Pediatric Hemato-Oncology Research Laboratory

 Neutrophils protect the host through several mechanisms, including phagocytosis, release of cytotoxic molecules, and the formation of neutrophil extracellular traps. Our main project focuses on the role of NETs formation in Ewing sarcoma (EWS). EWS is the second most frequent primary malignant bone sarcoma in children and young adults. It is a highly aggressive cancer, with a survival rate of 70–80% for patients with standard-risk and localized disease and under 30% for those with metastatic disease. Correlation between NETs formation, tumorigenesis, tumor progression, and metastasis has been previously demonstrated in several malignancies including breast, lung, colorectal, pancreatic, blood, neurological, and cutaneous cancers, but not in pediatric tumors. Following our observation that NETs can serve as a novel prognostic factor at diagnosis for patients with EWS, our primary goal is to examine if NETs can serve as a novel therapeutic target for EWS.

Medulloblastoma (MB), a common brain tumor in childhood, affecting 20% of all children with CNS tumors, is associated with 60-80% long-term survival. Therefore, it is attractive to identify new prognostic markers in patients with medulloblastoma to aid in risk stratification and be used as a new treatment target. We are conducting a study focused on the role of Neutrophil Extracellular Traps (NETs) formation in MB, which has been shown to take part in different disease states, including cancer.

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory disorders. The chronic inflammatory response in IBD is associated with increased intestinal epithelial permeability, which promotes the massive recruitment of neutrophils. Neutrophils contribute to IBD pathogenesis through a variety of mechanisms. Neutrophil Extracellular Traps (NETs) are web-like structures that protrude from the membrane of activated neutrophils to the extracellular space, comprising condensed chromatin, DNA, and content derived from granules. In pediatric IBD, NETs have been observed in samples from patients with both CD and UC. Importantly, NETs are generated by neutrophils in the peripheral blood of patients with active IBD. Moreover, essential constituents in IBD have recently been implicated in promoting NETosis. TNF-α inhibition promoted reduced colonic release of NETs in UC patients. While most evidence demonstrated the relation between NETs and tissue damage in IBD was derived from adult studies, the role of NETs in the pathogenesis of pediatric IBD is unclear. Based on our preliminary evidence, we believe that NETosis plays a pivotal role in IBD pathogenesis, which contributes to the disease progression and may be related to IBD outcome and complications.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, causing significant morbidity. Despite the dramatic improvement in treatment, many patients do not achieve complete remission, and biomarkers for subclinical disease, flares, and response to treatment are lacking. NETs play key roles in the pathogenesis of autoimmune and inflammatory conditions. In our scientific project, we characterized neutrophil enzyme activity and NETs formation in oligoarticular and polyarticular Juvenile Idiopathic Arthritis and explored their association with disease activity.

Resident physicians with long-term night shift schedules during their postgraduate training will likely experience sleep deprivation. Insufficient sleep affects the immune system, including neutrophils, central players in the innate immune system. Recent studies demonstrated altered numbers of circulating neutrophils, decreased phagocytosis, and NADPH oxidase activity associated with sleep deprivation. However, the formation of neutrophil extracellular traps (NETs), one of the processes to protect against invading pathogens, was not studied in relation to sleep deprivation. We set out to evaluate the impact of sleep deprivation on the disruption of neutrophil function among resident physicians. Following a night shift and at least 3 nights of self-reported sufficient sleep, resident physicians exhibited reduced NETs release compared to controls, who were hospital workers who did not engage in night shifts. Enzymatic activity levels of core proteins of NETs formation, neutrophil elastase (NE), and myeloperoxidase (MPO) were significantly lower among sleep-deprived residents compared to the control group. The impact of sleep deprivation-induced decrease in NETs formation on the increased risk of infection and poor infection outcome warrants further study.