scholarly journals Erratum to: “Ex Vivo Intact Tissue Analysis Reveals Alternative Calcium-Sensing Behaviors in Parathyroid Adenomas”

2021 ◽  
Keyword(s):  
Ex Vivo ◽  
Tissue Analysis ◽  
Intact Tissue ◽  
Calcium Sensing ◽  
Parathyroid Adenomas

scholarly journals Ex vivo intact tissue analysis reveals alternative calcium-sensing behaviors in parathyroid adenomas

2021 ◽  
Author(s):  
James Koh ◽  
Run Zhang ◽  
Sanziana Roman ◽  
Quan-Yang Duh ◽  
Jessica Gosnell ◽  
...  
Keyword(s):  
Response Curve ◽  
Clinical Presentation ◽  
Ex Vivo ◽  
Endocrine Surgery ◽  
Parathyroid Tumor ◽  
Mineral Density ◽  
Biochemical Basis ◽  
Intact Tissue ◽  
Calcium Sensing ◽  
Parathyroid Adenomas

Abstract Context The biochemical basis for clinical variability in primary hyperparathyroidism (PHPT) is poorly understood. Objectives To define parathyroid tumor biochemical properties associated with calcium sensing failure in PHPT patients, and to relate differences in these profiles to variations in clinical presentation. Design Pre-operative clinical data were evaluated for correlation to parathyroid tumor biochemical behavior. Setting An endocrine surgery referral center at a large, public university hospital. Patients and Other Participants A sequential series of 39 patients undergoing surgery for PHPT. Main Outcome Measures An intact tissue, ex vivo interrogative assay was employed to evaluate the calcium-sensing capacity of parathyroid adenomas relative to normal donor glands. Tumors were functionally classified based on calcium dose-response curve profiles, and clinical parameters were compared among the respective classes. Changes in the relative expression of CASR, RGS5, and RCAN1, three key components in the calcium/PTH signaling axis were evaluated as potential mechanisms for calcium-sensing failure. Results Parathyroid adenomas grouped into three distinct functional classes. Tumors with diminished calcium sensitivity were the most common (18 of 39) and were strongly associated with reduced bone mineral density (p=0.0009). Tumors with no calcium sensing deficit (11 of 39) were associated with higher pre-operative PTH (p = 0.036). A third group (6/39) displayed a non-sigmoid calcium/PTH response curve; four of these six tumors expressed elevated RCAN1. Conclusions Calcium-sensing capacity varies among parathyroid tumors but down-regulation of the calcium sensing receptor (CASR) is not an obligate underlying mechanism. Differences in tumor calcium responsiveness may contribute to variations in PHPT clinical presentation.

scholarly journals The Calcium Sensing Receptor: From Understanding Parathyroid Calcium Homeostasis to Bone Metastases

2008 ◽  
Vol 90 (4) ◽  
pp. 271-277 ◽  
Author(s):  
Radu Mihai
Keyword(s):  
Breast Cancer ◽  
Bone Metastases ◽  
Intracellular Calcium ◽  
Calcium Homeostasis ◽  
Membrane Trafficking ◽  
Calcium Concentration ◽  
Fluorescent Microscopy ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Parathyroid Adenomas

The cloning of the calcium sensing receptor (CaR) confirmed that parathyroid cells monitor extracellular calcium concentration ([Ca2+]ext) via a receptor-type mechanism. This lead to the hypothesis that abnormalities in the expression and/or function of the CaR could explain the biochemical abnormalities in primary hyperparathyroidism (PHPT). Cultured cells from parathyroid adenomas of patients operated for PHPT were used to monitor real-time changes in intracellular calcium concentration ([Ca2+]i) as measured by fluorescent microscopy using the Fura-2/AM dye. We found that CaR agonists trigger release of intracellular calcium pools and such responses are amplified by increasing the affinity of IP3 receptors. Using confocal microscopy to monitor membrane trafficking in living parathyroid cells labelled with the fluorescent dye FM1-43, we found that a decrease in [Ca2+]i rather than an absolute change in [Ca2+]ext is the main stimulus for exocytosis from human parathyroid cells. These data suggest that, in PHPT, a defective signalling mechanism from the CaR allows cells from parathyroid adenomas to maintain low [Ca2+]i with uninhibited PTH secretion in the face of hypercalcaemia. Over longer periods of time, CaR controls parathyroid proliferation via changes in tyrosine phosphorylation. We found that multiple proteins of molecular weight 20–65 kDa are phosphorylated within 10–60 min in response to CaR agonists. Further work demonstrated that high [Ca2+]i stimulates the expression of bcl-2 oncoprotein in cultured human parathyroid cells and that, in parathyroid adenomas, predominant expression of bcl-2 rather than bax oncoprotein might prevent apoptosis and explain the slow growth rate of these tumours. More recently, it became apparent that CaR stimulates cell proliferation in several cell types not involved in calcium homeostasis. Using archived histological material from 65 patients who died with metastatic breast cancer, we identified CaR expression predominantly in tumours from patients who developed bone rather than visceral metastases (35 of 49 versus 7 of 16; P < 0.01, chi-squared test). These data suggest that CaR expression has the potential to become a new biological marker predicting the risk of bone metastases in patients with breast cancer. A prospective study should investigate if patients with CaR-positive tumours are more likely to develop bone metastases and whether they could benefit more from prophylactic treatment with bisphosphonates or the newly developed CaR antagonists.

Calcium-sensing receptor expression and signalling in human parathyroid adenomas and primary hyperplasia

2000 ◽  
Vol 52 (3) ◽  
pp. 339-348 ◽  
Author(s):  
Sabrina Corbetta ◽  
Giovanna Mantovani ◽  
Andrea Lania ◽  
Stefano Borgato ◽  
Leonardo Vicentini ◽  
...  
Keyword(s):  
Receptor Expression ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Parathyroid Adenomas

Decreased expression of calcium-sensing receptor messenger ribonucleic acids in parathyroid adenomas

Surgery ◽  
1998 ◽  
Vol 124 (6) ◽  
pp. 1094-1099 ◽  
Author(s):  
Filip Farnebo ◽  
Anders Höög ◽  
Kerstin Sandelin ◽  
Catharina Larsson ◽  
Lars-Ove Farnebo
Keyword(s):  
Calcium Sensing Receptor ◽  
Ribonucleic Acids ◽  
Calcium Sensing ◽  
Parathyroid Adenomas

scholarly journals Ex vivo Fluorescence Confocal Microscopy: Chances and Changes in the Analysis of Breast Tissue

2021 ◽  
Author(s):  
Maja Carina Nackenhorst ◽  
Mohammad Kasiri ◽  
Bernd Gollackner ◽  
Heinz Regele
Keyword(s):  
Adipose Tissue ◽  
Confocal Microscopy ◽  
Ex Vivo ◽  
Tissue Imaging ◽  
Tissue Analysis ◽  
Frozen Sections ◽  
Histologic Diagnosis ◽  
Tissue Samples ◽  
Fluorescence Confocal Microscopy ◽  
Medical University

Abstract Background: Rapid histologic diagnosis of frozen sections is essential for a variety of surgical procedures. Frozen sections however, require specialized lab equipment, are prone to freezing artifacts and are not applicable to all types of tissue. Adipose tissue is especially difficult to process in frozen sections. Although these limitations are well known, no alternative method for microscopic tissue analysis that might replace frozen sections could be established. Our objective was to evaluate whether tissue imaging based on ex vivo fluorescent confocal microscopy (FCM) is applicable for rapid microscopic assessment of breast tumors specimens with abundant adipose tissue.Methods: We evaluated 17 tissue samples from mastectomy specimens, rich in adipose tissue, submitted to the department of pathology at the Medical University of Vienna. We conducted our study on the FCM VivaScope® 2500M-G4 (Mavig GmbH, Munich, Germany; Caliber I.D.; Rochester NY, USA).Results: When comparing FCM to frozen sections, we found a very similar overall processing time for FCM images and frozen sections respectively. Image quality was mostly superior to frozen sections (especially for adipose tissue and nuclear detail) but inferior to H&E stained FFPE sections. Limitations of the technology were uneven coloring, invisibility of ink applied for marking tissue margins and distortion artifacts if too much pressure is applied to the tissue. Conclusion: FCM has the potential to expand the application and usefulness of rapid tissue analysis as speed is comparable and quality exceeds that of frozen sections especially in tissues rich in adipose cells such as breast specimen.

Osteocalcin may participate to the bone-parathyroid crosstalk through activation of the calcium-sensing receptor in human parathyroid adenomas

2020 ◽  
Author(s):  
Chiara Verdelli ◽  
Tavanti Giulia Stefania ◽  
Riccardo Maggiore ◽  
Gilberto Mari ◽  
Veronica Sansoni ◽  
...  
Keyword(s):  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Parathyroid Adenomas

l-Type amino acids stimulate gastric acid secretion by activation of the calcium-sensing receptor in parietal cells

2005 ◽  
Vol 289 (4) ◽  
pp. G664-G669 ◽  
Author(s):  
Stephanie M. Busque ◽  
Jane E. Kerstetter ◽  
John P. Geibel ◽  
Karl Insogna
Keyword(s):  
Amino Acids ◽  
Atpase Activity ◽  
Acid Secretion ◽  
Ex Vivo ◽  
Parietal Cells ◽  
Secretory Cells ◽  
Calcium Sensing Receptor ◽  
Gastric Glands ◽  
Calcium Sensing ◽  
System L

Parietal cells are the primary acid secretory cells of the stomach. We have previously shown that activation of the calcium-sensing receptor (CaSR) by divalent (Ca2+) or trivalent (Gd3+) ions stimulates acid production in the absence of secretagogues by increasing H+,K+-ATPase activity. When overexpressed in HEK-293 cells, the CaSR can be allosterically activated by l-amino acids in the presence of physiological concentrations of extracellular Ca2+ (Cao2+; 1.5–2.5 mM). To determine whether the endogenously expressed parietal cell CaSR is allosterically activated by l-amino acids, we examined the effect of the amino acids l-phenylalanine (l-Phe), l-tryptophan, and l-leucine on acid secretion. In ex vivo whole stomach preparations, exposure to l-Phe resulted in gastric luminal pH significantly lower than controls. Studies using d-Phe (inactive isomer) failed to elicit a response on gastric pH. H+-K+-ATPase activity was monitored by measuring the intracellular pH (pHi) of individual parietal cells in isolated rat gastric glands and calculating the rate of H+ extrusion. We demonstrated that increasing Cao2+ in the absence of secretagogues caused a dose-dependent increase in H+ extrusion. These effects were amplified by the addition of amino acids at various Cao2+ concentrations. Blocking the histamine-2 receptor with cimetidine or inhibiting system l-amino acid transport with 2-amino-2-norbornane-carboxylic acid did not affect the rate of H+ extrusion in the presence of l-Phe. These data support the conclusion that amino acids, in conjunction with a physiological Cao2+ concentration, can induce acid secretion independent of hormonal stimulation via allosteric activation of the stomach CaSR.

scholarly journals Decrease in vitamin D receptor and calcium-sensing receptor in highly proliferative parathyroid adenomas

2003 ◽  
pp. 403-411 ◽  
Author(s):  
S Yano ◽  
T Sugimoto ◽  
T Tsukamoto ◽  
K Chihara ◽  
A Kobayashi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Serum Levels ◽  
Clinical Severity ◽  
Regression Analyses ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Strong Positive Relationship ◽  
Parathyroid Adenomas ◽  
Single Regression

OBJECTIVE: A significant decrease in vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) protein expression has been demonstrated recently in parathyroid (PT) adenomas. In this study, we investigated the relationships between the proliferative activity of parathyroid glands (PTGs) and the expression of VDR as well as CaSR, and compared it with the clinical severity in patients with primary hyperparathyroidism (1 degrees HPT). DESIGN: Seven patients with 1 degrees HPT were included in this study. Four patients with thyroid carcinoma served as controls. METHODS: Immunohistochemical staining was performed on serial sections of PTGs with specific antibodies against CaSR, VDR, and Ki67. Areas examined in each section were selected at random in relation to the gland size. The number of Ki67-positive cells was expressed as a labeling index (LI; positive cells per 1000 PT cells). The expression of CaSR and VDR was semi-quantitatively analyzed based on the intensity of staining. After averages of the scores from all areas were calculated, CaSR and VDR scores, and Ki67 LI were assigned to each gland for use in statistical analyses. RESULTS: In PT adenomas, scores of VDR and CaSR were markedly lower than in normal PTGs (P<0.01), while the proportion of Ki67-positive cells in PT adenomas was significantly higher than in normal PTGs (P<0.01). Single regression analyses revealed that Ki67 LI was positively correlated with serum levels of intact parathyroid hormone and Ca, and PTG weight (R=0.70, P<0.05, R=0.78, P<0.01 and R=0.84, P<0.05 respectively). Ki67 LI was negatively correlated with CaSR and VDR scores (R=-0.78, P<0.01 and R=-0.72, P<0.05 respectively). Moreover, there was a strong positive relationship between CaSR and VDR expression (R=0.95, P<0.001). CONCLUSIONS: Marked decreases in VDR and CaSR expression could, at least in part, be responsible for the high proliferation of PT cells and the pathological progression of 1 degree HPT.

scholarly journals Reduced Calcium Sensing Receptor (CaSR) Expression Is Epigenetically Deregulated in Parathyroid Adenomas

2020 ◽  
Vol 105 (9) ◽  
pp. 3015-3024
Author(s):  
Priyanka Singh ◽  
Sanjay Kumar Bhadada ◽  
Divya Dahiya ◽  
Ashutosh Kumar Arya ◽  
Uma Nahar Saikia ◽  
...  
Keyword(s):  
Protein Expression ◽  
Parathyroid Adenoma ◽  
Histone Modifications ◽  
Chromatin Immunoprecipitation ◽  
Methylation Status ◽  
Sequencing Analysis ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Bisulphite Sequencing ◽  
Parathyroid Adenomas

Abstract Aim Reduced calcium sensing receptor (CaSR) expression has been implicated in parathyroid tumorigenesis, but the underlying mechanism remains elusive. Accordingly, we aimed to explore the epigenetic changes (DNA methylation and histone modifications) involved in CaSR regulation in sporadic parathyroid adenomas and correlate epigenetic state with disease indices. Experimental Design Forty sporadic parathyroid adenomas and 10 control parathyroid tissues were studied. Real-time quantitative PCR (qPCR) for mRNA and immunohistochemistry for protein expression of CaSR were performed. The methylation status of the CaSR promoter 2 was determined by bisulphite sequencing analysis of sodium bisulphite-converted DNA. To determine the role of histone modifications in the CaSR regulation, chromatin immunoprecipitation-qPCR assay was performed. Results Real-time qPCR revealed reduced CaSR mRNA expression with a fold reduction of 0.12 (P &lt; 0.0001) in parathyroid adenomas. Immunohistochemistry revealed reduced protein expression of CaSR in 90% (36/40) of adenomas. The promoter 2 region of CaSR displayed significant hypermethylation in 45% (18/40) of the adenomas compared with the controls (6.7%; 1 of 10) (P &lt; 0.002). Bisulphite sequencing analysis revealed maximum methylated CpG at glial cell missing 2 binding site on the CaSR promoter 2 compared to other CpG sites. The methylation status of CaSR correlated directly with plasma intact parathyroid hormone levels in patients with parathyroid adenoma. With chromatin immunoprecipitation-qPCR analysis, H3K9me3 levels showed increased enrichment by 10-fold in adenomas and correlated with CaSR-mRNA expression (r = 0.61; P &lt; 0.003). Treatment with 5-aza-2′deoxycytidine restored the expression of CaSR in a parathyroid cell line. Conclusion Our data suggest that hypermethylation and increased H3K9me3 of the CaSR promoter 2 are involved in silencing CaSR expression in sporadic parathyroid adenoma.

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