Exploring the Role of IL-1β/IL-1R in the Pathogenesis of K-ras Mutant Lung Cancer

As the leading cause of cancer-related deaths worldwide, the development of targeted therapeutics to treat lung cancer remains crucial. Non-small cell lung cancer (NSCLC), the most common histological subtype predominantly comprises lung adenocarcinoma with driver mutations in the K-ras oncogene (KM-LUAD). KM-LUAD progression partly occurs through activation of the NF-κB pathway initiating an inflammatory response and creating a pro-tumor microenvironment. Notably, the pro-inflammatory cytokine IL-1β a potent activator and product of the NF-κB pathway is elevated in the lungs and sera of KM-LUAD patients. We have shown that IL-1β blockade promotes an anti-tumor immune phenotype in a mouse model of KM-LUAD driven by lung epithelial cell-specific expression of K-rasG12D (CCSPCre/LSL-K-rasG12D, CC-LR mouse), suggesting that IL-1β mediates tumor-promoting inflammation. Yet, cell-specific mechanisms that underlie this effect are still poorly understood. Thus, we sought to elucidate the role of IL-1β signaling via its ability to bind to its receptor, IL-1R, by conditionally knocking out IL-1R in K-ras-mutant lung epithelial cells in CC-LR mice (LR/IL-1RΔ/Δ). Tumor development as well as immune microenvironment in 14 and 18-week-old LR/IL-1RΔ/Δ mice in comparison to control CC-LR littermates were studied. Notably a 30% reduction in tumor burden in LR/IL-1RΔ/Δ mice was evident at both time points tested when compared to their CC-LR counterpart. Reduced tumorigenesis was shown to be driven by decreased angiogenesis and an overall age-dependent effect on tumor-promoting inflammation was seen. Tumor reduction in 14-week-old LR/IL-1RΔ/Δ mice was associated with an abundance of myeloid cell subsets as well as a shift in dendritic cell phenotype suggesting an increase in T-cell priming. This differed in 18-week-old LR/IL-1RΔ/Δ mice where a stronger response to epithelial IL-1R targeting with a significant reduction in T-cell associated markers as well as NF-κB activation was observed. Overall, these findings provide insight into cell-specific mechanisms underlying the tumor-promoting effects of IL-1β signaling and support the role of tumor cell-intrinsic factors in this process via shaping the tumor microenvironment

Tumor Cell Specific Function of IL-1 Signaling in the Pathogenesis of K-ras Mutant Lung Cancer

Department of Pulmonary Medicinehttps://openworks.mdanderson.org/sumexp22/1113/thumbnail.jp

Elucidating the Mechanistic Role of IL-1R in Late-Stage K-ras Mutant Lung Cancer: Uncovering Therapeutic Potential

https://openworks.mdanderson.org/sumexp23/1088/thumbnail.jp

Regulation of Global Transcription in Escherichia coli by Rsd and 6S RNA

In Escherichia coli, the sigma factor σ70 directs RNA polymerase to transcribe growth-related genes, while σ38 directs transcription of stress response genes during stationary phase. Two molecules hypothesized to regulate RNA polymerase are the protein Rsd, which binds to σ70, and the non-coding 6S RNA which binds to the RNA polymerase-σ70 holoenzyme. Despite multiple studies, the functions of Rsd and 6S RNA remain controversial. Here we use RNA-Seq in five phases of growth to elucidate their function on a genome-wide scale. We show that Rsd and 6S RNA facilitate σ38 activity throughout bacterial growth, while 6S RNA also regulates widely different genes depending upon growth phase. We discover novel interactions between 6S RNA and Rsd and show widespread expression changes in a strain lacking both regulators. Finally, we present a mathematical model of transcription which highlights the crosstalk between Rsd and 6S RNA as a crucial factor in controlling sigma factor competition and global gene expression

Table S4

Table S4: Primers used in this stud

Supplemental Material for Lal, Krishna, and Seshasayee, 2018

Supplementary material (final submission) for G3/2018/200265R

Association of insurance types and outcomes in acute promyelocytic leukemia

Understanding the association between insurance status and survival in an evolving US healthcare system remains a challenge but is essential to address healthcare disparities. We utilized National Cancer Database to evaluate the effects of insurance type on one-month mortality and overall survival (OS) in patients with acute promyelocytic leukemia. Among patients \u3c 65 years, one-month mortality was worse for uninsured patients and patients with Medicare compared to patients with private insurance. OS was similar between patients with private insurance and uninsured patients but worse for patients with Medicare and Medicaid/other government insurance. In multivariate analysis, older age and greater comorbidity burden conferred worse OS. For patients ≥ 65 years, insurance type did not affect one-month mortality and OS. Older age, greater comorbidity burden, and treatment at non-academic centers conferred worse one-month mortality and OS. Our results highlight healthcare disparities based on insurance types for both younger and older patients

Association of Insurance Types and Survival in Acute Promyelocytic Leukemia (APL)

Introduction: Health insurance, or lack thereof, is a significant barrier to health care access in the United States. Patients without insurance or with inadequate coverage are more likely to delay or forego treatment, even with acute illness or significant symptoms, leading to worse health outcomes. We aimed to analyze if insurance types impacted one-month mortality and overall survival (OS) in younger patients with APL