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Calcium Sensing Receptor (calcium + sensing_receptor)
Selected AbstractsDifferential expression of the calcium sensing receptor and combined loss of chromosomes 1q and 11q in parathyroid carcinomaTHE JOURNAL OF PATHOLOGY, Issue 1 2004Carola J Haven Abstract Malignant transformation of parathyroid tumours is rare. Nevertheless, this small subset of malignant tumours often creates diagnostic and therapeutic problems. In this work, the morphological characteristics of 26 primary parathyroid carcinomas and seven metastases have been studied. Furthermore, immunohistochemical expression profiles for the calcium sensing receptor (CASR), cyclin D1 (CCND1), and Ki-67 were determined for parathyroid carcinomas and compared with adenomas and hyperplasias using a tissue microarray. Loss of heterozygosity (LOH) of the chromosome 1q region containing the HRPT2 gene and chromosome 11q (MEN1) was determined in the carcinomas. In contrast to the adenomas and hyperplasias, 31% of carcinomas demonstrated down-regulation of CASR. A significant correlation was found between CASR expression and the Ki-67 proliferation index. Chromosome 1q and chromosome 11q LOH were found in 12 of 22 (55%) and 11 of 22 (50%) carcinomas tested, respectively. Combined 1q and 11q LOH was seen in 8 of 22 (36%) carcinomas, in contrast to the low percentage of LOH reported in both regions in adenomas. In conclusion, this study demonstrates that combined 1q and 11q LOH in parathyroid tumours is suggestive of malignant behaviour. Strong down-regulation of the CASR protein is seen in a proportion of parathyroid carcinomas with a high proliferation index. Copyright © 2004 John Wiley & Sons, Ltd. [source] Heterogeneous Disease Modeling for Hardy-Weinberg Disequilibrium in Case-Control Studies: Application to Renal Stones and Calcium-Sensing Receptor PolymorphismsANNALS OF HUMAN GENETICS, Issue 2 2009D. C. Hamilton Summary Renal stone formation due to hypercalciuria is a relatively common disorder with clear evidence for genetic predisposition, but cryptic phenotypic heterogeneity has hampered identification of candidate genes. The R990G single-nucleotide polymorphism (SNP) of the calcium sensing receptor (CASR) gene has been associated with hypercalciuria in stone formers and shows the appropriate functional phenotype in cell culture. In our preliminary association analysis of a case-control cohort, however, we observed significant Hardy-Weinberg disequilibrium (HWD) for the cases (n= 223), but not controls (n= 676) at the R990G locus, pointing us toward the general disease model incorporating HWD. Because there is an adjacent CASR SNP, A986S, which is in negative linkage disequilibrium with R990G, we extended the general disease model to enable testing of a two-site hypothesis. In our data set, there is no lack of fit (P= .345) for the single-locus model for the R990G genotype, and likelihood ratio testing favors a recessive effect with an eight-fold increase in risk (P < .001) for GG homozygotes, relative to wild-type, based on a population prevalence of 2%. Addition of the A986S genotype provides no additional information either by itself or when included in our two-site model. [source] Two enantiomerically pure cyclic arenesulfonamide hydrochloride saltsACTA CRYSTALLOGRAPHICA SECTION C, Issue 2 2009Lionel Kiefer The crystal structures of N -[(1R)-1-(1-naphthyl)ethyl]-3,4-dihydro-2H -1,2-benzothiazin-4-aminium 1,1-dioxide chloride, C20H21N2O2S+·Cl,, (I), a six-membered cyclic sulfonamide, and (1R)- N -[(5,5-dioxo-6,7-dihydrodibenzo[d,f][1,2]thiazepin-7-yl)methyl]-1-(1-naphthyl)ethanaminium chloride, C26H25N2O2S+·Cl,, (II), a seven-membered cyclic sulfonamide, both representative of a novel family of agonists of the extracellular calcium sensing receptor (CaSR) of possible clinical importance, are reported. The known chirality of the naphthylethylamine precursor has enabled assignment of the absolute configuration of both compounds, which is crucial for the receptor recognition. The crystal structures, though different, reveal for these agonists a notable absence of intramolecular ,,, stacking between their respective aromatic groups. This suggests a common structural feature that allows CaSR agonists to be distinguished from antagonists, since in the latter, such interactions have been shown to be important. The connectivities between molecules in the crystal structures are also different, but both involve hydrogen bonding mediated by chloride ions as a common dominant feature. [source] Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS)CLINICAL ENDOCRINOLOGY, Issue 5 2006Justin G. S. Won Summary Objective, Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease. Patients, Ten consecutive patients with NIPHS (nine men and one woman, aged 29,78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests. Results, All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of ,-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6·1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of ,-cell peptides to meal stimulation. Conclusions, Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from ,-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying ,-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6·1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted. [source] | ||||||||||