Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25‐dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids, calcitriol upregulates stemness‐related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7, and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness‐related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.

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J. Neurochem. (2010) 115, 283–295. Abstract Adenosine A2A receptors (A2ARs) are G‐protein coupled receptors that stimulate adenylyl cyclase activity. The most A2ARs‐enriched brain region is the striatum, in which A2ARs are largely restricted to GABAergic neurons of the indirect pathway. We recently described how DNA methylation controls basal A2AR expression levels in human cell lines. The present report provides clues about the molecular mechanisms that promote human brain region‐specific A2AR gene (ADORA2A) basal expression. The transcription factors ZBP‐89 and Yin Yang‐1 (YY1) have been characterized as regulators of ADORA2A in SH‐SY5Y cells by means of specific expression vectors/siRNAs transient transfection and chromatin immunoprecipitation assay. ZBP‐89 plays a role as an activator and YY1 as a repressor. No differences were found in ZBP‐89 levels with western blot between the putamen and cerebellum of human postmortem brains. However, increased YY1 levels and DNA methylation percentage in the 5′ untranslated region of ADORA2A, using SEQUENOM MassArray, were found in the cerebellum with respect to the putamen of human brains, showing an inverse relationship with A2AR levels in the two cerebral regions.

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Introduction: ALK-negative anaplastic large cell lymphoma (ALCL) is a CD30+ T-cell neoplasm which can sometimes harbour a DUSP22 rearrangement (DUSP22-R) on 6p25.3. In the first clinical report, the 5-year OS of 22 patients with DUSP22-R was 90% (Parrilla Castellar et al, Blood 2014). However, in a later work from the British Columbia Cancer Lymphoid Cancer database, the 5-year OS of 12 patients with DUSP22-R was 40% (Hapgood et al, BJH 2019). Thus, the prognostic impact of DUSP22-R is currently unclear.Methods: Systemic ALK-negative ALCL cases were collected through the LYSA pathology institute and Tenomic, a transnational research consortium on T-cell lymphomas involving several centers in France, Belgium and Switzerland. For the purpose of the present study, two expert hematopathologists (L.d.L. and P.G.) reviewed cases coded as ALK-negative ALCL or CD30+ PTCL-NOS and extended the phenotypic analysis to reclassify them according to the WHO classification. FISH studies for DUSP22 and TP63 rearrangements were carried out and analysed centrally. Clinical features and outcomes are described.Results: Among the 100 retrieved ALK-negative ALCL cases, 45 harboured a DUSP22-R. As shown in the Table below, bone involvement was the only significant parameter, more frequent in DUSP22-R cases (p = 0.01). Median follow-up of living patients was 4.3 years. 5-year PFS was 32% for the 100 patients, including 46% and 21% for the DUSP22-R and non-R patients, respectively (p < 0.01). 5-year OS was 50% for the 100 patients, including 57% and 45% for the DUSP22-R and non-R patients, respectively (p = 0.32). Conclusion:In our cohort, the largest to date, DUSP22-R had no statistically significant impact on OS.