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Ahr in action: GPR15 is an orphan chemokine receptor that is critical for homing of CD4+ T cells to the large intestine, but regulation of GPR15 expression is not well understood. Xiong et al. identified a role for the aryl hydrocarbon receptor (Ahr) in driving expression of GPR15 in mice and humans. Ahr binds to open chromatin sites in the Gpr15 locus to enhance expression. In regulatory T cells (Tregs), the Foxp3 transcription factor can interact with Ahr to enhance binding to the Gpr15 locus and further increase expression. RORγt can compete with Ahr binding and inhibit GPR15 expression in Tregs and TH17 cells. These results reveal a mechanism by which GPR15 expression in CD4+ T cells is modulated by the Ahr-Foxp3-RORγt axis. The orphan chemoattractant receptor GPR15 is important for homing T lymphocytes to the large intestine, thereby maintaining intestinal immune homeostasis. However, the molecular mechanisms underlying the regulation of GPR15 expression remain elusive. Here, we show a central role of the aryl hydrocarbon receptor (Ahr) in promoting GPR15 expression in both mice and human, thus gut homing of T lymphocytes. Mechanistically, Ahr directly binds to open chromatin regions of the Gpr15 locus to enhance its expression. Ahr transcriptional activity in directing GPR15 expression was modulated by two transcription factors, Foxp3 and RORγt, both of which are expressed preferentially by gut regulatory T cells (Tregs) in vivo. Specifically, Foxp3 interacted with Ahr and enhanced Ahr DNA binding at the Gpr15 locus, thereby promoting GPR15 expression. In contrast, RORγt plays an inhibitory role, at least in part, by competing with Ahr binding to the Gpr15 locus. Our findings thus demonstrate a key role for Ahr in regulating Treg intestinal homing under the steady state and during inflammation and the importance of Ahr-RORγt-Foxp3 axis in regulating gut homing receptor GPR15 expression by lymphocytes. [ABSTRACT FROM AUTHOR]

* Context.--Inflammatory bowel disease (IBD) is a longstanding chronic active inflammatory process in the bowel with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic active inflammatory processes contribute to multistage progression of human cancer development, including reactive oxygen and nitrogen species, aberrant arachidonic acid metabolites and cytokines/growth factors, and immune dysfunction. These molecular events in IBD lead to genetic abnormality and promote aberrant cell proliferation, which further lead to epithelial changes encompassing a broad spectrum from inflammation-induced hyperplasia to dysplasia. Objective.--To review the (1) epidemiologic and molecular pathogenesis of the risk for colorectal cancer in IBD, (2) morphologic characterization, biomarker(s), and classification of dysplastic lesions, and (3) clinical management of dysplastic lesions arising in IBD. Data Sources.--The different IBD-related dysplastic lesions are illustrated by using morphology in conjunction with molecular pathways, and the 'field cancerization' theory and its potential significance are discussed with a review of the literature. Conclusions.--Patients with IBD are at increased risk of developing colorectal cancer. The risk of developing carcinoma is related to the extent/duration/activity of the patient's disease. There is no consensus regarding the extent of carcinoma risk associated with IBD; however, all would agree that patients with IBD represent a group at significant risk for developing carcinoma and as such, warrant adequate surveillance and prevention. With better screening modalities and detection/characterization of dysplastic lesions, IBD-associated serrated lesions, and 'field cancerization,' we will improve our understanding of and approach to risk stratification. (Arch Pathol Lab Med. 2013;137:338-350; doi: 10.5858/arpa.2012-0086-RA), Chronic inflammation is a well-recognized risk factor for human cancer development, and at least one-third of all human cancers have been associated with inflammation, for example, long-standing chronic inflammatory bowel [...]

Undifferentiated carcinoma of the esophagus and gastroesophageal junction is a recently recognized entity in the fifth edition of the World Health Organization Classification of Digestive Tumors and is diagnostically challenging, particularly on small biopsies. SMARCA4 and SMARCA2 are chromatin remodeling genes with key roles in oncogenesis. We retrieved 14 cases of SMARCA4/SMARCA2-deficient undifferentiated carcinoma of the gastroesophageal junction and esophagus from the authors' institutions. The tumors showed similar histologic findings: the sheet-like proliferation of tumor cells characterized by discohesion, large nuclei, and prominent macronucleoli with many tumor cells exhibiting a rhabdoid appearance. In 8 cases, adjacent specialized intestinal metaplasia was noted and 3 cases exhibited adjacent high-grade dysplasia. Immunohistochemically, tumors variably expressed keratins and disclosed loss of expression of SMARCA4 in 12 and SMARCA2 in 7 cases. In 2 cases SMARCA2 alone was lost without SMARCA4 loss. A mutant p53 immunohistochemical pattern was seen in 4 of 4 cases, 3 of which showed diffuse, strong nuclear expression, and 1 case displayed a complete loss of nuclear expression of p53, including invasive carcinoma and associated dysplasia, when present. Limited clinical follow-up was available, but 3 patients died of disease within 0.6, 2, and 7 months of diagnosis. We present the first series of undifferentiated carcinoma of the esophagus and gastroesophageal junction with this characteristic morphology associated with loss of SMARCA4 and/or SMARCA2 expression. This tumor type likely arises from dedifferentiation of a lower grade carcinoma in some cases, and Barrett esophagus and appears to be associated with an aggressive clinical course., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The purpose of our study was to compare the utility of MR elastography (MRE) and diffusion-weighted imaging (DWI) in characterizing fibrosis and chronic hepatitis in patients with chronic liver diseases., Subjects and Methods: Seventy-six patients with chronic liver disease underwent abdominal MRI, MRE, and DWI. Severities of liver fibrosis and chronic hepatitis were graded by histopathologic analysis according to standard disease-specific classifications. The overall predictive ability of MRE and DWI in assessment of fibrosis was compared by constructing a receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC) on the basis of histopathologic analysis., Results: Using ROC analysis, MRE showed greater capability than DWI in discriminating stage 2 or greater (≥ F2), stage 3 or greater (≥ F3), and cirrhosis (≥ F4), shown as significant differences in AUC (p = 0.003, p = 0.001, and p = 0.001, respectively). Higher sensitivity and specificity were shown by MRE in predicting fibrosis scores ≥ F2 (91% and 97%), scores ≥ F3 (92% and 95%), and scores F4 (95% and 87%) compared with DWI (84% and 82%, 88% and 76%, and 85% and 68%, respectively). Although MRE had higher ability in identification of liver with fibrosis scores ≥ F1 than DWI, a significant difference was not seen (p = 0.398). Stiffness values on MRE increased in relation to increasing severity of fibrosis confirmed by histopathology scores; however, a consistent relationship between apparent diffusion coefficient (ADC) values and stage of fibrosis was not shown. In addition, liver tissue with chronic hepatitis preceding fibrosis may account for mild elevation of liver stiffness., Conclusion: MRE had greater predictive ability in distinguishing the stages of liver fibrosis than DWI.