Although basal cell hyperplasia is a histologic hallmark of eosinophilic esophagitis (EoE), little is known about the capabilities of epithelial renewal and differentiation in the EoE inflammatory milieu. In murine esophageal epithelium, there are self-renewing and slowly proliferating basal stem-like cells characterized by concurrent expression of CD73 (5'-nucleotidase ecto) and CD104 (integrin β4). Here, we investigated CD73⁺CD104⁺ cells within the basal population of human esophageal epithelium and clarified the biological significance of these cells in the EoE epithelium. We performed flow cytometry on esophageal biopsy samples from EoE and non-EoE patients to determine the quantity of CD73⁺CD104⁺ cells in the epithelium. Simulating the EoE milieu we stimulated primary patient-derived and immortalized cell line–derived esophageal organoids with interleukin (IL)4 and IL13 and analyzed by flow cytometry, immunohistochemistry, and quantitative reverse-transcription polymerase chain reaction. We performed single-cell RNA sequencing on primary organoids in the setting of IL13 stimulation and evaluated the CD73⁺CD104⁺ population. We performed fluorescent-activated cell sorting to purify CD73⁺CD104⁺ and CD73^- CD104⁺ populations and seeded these groups in organoid culture to evaluate the organoid formation rate and organoid size. We used RNA interference to knock down CD73 in esophageal organoids to evaluate organoid formation rates and size. We evaluated the effects of signal transducer and activator of transcription 6 (STAT6) signaling inhibition by RNA interference, a STAT6 inhibitor, AS1517499, as well as the proton pump inhibitor omeprazole. EoE patients showed decreased epithelial CD73⁺CD104⁺ cell content. IL4 and IL13 stimulation depleted this population in 3-dimensional organoids with a recapitulation of basal cell hyperplasia as corroborated by single-cell RNA sequencing of the organoids, which suggests depletion of CD73⁺CD104⁺ cells. The CD73⁺CD104⁺ population had enhanced organoid formation compared with the CD73^-CD104⁺ population. Similarly, knock-down of CD73 resulted in decreased organoid formation rate. Genetic and pharmacologic inhibition of STAT6 prevented T helper 2 cytokine-induced depletion of CD73⁺CD104⁺ cells. Lastly, omeprazole treatment prevented the effects of IL4 and IL13 on the CD73⁺CD104⁺ population. This study addressed the role of CD73⁺CD104⁺ cells in epithelial renewal and homeostasis in the context of EoE. The depletion of the CD73⁺CD104⁺ self-renewal population by helper T cell 2 cytokines in EoE milieu may be perpetuating epithelial injury. Future therapies targeting epithelial restitution in EoE could decrease the need for immune modulation and steroid therapy.

Objectives: It has been reported that there is an association between the nutritional condition and the prognosis of cancer. Here, we evaluated the relation between the prognostic nutritional index (PNI) and colorectal cancer (CRC). Methods: A total of 184 patients with CRC who underwent curative surgery from October 2011 to December 2012 at the Osaka University Hospital were investigated. According to the median PNI value of our data set, patients were classified into a high-PNI (>= 46) group and a low- PNI (<46) group. The relationship between the PNI and the disease-free survival (DFS) and overall survival (OS) was analyzed by a Cox regression model. Results: A low PNI was significantly associated with poor DFS (P = 0.006) and OS (P < 0.001). A multivariate analysis showed that low PNI, venous invasion (present), and tumor location (rectum) were independent risk factors for recurrence. Low PNI, advanced age, and venous invasion were found to be independent risk factors for mortality. Using these clinicopathological factors, we developed nomograms to predict DFS and OS. The concordance index was 0.828 for DFS and 0.756 for OS. Conclusions: A low PNI is a prognostic indicator for recurrence and mortality in CRC. Nomograms constructed by clinicopathological factors including the PNI can provide individual prognostic outcomes.