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The authors used the mTOR inhibitor sirolimus to treat four infants with severe hyperinsulinemic hypoglycemia that was unresponsive to maximal doses of diazoxide and octreotide. All the patients had a clear glycemic response to treatment with sirolimus. Hyperinsulinemic hypoglycemia, a major cause of severe hypoglycemia during the neonatal period, is characterized by inappropriate insulin secretion from pancreatic beta cells in the presence of low blood glucose levels. 1 The condition may result from defects in key genes involved in the regulation of insulin secretion from beta cells, including ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, and UCP2 . 1 , 2 Two major histologic subtypes have been described: diffuse and focal. 3 Mutations in ABCC8 and KCNJ11 are associated with severe hyperinsulinemic hypoglycemia that is unresponsive to medical treatment with diazoxide and octreotide. 1 The only treatment option currently available for . . .

Objectives Investigate the relationship between quantified terminal ileal (TI) motility and histopathological activity grading, Crohn Disease MRI Index (CDMI) and faecal calprotectin. Methods Retrospective review of children with Crohn disease or unclassified inflammatory bowel disease, who underwent MR enterography. Dynamic imaging for 25 patients (median age 12, range 5 to 16) was analysed with a validated motility algorithm. The TI motility score was derived. The primary reference standard was TI Endoscopic biopsy Assessment of Inflammatory Activity (eAIS) within 40 days of the MR enterography. Secondary reference standards: (1) the Crohn Disease MRI Index (CDMI) and (2) faecal calprotectin levels. Results MR enterography median motility score was 0.17 a.u. (IQR 0.12 to 0.25; range 0.05 to 0.55), and median CDMI was 3 (IQR 0 to 5.5). Forty-three percent of patients had active disease (eAIS > 0) with a median eAIS score of 0 (IQR 0 to 2; range 0 to 5). The correlation between eAIS and motility was r  = − 0.58 ( p  = 0.004, N  = 23). Between CDMI and motility, r  = − 0.42 ( p  = 0.037, N  = 25). Motility score was lower in active disease (median 0.12 vs 0.21, p  = 0.020) while CDMI was higher (median 5 vs 1, p  = 0.04). In a subset of 12 patients with faecal calprotectin within 3 months of MR enterography, correlation with motility was r  = − 0.27 ( p  = 0.4). Conclusions Quantified terminal ileum motility decreases with increasing histopathological abnormality in children with Crohn disease, reproducing findings in adults. TI motility showed a negative correlation with an MRI activity score but not with faecal calprotectin levels. Key Points • It is feasible to perform MRI quantified bowel motility assessment in children using free-breathing techniques. • Bowel motility in children with Crohn disease decreases as the extent of intestinal inflammation increases. • Quantified intestinal motility may be a candidate biomarker for treatment efficacy in children with Crohn disease.

Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of,  NOTCH1 whilst removing its negative regulator, NRARP . Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP  expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1  rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma. Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.

Understanding tumor origins and the similarities and differences between organ-specific cancers is important for determining treatment options. Young et al. generated more than 72,000 single-cell transcriptomes from healthy and cancerous human kidneys. From these data, they determined that Wilms tumor, a pediatric kidney cancer, originates from aberrant fetal cells, whereas adult kidney cancers are likely derived from a specific subtype of proximal convoluted tubular cell. Science , this issue p. 594 Single-cell mRNAs of normal and cancerous kidney cells reveal the cellular identity of childhood and adult tumors. Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.

Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference “cellular signals” in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of “fetalness” with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer. Transcriptomic analysis may provide information about the differentiation state and cell of origin of a cancer. Here, the authors assess mRNA signals in 1300 childhood and adult renal tumors and report a fetal origin of childhood tumors and no dedifferentiation of adult tumors.

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly, or via crosstalk with immune cells. We used single cell RNA sequencing to resolve the spatio-temporal immune topology of the human kidney. We reveal anatomically-defined expression patterns of immune genes within the epithelial compartment, with anti-microbial peptide transcripts evident in pelvic epithelium in the mature, but not fetal kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with post-natal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune crosstalk orchestrated localization of anti-bacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.

Abstract Neuroblastoma is an embryonal childhood cancer that arises from aberrant development of the neural crest, mostly within the fetal adrenal medulla. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n=16,591) with fetal adrenal single cell transcriptomes (n=57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients and clinical phenotypes. We substantiated our findings in 652 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that there exists a pan-neuroblastoma cancer cell state which may be an attractive target for novel therapeutic avenues. Competing Interest Statement The authors have declared no competing interest.

Abstract The cellular transcriptome may provide clues into the differentiation state and origin of human cancer, as tumor cells may retain patterns of gene expression similar to the cell they derive from. Here, we studied the differentiation state and cellular origin of human kidney tumors, by assessing mRNA signals in 1,300 childhood and adult renal tumors, spanning seven different tumor types. Using single cell mRNA reference maps of normal tissues generated by the Human Cell Atlas project, we measured the abundance of reference “cellular signals” in each tumor. Quantifying global differentiation states, we found that, irrespective of tumor type, childhood tumors exhibited fetal cellular signals, thus replacing the long-held presumption of “fetalness” with a precise, quantitative readout of immaturity. By contrast, in adult cancers our assessment refuted the suggestion of dedifferentiation towards a fetal state in the overwhelming majority of cases, with the exception of lethal variants of clear cell renal cell carcinoma. Examining the specific cellular phenotype of each tumor type revealed an intimate connection between the different mesenchymal populations of the developing kidney and childhood renal tumors, whereas adult tumors mostly represented specific mature tubular cell types. RNA signals of each tumor type were remarkably uniform and specific, indicating a possible therapeutic and diagnostic utility. We demonstrated this utility with a case study of a cryptic renal tumor. Whilst not classifiable by clinical pathological work-up, mRNA signals revealed the diagnosis. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵† Joint first authors.