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Highlights d Single-cell RNA-seq resolves human early T lymphopoiesis and thymus organogenesis d The first ETPs in the thymus share transcriptional features of TSPs in human fetal liver d Pre-thymic lymphoid progenitors are transcriptomically identified in human AGM region d Cortical TECs mature earlier than medullary TECs in human thymic primordium

BackgroundIntestinal metaplasia of the bladder is an uncommon glandular proliferation. We examined a large series of intestinal metaplasia for the clinicopathological features and discuss the significance of this lesion.MethodsAll cases of intestinal metaplasia diagnosed in our institution between 1990 and 2014 were retrospectively reviewed. Patients with a history of urothelial carcinoma or concurrent adenocarcinoma were excluded. Patient characteristics, pathological features, and follow-up outcomes were obtained.ResultsWe identified 89 patients with intestinal metaplasia during this period. Sixty seven were men and 22 were women. Mean age at diagnosis was 57 years (range 23–81). Common presenting complaints included haematuria (73 cases), mucosuria (13 cases), and irritative voiding symptoms (seven cases). The majority of intestinal metaplasias located on or near the trigone (67 cases). Eighty-two patients underwent transurethral resection of their lesions. Partial cystectomy was performed in the remaining seven patients. The mean follow-up of 78 patients was 105 months (range 6–255). One case of bladder adenocarcinoma was indentified 6 months later. The initial histologic findings had revealed intestinal metaplasia with severe dysplasia. Four patients presented recurrence during the follow-up, and this occurred 9, 13, 17 and 24 months after the surgery.ConclusionsAlthough intestinal metaplasia can be treated effectively by transurethral resection in most cases, its potential malignancy need to be taken into consideration after the evidence of recurrences and its association with bladder adenocarcinoma. Therefore, it is necessary to perform close surveillance following the surgery, particularly in patients with dysplastic changes.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm caused by aberrant activation of the mitogen-activated protein kinase (MAPK) pathway. Circulating myeloid cells from patients often carry disease-associated mutations and can be differentiated into langerinhigh LCH-like cells in vitro, but their detailed immune-phenotypic and molecular profiles are lacking and could shed key insights into disease biology. Here we recruited 217 pediatric LCH patients and took blood and tissue samples for BRAFV600E analysis. Immune-phenotyping of the circulating Lin-HLA-DR+ immune population in 49 of these patients revealed that decreased frequency of pDC was significantly linked to disease severity. By single-cell RNA sequencing of samples from 14 patients, we identified key changes in expression of RAS-MAPK-ERK signaling-related genes and transcription factors in distinct members of the mononuclear phagocyte system in the presence of BRAFV600E. Moreover, treatment of patients with the BRAF inhibitor Dabrafenib resulted in MAPK cascade inhibition, inflammation prevention, and regulation of cellular metabolism within mononuclear phagocytes. Finally, we also observed elevated expression of RAS-MAPK-ERK signaling-related genes in a CD207+CD1a+ cell subcluster in skin. Taken together, our data extends the molecular understanding of LCH biology at single-cell resolution, which might contribute to improvement of clinical diagnostics and therapeutics, and aid in the development of personalized medicine approaches.

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