Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism.
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Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder caused by a failure of calcium sensing secondary to tumour development in one or more of the parathyroid glands. Parathyroid adenomas are comprised of distinct cellular subpopulations of variable clonal status that exhibit differing degrees of calcium responsiveness. To gain a clearer understanding of the relationship among cellular identity, tumour composition and clinical biochemistry in PHPT, we developed a novel single cell platform for quantitative evaluation of calcium sensing behaviour in freshly resected human parathyroid tumour cells. Live-cell intracellular calcium flux was visualized through Fluo-4-AM epifluorescence, followed by in situ immunofluorescence detection of the calcium sensing receptor (CASR), a central component in the extracellular calcium signalling pathway. The reactivity of individual parathyroid tumour cells to extracellular calcium stimulus was highly variable, with discrete kinetic response patterns observed both between and among parathyroid tumour samples. CASR abundance was not an obligate determinant of calcium responsiveness. Calcium EC50 values from a series of parathyroid adenomas revealed that the tumours segregated into two distinct categories. One group manifested a mean EC50 of 2.40 mM (95% CI: 2.37-2.41), closely aligned to the established normal range. The second group was less responsive to calcium stimulus, with a mean EC50 of 3.61 mM (95% CI: 3.45-3.95). This binary distribution indicates the existence of a previously unappreciated biochemical sub-classification of PHPT tumours, possibly reflecting distinct etiological mechanisms. Recognition of quantitative differences in calcium sensing could have important implications for the clinical management of PHPT.
Published Version (Please cite this version)10.1111/jcmm.12732
Publication InfoAllbritton, NL; DiSalvo, M; Hogue, JA; Koh, James; Olson, JA; Shi, Y; ... Wang, Y (2016). Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism. J Cell Mol Med, 20(2). pp. 351-359. 10.1111/jcmm.12732. Retrieved from http://hdl.handle.net/10161/12535.
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Assistant Professor of Surgery
The major effort in the lab is directed towards investigating how tumor-specific dysregulation of the pRB signaling pathway affects downstream gene expression and the cellular response to DNA damage. Four projects are currently underway. First, we are utilizing a modified chromatin immunoprecipitation approach to capture and identify genomic DNA target sequences conditionally associated with pRB-containing complexes recovered from intact chromatin in untransformed primary human cells. Se
Professor of Surgery
Julie Ann Sosa, MD MA FACS is Chief of Endocrine Surgery at Duke University and leader of the endocrine neoplasia diseases group in the Duke Cancer Institute and the Duke Clinical Research Institute. She is Professor of Surgery and Medicine. Her clinical interest is in endocrine surgery, with a focus in thyroid cancer. She is widely published in outcomes analysis, as well as cost-effectiveness analysis, meta-analysis, and survey-based research, and she is director of health services research for
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