ObjectiveThere is strong evidence for an involvement of different classes of non-coding RNAs, including microRNAs and long non-coding RNAs, in the regulation of β-cell activities and in diabetes development. Circular RNAs were recently discovered to constitute a substantial fraction of the mammalian transcriptome but the contribution of these non-coding RNAs in physiological and disease processes remains largely unknown. The goal of this study was to identify the circular RNAs expressed in pancreatic islets and to elucidate their possible role in the control of β-cells functions.MethodsWe used a microarray approach to identify circular RNAs expressed in human islets and searched their orthologues in RNA sequencing data from mouse islets. We then measured the level of four selected circular RNAs in the islets of different Type 1 and Type 2 diabetes models and analyzed the role of these circular transcripts in the regulation of insulin secretion, β-cell proliferation, and apoptosis.ResultsWe identified thousands of circular RNAs expressed in human pancreatic islets, 497 of which were conserved in mouse islets. The level of two of these circular transcripts, circHIPK3 and ciRS-7/CDR1as, was found to be reduced in the islets of diabetic db/db mice. Mimicking this decrease in the islets of wild type animals resulted in impaired insulin secretion, reduced β-cell proliferation, and survival. ciRS-7/CDR1as has been previously proposed to function by blocking miR-7. Transcriptomic analysis revealed that circHIPK3 acts by sequestering a group of microRNAs, including miR-124-3p and miR-338-3p, and by regulating the expression of key β-cell genes, such as Slc2a2, Akt1, and Mtpn.ConclusionsOur findings point to circular RNAs as novel regulators of β-cell activities and suggest an involvement of this novel class of non-coding RNAs in β-cell dysfunction under diabetic conditions.

BACKGROUND: New developments in the treatment of lung cancer have necessitated the further histologic and cytologic subtyping of nonsmall cell lung carcinomas. Thyroid transcription factor‐1 (TTF‐1) long has served as the predominant marker for demonstrating lung origin. However, it is also expressed in a variety of other tumors, particularly neuroendocrine neoplasms and, to a much lesser degree, squamous cell carcinoma of the lung. Napsin‐A, which is expressed in lung tissue, is a relatively new marker for lung adenocarcinoma. In this study, the authors examined the utility of napsin‐A compared with TTF‐1 in cytologic specimens of primary and metastatic, poorly differentiated lung adenocarcinomas. METHODS: The archives of the Department of Pathology at The Johns Hopkins Hospital were searched for cytologic cases of poorly differentiated lung adenocarcinoma that were histologically confirmed. In total, 75 patients (cases) along with 95 controls were included, each of whom had adequate cell block material for TTF‐1 and napsin‐A staining. Tissue microarrays of lung adenocarcinoma also were examined. RESULTS: TTF‐1 and napsin‐A were detected in 61 of 75 cases (81.3%) and in 49 of 75 cases (65.3%), respectively. The sensitivity and specificity of TTF‐1 were 81% each; and napsin‐A had a greater specificity of 96%, and sensitivity of 65%. Napsin‐A was not detected in small cell carcinomas or in other carcinomas of nonlung origin except for renal cell carcinoma. CONCLUSIONS: Although TTF‐1 had a higher sensitivity, napsin‐A was useful as a surrogate marker when encountering a poorly differentiated lung adenocarcinoma or an unknown primary tumor, particularly in cytologic specimens and difficult cases. The current results indicate that the dual use of both markers may be necessary to improve diagnostic accuracy. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.

Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of β-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding β-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder.

Inflammatory Myofibroblastic Tumor (IMT) is a rare spindle cell neoplasm with a relatively indolent course. Its morphology may be confused with both reactive processes and/or malignant neoplasms on FNA specimens. Herein we discuss the cytologic features and IHC studies of IMT. The archives of the Department of Pathology at the Johns Hopkins Hospital were searched for IMT. A total of 257 cases were identified over a period of 11 years. Among them, 20 cases had cytology material. The patients' ages ranged from 7 to 81 years old with a median age of 54 years. The locations of the tumor in descending order were: liver (9/20, 45%), lung (8/20, 40%), abdomen (1/20, 5%), pelvis (1/20, 5%), and kidney (1/20, 5%). On FNA, the majority of tumors consisted of bland spindle cells with oval nuclei and small prominent nucleoli in a background of lymphocytes and plasma cells. Focal cytological atypia and "ganglion-like" cells were identified in 7 cases, likely related to the risk of metastases and malignant transformation. The lesional cells expressed ALK (8/17, 47.1%) and actin (10/10, 100%), but with variable expression of cytokeratin. Ki-67 showed low proliferative indices. ALK gene rearrangement was detected by FISH in three out of three cases and correlated with ALK protein expression by IHC. The cytologic diagnosis of IMT is challenging. When encountering a spindle cell lesion with prominent inflammatory component, a high index of suspicion in combination with the use of ancillary studies increases the diagnostic yield of IMT.