Summary: Mammalian Peptidoglycan Recognition Proteins (PGRPs) kill both Gram‐positive and Gram‐negative bacteria through simultaneous induction of oxidative, thiol and metal stress responses in bacteria. However, metabolic pathways through which PGRPs induce these bactericidal stress responses are unknown. We screened Keio collection of Escherichia coli deletion mutants and revealed that deleting genes for respiratory chain flavoproteins or for tricarboxylic acid (TCA) cycle resulted in increased resistance of E. coli to PGRP killing. PGRP‐induced killing depended on the production of hydrogen peroxide, which required increased supply of NADH for respiratory chain oxidoreductases from central carbon catabolism (glycolysis and TCA cycle), and was controlled by cAMP‐Crp. Bactericidal PGRP induced a rapid decrease in respiration, which suggested that the main source of increased production of hydrogen peroxide was a block in respiratory chain and diversion of electrons from NADH oxidoreductases to oxygen. CpxRA two‐component system was a negative regulator of PGRP‐induced oxidative stress. By contrast, PGRP‐induced thiol stress (depletion of thiols) and metal stress (increase in intracellular free Zn²⁺ through influx of extracellular Zn²⁺) were mostly independent of oxidative stress. Thus, manipulating pathways that induce oxidative, thiol and metal stress in bacteria could be a useful strategy to design new approaches to antibacterial therapy.

Background and Aims: The social determinants of health can pose barriers to accessing cancer screening and treatment and have been associated with cancer mortality. However, it is not clear whether area deprivation is independently associated with mortality in HCC and cholangiocarcinoma when controlling for individual-level social determinants of health. Approach and Results: The cohort included individuals over 18 years old diagnosed with HCC (N=3460) or cholangiocarcinoma (N=781) and reported to the Indiana State Cancer Registry from 2009 to 2017. Area disadvantage was measured using the social deprivation index (SDI). SDI was obtained by linking addresses to the American Community Survey. Individual social determinants of health included race, ethnicity, sex, marital status, and insurance type. The primary outcome was mortality while controlling for SDI and individual social determinants of health by means of Cox proportional hazard modeling. In HCC, living in a neighborhood in the fourth quartile of census-track SDI (most deprived) was associated with higher mortality (HR: 1.14, 95% CI, 1.003–1.30, p=0.04) than living in a first quartile SDI neighborhood. Being uninsured (HR: 1.64, 95% CI, 1.30–2.07, p<0.0001) and never being married (HR: 1.31, 95% CI, 1.15–1.48, p<0.0001) were also associated with mortality in HCC. In cholangiocarcinoma, SDI was not associated with mortality. Conclusions: Social deprivation was independently associated with mortality in HCC but not cholangiocarcinoma. Further research is needed to better understand how to intervene on both area and individual social determinants of health and develop interventions to address these disparities.

INTRODUCTION: Disparities in hepatocellular carcinoma (HCC) outcomes are shaped by intersecting social determinants of health. We hypothesized that patients experience distinct combinations of socioeconomic barriers that cluster into social risk phenotypes associated with differences in diagnosis, treatment, and survival. METHODS: We analyzed data from 4,877 adults diagnosed with HCC in the Indiana State Cancer Registry (2009–2020). Latent class analysis was performed using sex, race, insurance, marital status, occupation, neighborhood Social Deprivation Index, and distances to screening and Indiana University Hospital. Outcomes included early-stage diagnosis, receipt of curative therapy, and 2-year mortality. RESULTS: Among 4,877 patients, 15.8% were non-White and 24.7% were female. Latent class analysis identified 6 distinct risk classes: (i) minimal barriers, (ii) publicly insured—married women, (iii) publicly insured—unpartnered men, (iv) rural and geographically distant, (v) structurally marginalized, and (vi) unseen and uninsured. Class 1 had the most favorable characteristics (83.7% private insurance, 16.8% professional occupation) and best outcomes: 55.4% early-stage diagnosis, 24.4% curative therapy, and 55.4% 2-year mortality. All other classes had significantly worse outcomes. Compared with class 1, patients in class 6 had the lowest early-stage diagnosis (39.7%) and curative therapy (10.5%) and highest 2-year mortality (83.6%; odds ratio 4.12, 95% confidence interval 3.06–5.54, P < 0.001). Classes 4 and 5, reflecting rural and racially marginalized groups, also had significantly lower odds of early diagnosis and treatment. DISCUSSION: Social risk phenotypes based on intersecting social determinants of health were strongly associated with HCC outcomes and may inform future risk-based intervention strategies.

Background Nod2 is involved in innate immune responses to bacteria, regulation of metabolism, and sensitivity to cancer. A Nod2 polymorphism is associated with breast cancer, but the role of Nod2 in the development and progression of breast cancer is unknown. Methods Here, we tested the hypothesis that Nod2 protects mice from breast cancer using the 4T1 orthotopic model of mammary tumorigenesis. WT and Nod2^−/− mice were injected with 4T1 mammary carcinoma cells and the development of tumors was monitored. A detailed analysis of the tumor transcriptome was performed and genes that were differentially expressed and pathways that were predicted to be altered between WT and Nod2^−/− mice were identified. The activation of key signaling molecules involved in metabolism and development of cancer was studied. Results Our data demonstrate that Nod2^−/− mice had a higher incidence and larger tumors than WT mice. Nod2^−/− mice had increased expression of genes that promote DNA replication and cell division, and decreased expression of genes required for lipolysis, lipogenesis, and steroid biosynthesis compared with WT mice. Nod2^−/− mice also had lower expression of genes required for adipogenesis and reduced levels of lipids compared with WT mice. The tumors in Nod2^−/− mice had decreased expression of genes associated with PPARα/γ signaling, increased activation of STAT3, decreased activation of STAT5, and no change in the activation of ERK compared with WT mice. Conclusions We conclude that Nod2 protects mice from the 4T1 orthotopic breast tumor, and that tumors in Nod2^−/− mice are predicted to have increased DNA replication and cell proliferation and decreased lipid metabolism compared with WT mice.

Nod2 is involved in innate immunity to bacteria, regulation of metabolism, and sensitivity to cancer. Nod2 polymorphism is associated with breast cancer, but the role of Nod2 in the development and progression of breast cancer is unknown. Here, we tested the hypothesis that Nod2 protects mice from breast cancer using the 4T1 orthotopic model of mammary tumorigenesis. We demonstrate that Nod2^−/− mice have higher incidence and larger tumors than WT mice. Detailed analysis of the tumor transcriptome showed that Nod2^−/− mice had increased expression of genes that promote DNA replication and cell division and decreased expression of genes required for lipolysis, lipogenesis, and steroid biosynthesis compared with WT mice. Nod2^−/− mice also had lower expression of genes required for adipogenesis and higher delipidation than WT mice. The tumors in Nod2^−/− mice had decreased expression of genes associated with PPARα/γ signaling, increased activation of STAT3, decreased activation of STAT5, and no change in the activation of ERK compared with WT mice. Thus, we demonstrate that Nod2 protects mice from the 4T1 orthotopic breast tumor, and that tumors in Nod2^−/− mice have higher DNA replication, cell cycling and delipidation than WT mice.