This study piloted a pan‐solid‐tumor next generation sequence (NGS)‐based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 “epithelioid” nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4‐15 mm); median thickness 2.25 mm (range 0.25‐12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4‐71) and all other lesions (median 8/tumor, range 3‐17) (P < 0.004) and malignant (median 16/tumor, range 4‐71) vs benign lesions (median 7/tumor, range 3‐14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS‐based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH‐non‐concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed.
Background Somatic mosaicism is to date an uncommon finding in genetic autoinflammatory syndromes such as Cryopyrin‐associated periodic syndrome, Blau syndrome, and TNF receptor‐associated periodic syndrome (TRAPS). However, somatic mosaicism may be particularly important in adult‐onset or atypical phenotypes of these conditions. Herein, we report a unique adult‐onset TRAPS patient presenting with intermittent daily fever for 3 weeks, rash, peritonitis, and lymphadenopathy, who was found with hematopoietic mosaicism involving different white blood cell populations. Methods Patient's lymphocyte genomic DNA was initially analyzed by periodic fever seven‐gene next‐generation sequencing panel. Genomic DNAs extracted from patient's hair roots, buccal swab, and subpopulations of white blood cells were subsequently examined on the identified TNFRSF1A variant using Sanger sequencing. Results A de novo mosaic missense variant, c.265 T>C(p.Phe89Leu), in the TNFRSF1A gene was found in the patient's buccal swab, B cells, neutrophils, and NK cells but not detected in monocytes, T cells, and hair roots. Conclusion These data provide additional information about somatic mosaicism in autoinflammatory conditions and provide new insights regarding cellular players that are indispensable for the phenotypic expression of TRAPS.
The pathophysiology of dry eye disease (DED) remains largely unknown, accounting in part for the lack of successful treatments. We explored the pathophysiology of DED using a rabbit model of chronic DED induced with 3 weekly injections of Concanavalin A into the periorbital lacrimal glands. The transcriptome of full-thickness’s conjunctival tissue from rabbits with DED and from normal controls was determined using microarrays and, as needed, confirmatory real-time polymerase chain reactions. Results were subjected to bioinformatic analysis. DED induced large-scale changes in gene transcription involving 5,184 genes (22% of the total). Differentially expressed genes could be segregated into: functional modules and clusters; altered pathways; functionally linked genes; and groups of individual genes of known or suspected pathophysiological relevance to DED. A common feature of these subgroups is the breadth and magnitude of the changes that encompass ocular immunology and essentially all aspects of cell biology. Prominent changes concerned innate and adaptive immune responses; ocular surface inflammation; at least 25 significantly altered signaling pathways; a large number of chemokines; cell cycle; and apoptosis. Comparison of our findings to the limited extant transcriptomic data from DED patients associated with either Sjogren’s syndrome or non-Sjogren’s etiologies revealed a significant correlation between human and rabbit DED transcriptomes. Our data, establishing the large-scale transcriptomic changes of DED and their potential similarity to the human, underscore the enormous complexity of DED; establish a robust animal model of DED; will help expand our understanding of its pathophysiology; and could guide the development of successful therapeutic strategies.
Zusammenfassung Nachweis eines LH‐Rezeptor‐Bindungs‐Inhibitors im Schafhoden Aus Wäßrigen Extrakten des Widderhodens wurde mittels der Sephadex‐Säulen‐Chromatographie ein LH‐Rezeptor‐Bindungs‐Inhibitor (LH‐RBI) isoliert. Die Sephadex‐G‐75‐Fraktion I hemmte die Bindung von J125 LH an die Ratten‐Hoden‐Rezeptoren. Eine weitere Reinigung der Sephadex‐G‐75‐I Fraktion an der G‐200‐Säule ergab 4 Fraktionen (I‐IV); der maximale Hemmeffekt auf den J125‐LH‐RBI an den Rattenhoden war ausschließlich mit der Fraktion I gekoppelt. Fraktion II ergab ausschließlich eine marginale Hemmung, während die Fraktionen III und IV keinen Hemmeffekt auf die J125‐LH‐Bindung an die Rattenhoden‐Rezeptoren zeigten. Die Ergebnisse deuten nach Ansicht der Verfasser darauf hin, daß der aus Widderhoden isolierte LH‐RBI Protein ist mit einem Molekulargewicht von über 10 000 Daltons.
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