Smyrk, Thomas

Abstract Background There is increased recognition of duodenal disturbances (inflammation, altered mucosal protein expression, and chemosensitivity) in functional dyspepsia (FD). Besides sensorimotor functions, enteric submucosal neurons also regulate epithelial ion transport. We hypothesized that duodenal mucosal ion transport and expression of associated genes are altered in FD. Methods Duodenal mucosal ion transport (basal and acetylcholine‐ and glucose‐evoked changes in short‐circuit current [Isc]) and expression of associated genes and regulatory miRNAs were evaluated in 40 FD patients and 24 healthy controls. Results Basal Isc (FD: 88.2 [52.6] μA/cm 2 vs healthy: 20.3 [50.2] μA/cm 2 ; P ≤ .0001), acetylcholine‐evoked Isc (FD: Emax 50.4 [35.8] μA/cm 2 vs healthy: 16.6 [15] μA/cm 2 ; P ≤ .001), and glucose‐evoked Isc responses (FD: E max 69.8 [42.1] μA/cm 2 vs healthy: 40.3 [24.6] μA/cm 2 ; P = .02) were greater in FD than in controls. The Emax for glucose was greater in FD patients on selective serotonin reuptake inhibitors. In FD, the mRNA expression of SLC4A7 and SLC4A4 , which transport bicarbonate into cells at the basolateral surface, and the apical anion exchanger SLC26A3 were reduced (false discovery rate <0.05), the serotonin receptor HTR4 was increased, and the serotonin transporter SLC6A4 was decreased. Selected miRNAs (hsa‐miR‐590‐3p, hsa‐miR‐32‐5p) that target genes associated with ionic transport were upregulated in FD. Conclusions Compared to controls, FD patients had greater baseline and agonist‐evoked duodenal mucosal secretory responses. These findings may be explained by reduced gene expression, which would be anticipated to reduce luminal bicarbonate secretion. The upregulated miRNAs may partly explain the downregulation of these genes in FD.

BACKGROUND: After IPAA, 8% of patients with ulcerative colitis are later diagnosed with Crohn’s disease of the pouch, associated with an increased rate of pouch failure. No study has reported on how often the clinical diagnosis is correlated with histologic findings of Crohn’s disease in the excised pouch. OBJECTIVE: The purpose of this study was to determine whether the clinical diagnosis is consistent with pathologic confirmation at pouch excision. SETTINGS: The study was conducted at a tertiary IBD referral center. PATIENTS: Patients with chronic ulcerative colitis who underwent pouch excision for presumed Crohn’s disease of the pouch were included. MAIN OUTCOME MEASURES: Preoperative evaluation and pathologic variables at the time of pouch excision were measured. RESULTS: A total of 35 patients underwent pouch excision for Crohn’s disease of the pouch based on a combination of clinical, radiographic, and endoscopic findings. Seven (20%) had surgical pathology consistent with Crohn’s disease at pouch excision. There were no differences in those 7 patients and the remaining 28 in terms of diagnosis at colectomy, primary pouch symptoms, prepouch inflammation, ulceration, or granulomas at endoscopy. In the nonpathology-confirmed Crohn’s disease, 40% (n = 11) had an anastomotic leak at time of IPAA versus 0% in the Crohn’s disease group, and 86% (n = 24) had symptoms of pouch dysfunction within 5 months of ileostomy reversal versus 13 months in the Crohn’s disease group. Of 28 without pathology-confirmed Crohn’s disease, 100% (n = 28) were treated with antibiotics, 68% (n = 19) with steroids, 59% (n = 16) with immunomodulators, and 57% (n = 15) with biologic therapy for Crohn’s disease of the pouch. LIMITATIONS: The study was limited by its single-center scope and lack of an established definition for Crohn’s disease of the pouch. CONCLUSIONS: Pathologic confirmation of Crohn’s disease was given to only one fifth of patients who underwent pouch excision for Crohn’s disease of the pouch. Given the histologic variability in Crohn’s disease, it may be unreasonable to expect histologic confirmation in every case; still, the diagnosis of Crohn’s disease of the pouch may be overly ascribed, resulting in unnecessary immunosuppressive medications and exclusion from consideration for pouch reconstructive surgery. See Video Abstract at http://links.lww.com/DCRA432.

Abstract Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote KrasG12D-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer–promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1–STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. Significance: Our study points to the existence of an oncogenic NFATc1–STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1–STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. Cancer Discov; 4(6); 688–701. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 621