IRONMAN: A Novel International Registry of Men With Advanced Prostate Cancer.

PURPOSE: To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population. PATIENTS AND METHODS: Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires. RESULTS: Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service. CONCLUSION: To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.

beta2-agonists promote host defense against bacterial infection in primary human bronchial epithelial cells.

BACKGROUND: Airway epithelial cells are critical in host defense against bacteria including Mycoplasma pneumoniae (Mp) in chronic obstructive pulmonary disease (COPD) and asthma. beta2-agonists are mainstay of COPD and asthma therapy, but whether beta2-agonists directly affect airway epithelial host defense functions is unclear. METHODS: Epithelial cells from bronchial brushings of normal (n = 8), asthma (n = 8) and COPD (n = 8) subjects were grown in air-liquid interface cultures, and treated with cigarette smoke extract (CSE) and/or Th2 cytokine IL-13, followed by Mp infection and treatment with beta2-agonists albuterol and formoterol for up to seven days. Mp and host defense proteins short palate, lung, and nasal epithelial clone 1 (SPLUNC1) and beta-defensin-2 were quantified. Expression of beta2-adrenergic receptors was also measured by real-time quantitative RT-PCR. RESULTS: (R)- or racemic albuterol and (R,R)- or racemic formoterol significantly decreased Mp levels in normal and asthma epithelial cells. Normal cells treated with Mp and (R)- or racemic albuterol showed an increase in SPLUNC1, but not in beta-defensin-2. COPD cells did not respond to drug treatment with a significant decrease in Mp or an increase in SPLUNC1. IL-13 attenuated drug effects on Mp, and markedly decreased SPLUNC1 and beta2-adrenergic receptors. CONCLUSIONS: These results for the first time show that beta2-agonists enhance host defense functions of primary bronchial epithelial cells from normal and asthma subjects, which is attenuated by IL-13.

Impact of cigarette smoke exposure on innate immunity: a Caenorhabditis elegans model.

BACKGROUND: Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and lung cancer. Respiratory bacterial infections have been shown to be involved in the development of COPD along with impaired airway innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: To address the in vivo impact of cigarette smoke (CS) exclusively on host innate defense mechanisms, we took advantage of Caenorhabditis elegans (C. elegans), which has an innate immune system but lacks adaptive immune function. Pseudomonas aeruginosa (PA) clearance from intestines of C. elegans was dampened by CS. Microarray analysis identified 6 candidate genes with a 2-fold or greater reduction after CS exposure, that have a human orthologue, and that may participate in innate immunity. To confirm a role of CS-down-regulated genes in the innate immune response to PA, RNA interference (RNAi) by feeding was carried out in C. elegans to inhibit the gene of interest, followed by PA infection to determine if the gene affected innate immunity. Inhibition of lbp-7, which encodes a lipid binding protein, resulted in increased levels of intestinal PA. Primary human bronchial epithelial cells were shown to express mRNA of human Fatty Acid Binding Protein 5 (FABP-5), the human orthologue of lpb-7. Interestingly, FABP-5 mRNA levels from human smokers with COPD were significantly lower (p = 0.036) than those from smokers without COPD. Furthermore, FABP-5 mRNA levels were up-regulated (7-fold) after bacterial (i.e., Mycoplasma pneumoniae) infection in primary human bronchial epithelial cell culture (air-liquid interface culture). CONCLUSIONS: Our results suggest that the C. elegans model offers a novel in vivo approach to specifically study innate immune deficiencies resulting from exposure to cigarette smoke, and that results from the nematode may provide insight into human airway epithelial cell biology and cigarette smoke exposure.