Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.

Associations of Daily Versus Nondaily Smoking, Tobacco-Related Risk Perception, and Cancer Diagnosis Among Adults in the Population Assessment of Tobacco and Health (PATH) Study.

INTRODUCTION: Nondaily smoking has become increasingly common among cigarette smokers. Our objective was to determine whether current daily versus nondaily smoking differed by tobacco-related risk perceptions (TRRPs), demographic factors, and cancer history. METHODS: Participants were all adults in Waves 1-3 of the longitudinal cohort Population Assessment of Tobacco and Health Study who were current smokers at Wave 3 (N = 8307). The primary analysis was weighted logistic regression of daily versus nondaily smoking at Wave 3. TRRP measures were cigarette harm perception, worry that tobacco products will damage one's health, belief that smoking cigarettes causes [lung/bladder/mouth/liver] cancer, and nondaily cigarette harm perception (Likert-type scale). Other measures included demographic factors, other tobacco product use, minor at time of first cigarette, and cancer survivor status (yes/no). RESULTS: Among current smokers, daily versus nondaily smoking was significantly associated with being a minor at time of first cigarette (OR = 1.54, p < .001), TRRPs (OR = 0.83, p < .001; OR = 1.40, p < .001; and OR = 1.17, p = .009 [harm perception, worry, and nondaily cigarette harm perception, respectively]), and interaction between cancer survivor status and belief that smoking causes cancer (p < .001). TRRPs among current smokers did not differ significantly between cancer survivors and respondents without a cancer history. CONCLUSIONS: Respondents with lower harm perception, higher worry, and higher nondaily cigarette harm perception were more likely to be daily versus nondaily smokers. Respondents with higher belief that smoking causes cancer or who were cancer survivors were less likely to be daily (versus nondaily) smokers compared to respondents with low belief and no cancer history. IMPLICATIONS: This study is unique in that it examined associations of smoking cigarettes daily versus nondaily with tobacco-related risk perceptions and cancer survivorship-comparing cancer survivors to those without a cancer history. Given the increasing prevalence of nondaily smoking as compared with daily smoking in the general population, and the prognostic significance of smoking after cancer diagnosis, these findings fill a clinically important gap in the literature and provide a foundation for further research.

Physician peer group characteristics and timeliness of breast cancer surgery.

PURPOSE: Little is known about how the structure of interdisciplinary groups of physicians affects the timeliness of breast cancer surgery their patients receive. We used social network methods to examine variation in surgical delay across physician peer groups and the association of this delay with group characteristics. METHODS: We used linked Surveillance, Epidemiology, and End Results-Medicare data to construct physician peer groups based on shared breast cancer patients. We used hierarchical generalized linear models to examine the association of three group characteristics, patient racial composition, provider density (the ratio of potential vs. actual connections between physicians), and provider transitivity (clustering of providers within groups), with delayed surgery. RESULTS: The study sample included 8338 women with breast cancer in 157 physician peer groups. Surgical delay varied widely across physician peer groups (interquartile range 28.2-50.0%). For every 10% increase in the percentage of black patients in a peer group, there was a 41% increase in the odds of delayed surgery for women in that peer group regardless of a patient's own race [odds ratio (OR) 1.41, 95% confidence interval (CI) 1.15-1.73]. Women in physician peer groups with the highest provider density were less likely to receive delayed surgery than those in physician peer groups with the lowest provider density (OR 0.65, 95% CI 0.44-0.98). We did not find an association between provider transitivity and delayed surgery. CONCLUSIONS: The likelihood of surgical delay varied substantially across physician peer groups and was associated with provider density and patient racial composition.

The Health Status of Women with Children Living in Public and Assisted Housing: Linkage of the National Health Interview Survey to U.S. Department of Housing and Urban Development Administrative Data.

For more than a decade, the U.S. Department of Housing and Urban Development (HUD) and the National Center for Health Statistics (NCHS) have partnered to link NCHS national health survey data with HUD administrative records on persons participating in federal public and assisted housing programs. This study used 2015-18 National Health Interview Survey (NHIS)-HUD linked data to examine women 18-44 years old with children and renting their home who were receiving HUD assistance (n=852) and a comparison population of women of the same age with children, who were low-income renters but did not link to HUD records at the time of their NHIS interview (n=894). The population of HUD-assisted women differed from the comparison group on key sociodemographic characteristics and health indicators. HUD-assisted women were more likely to report their health as fair or poor and to being a current smoker. HUD-assisted women also were less likely to be uninsured and more likely to have a regular source of care. The findings in this article are exploratory but demonstrate how the NCHS-HUD-linked data can be a resource for researchers and policymakers in further examining housing status as an important social determinant of health.

Tobacco use profiles by respiratory disorder status for adults in the wave 1-wave 4 population assessment of tobacco and health (PATH) study.

Limited evidence exists on the association between electronic nicotine delivery systems (ENDS) and chronic respiratory disorders. This study examines the association of combustible tobacco and ENDS use with chronic respiratory disorders among US adults. Public-use data from the Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014), Wave 2 (2014-2015), Wave 3 (2015-2016), and Wave 4 (2016-2018) were pooled. Analyses focused on adults with W1-W4 respiratory disorder data and current tobacco use at W4, as well as youth entering the adult cohort at W2 through W4 (N = 26,072). We fit weighted multivariable logistic regression models for each respiratory outcome (asthma, COPD, bronchitis) using W4 longitudinal weights. Cigarette smokers (adjusted odds ratio [AOR] = 0.8, 95 % CI 0.7-0.9) were less likely to report an asthma diagnosis (p = 0.013). In contrast, ENDS users (AOR = 6.5, 95 % CI 3.7-11.5), cigarette smokers (AOR = 6.1, 95 % CI 4.0-9.1), dual users of cigarettes and ENDS (AOR = 5.4, 95 % CI 3.4-8.7), current users of non-cigarette combustible, smokeless, and polytobacco products (AOR = 4.4, 95 % CI 3.1-6.4), and former users of any product (AOR = 3.0, 95 % CI 1.9-4.7) had significantly elevated odds of reporting a diagnosis of COPD (p < 0.001). Similar patterns to COPD were observed for bronchitis (p < 0.001). Current and former tobacco use, including ENDS, were significantly associated with prevalence of self-reported COPD and bronchitis after controlling for demographic and psychosocial confounders.

Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators.

Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on the differential single-cell gene expression analysis of mesenchymal osteolineage cells close to, and further removed from, hematopoietic stem/progenitor cells (HSPCs) to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. We functionally examined, among the genes that were preferentially expressed in proximal cells, three secreted or cell-surface molecules not previously connected to HSPC biology-the secreted RNase angiogenin, the cytokine IL18, and the adhesion molecule Embigin-and discovered that all of these factors are HSPC quiescence regulators. Therefore, our proximity-based differential single-cell approach reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance the understanding of microenvironmental regulation of stem cell function.