BP). With nearly half of pregnancies unplanned and many antihypertensive medications teratogenic, appropriate contraception is critical in child-bearing age women with HTN. METHODS: Using the National Health and Nutrition Examination Surveys (NHANES) from 2001 to 2018, we evaluated contraception and antihypertensive medication use in women of child-bearing age (20-50 years). Women who had undergone sterilization or menopause were excluded. HTN was defined based on a self-reported provider diagnosis and BP \u3e /=130/80 mm Hg or antihypertensive medication use. Contraception included non-barrier methods (pills/patch/ring, injections, long-acting reversible contraceptives) or consistent condom use. Multivariable logistic regression was used to model the odds of contraception use. Temporal trends in contraception use were reported. RESULTS: Of the 8726 women, 12.4% had HTN with mean age (standard error) 36.0 (0.3) years. In women with HTN, 9.2% used non-barrier contraception and 10.4% used condoms only. Over half (52.7%) of women with HTN on antihypertensive medications were taking medications contraindicated in pregnancy, with no difference seen by contraceptive status. In logistic regression models, contraceptive use was lower in the older-aged women. In women with HTN on non-barrier contraception, combined hormonal contraceptive use declined, from 100% (2001-2006) to 81.4% (2013-2018, P \u3c 0.001). CONCLUSIONS: Many women with self-reported HTN are not using adequate contraception. Of the small proportion on non-barrier contraceptives, the majority are using estrogen-based, BP-raising methods

Social Determinants, Blood Pressure Control, and Racial Inequities in Childbearing Age Women With Hypertension, 2001 to 2018

Background Hypertension is an important modifiable risk factor of serious maternal morbidity and mortality. Social determinants of health (SDoH) influence hypertension outcomes and may contribute to racial and ethnic differences in hypertension control. Our objective was to assess SDoH and blood pressure (BP) control by race and ethnicity in US women of childbearing age with hypertension. Methods and Results We studied women (aged 20–50 years) with hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg or use of antihypertensive medication) in the National Health and Nutrition Examination Surveys 2001 to 2018. SDoH and BP control (systolic BP <140 mm Hg and diastolic BP <90 mm Hg) were examined by race and ethnicity (White race, Black race, Hispanic ethnicity, and Asian race). Using multivariable logistic regression, odds of uncontrolled BP by race and ethnicity were modeled, adjusting for SDoH, health factors, and modifiable health behaviors. Responses on hunger and affording food determined food insecurity status. Across women of childbearing age with hypertension (N=1293), 59.2% were White race, 23.4% were Black race, 15.8% were Hispanic ethnicity, and 1.7% were Asian race. More Hispanic and Black women experienced food insecurity than White women (32% and 25% versus 13%; both P<0.001). After SDoH, health factor, and modifiable health behavior adjustment, Black women maintained higher odds of uncontrolled BP than White women (odds ratio, 2.31 [95% CI, 1.08–4.92]), whereas Asian and Hispanic women showed no difference. Conclusions We identified racial inequities in uncontrolled BP and food insecurity among women of childbearing age with hypertension. Further exploration beyond the SDoH measured is needed to understand the inequity in hypertension control in Black women

Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species

Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells, and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into a spectrum of states, which might promote or limit tumor outgrowth but remain poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to map TIMs in non-small-cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate translational research of these populations, we also profiled TIMs in mice. In comparing TIMs across species, we identified a near-complete congruence of population structures among dendritic cells and monocytes; conserved neutrophil subsets; and species differences among macrophages. By contrast, myeloid cell population structures in patients' blood showed limited overlap with those of TIMs. This study determines the lung TIM landscape and sets the stage for future investigations into the potential of TIMs as immunotherapy targets