Bacterial dysbiosis has emerged as an accomplice to carcinogenesis in malignancies such as colon and liver cancer, and we have recently implicated the microbiome in the pathogenesis of pancreatic ductal adenocarcinoma (PDA) 1. However, the mycobiome has not been clearly implicated in tumorigenesis. We found that fungi migrate from the gut lumen to the pancreas. PDA tumors harbored a ~3000-fold increase in fungi compared to normal pancreas in both mice and humans. The composition of the PDA mycobiome was distinct from that of gut or normal pancreas based on alpha and beta diversity indices. Specifically, the fungal community infiltrating PDA tumors was markedly enriched for Malassezia in both mice and humans. Fungal ablation was tumor-protective in slowly progressive and invasive models of PDA whereas repopulation with Malassezia-but not Candida, Saccharomyces, or Aspergillus-accelerated oncogenesis. In parallel, we discovered that ligation of mannose-binding lectin (MBL), which binds fungal wall glycans to activate the complement cascade, was required for oncogenic progression whereas MBL or C3 deletion in the extra-tumoral compartment or C3aR knockdown in tumor cells were protective. Further, reprogramming of the mycobiome did not alter PDA progression in Mbl or C3 deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade via MBL activation.
Summary Pancreatic ductal adenocarcinoma (PDA) is characterized by immune-tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine-protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T-helper cell differentiation towards a mixed Th1/Th17 phenotype, leading to tumor-immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1- and ICOS-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor-immunity.
Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We found signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 with a peptide inhibitor was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in polymicrobial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing the retinoblastoma gene Rb1. We further show that Piezo1-mediated silencing of Rb1 is regulated via up-regulation of histone deacetylase 2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immunosuppressive myelopoiesis in cancer and infectious disease.
BackgroundThe American Heart Association (AHA) recently created the construct of “ideal cardiovascular health” based on 7 cardiovascular health metrics to measure progress toward their 2020 Impact Goal. The present study applied this construct to assess the baseline cardiovascular health of a rural population targeted with a community‐based cardiovascular disease prevention program.Methods and ResultsThe sample consists of 4754 New Ulm, Minn, adult residents who participated in either the 2009 or 2011 community heart health screenings offered by the Hearts Beat Back: The Heart of New Ulm (HONU) Project (mean age 52.1 years, 58.3% women). Data collected at the screenings were analyzed to replicate the AHA's ideal cardiovascular health measure and the 7 metrics that comprise the construct. Screening participants met, on average (±SD), 3.4 (±1.4) ideal cardiovascular health metrics. Only 1.0% of participants met the AHA's definition of ideal health in all metrics and 7.1% met ≤1 ideal health metric. Higher proportions of women met the ideal category in all metrics except physical activity. Women over the age of 60 were less likely to meet the ideal category for cholesterol and hypertension than were men in the same age range.ConclusionPrevalence of ideal cardiovascular health is extremely low in this rural population. To make progress toward the 2020 Impact Goal, targeted community‐based interventions must be implemented based on the most prevalent cardiovascular risk factors.
Purpose Because the occurrence of post-operative myocardial ischemia predicts subsequent cardiac morbidity and mortality, we determined the prevalence of and risk factors for myocardial ischemia in hip and knee arthroplasty patients. Methods High sensitivity cardiac troponin T (hs-cTnT) was measured on stored samples from post-operative day 2 in 394 hip and knee arthroplasty patients ≥ 65 years of age enrolled in the Genetics-InFormatics Trial (GIFT). Results Fifty-three (13.5%) participants had myocardial ischemia, of whom only three were diagnosed clinically during their hospitalization. The risk of myocardial ischemia increased with age (OR 3.52 per decade, 95% CI 2.00-6.19) and diabetes (OR 2.23, 95% CI 1.04-4.77). Myocardial ischemia was rarer with statins (OR 0.74, 95% CI 0.40-1.35) and more common with hypertension, coronary artery disease and tobacco use, although these were not statistically significant. Conclusions Subclinical myocardial ischemia occurs frequently after arthroplasty. Diabetic and elderly patients are at highest risk.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.