Autofluorescence pattern of parathyroid adenomas.
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ABSTRACT:
SUBMITTER: Demarchi MS
PROVIDER: S-EPMC7893478 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant human prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1× 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
| S-ECPF-GEOD-32387 | biostudies-other
Project description:Primary hyperparathyroidism is a common endocrinopathy that is mainly caused by benign parathyroid adenomas. The frequency, clinical presentation and complications of the disease show significant differences between genders, with the majority of cases being reported in postmenopausal women. Due to this gender predilection, several studies have investigated the role of sex hormones in the pathogenesis of the disease and their potential use as targets for optimal and gender-specific management. Epigenetic mechanisms that regulate gene transcription may also contribute to these differences between genders. In this review, we outline what is currently known regarding the role of sex hormones and the recent data on the role of non-coding RNAs in the differences between genders in primary hyperparathyroidism due to sporadic parathyroid adenomas.
| S-EPMC7216151 | biostudies-literature
Project description:In this study, we genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated in our institution during 2005-2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P<0.001). Further analysis of 21 LPTAs revealed low MIB1 proliferation index (0.1-1.5%), MEN1 mutations in five cases, and one HRPT2 (CDC73) mutation. Total or partial loss of parafibromin expression was observed in ten tumors, two of which also showed loss of APC expression. Using array CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%), and loss in 11q (33%). Totally, 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11, and 15q and gains in 3q, 5, 7p, 8p, 16q, 17p, and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes most frequently gain of 5 and loss of chromosome 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r=0.48, P=0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features.
| S-EPMC3359501 | biostudies-literature
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas.
2012-05-01 | GSE32387 | GEO
Project description:Contrast-free autofluorescence (AF) of the parathyroid glands (PTGs) and thyroid tissue occurs in the near-infrared (NIR) spectrum on excitation by light in the upper range of the visible spectrum or lower NIR spectrum. In vivo, PTGs autofluoresce more brightly than thyroid (by a factor of 2-20 times) and appear as a bright spot against surrounding thyroid, muscle or fat on a processed image which is generated in real-time. NIR-AF of PTGs was first described in 2009 although NIR-AF had previously been used in several other clinical applications. Since then there has been a great amount of interest in the use of NIR-AF in thyroid and parathyroid surgery with over 25 published reports of the utilisation of both self-built and proprietary NIR-AF devices in neck endocrine surgery. All of these reports have confirmed the feasibility of NIR-AF intraoperatively and its ability to detect PTGs, although the reported accuracy varies from 90-100%. Reports of the effect of NIR-AF on relevant clinical endpoints i.e., post-operative hypoparathyroidism in thyroidectomy and persistent disease in parathyroidectomy are however scant. There has been one multicentre clinical trial of NIR-AF in thyroidectomy but this did not report clinical outcomes and two single-centre, non-randomised studies which did report post-operative hypoparathyroidism but with differing results: one showing no benefit in 106 NIR-AF vs. 163 controls and one, a reduction of early hypocalcaemia from 20% to 5% in 93 NIR-AF patients vs. 420 controls. There were only 2 cases of permanent hypoparathyroidism across both studies and therefore no significant observable difference in this key outcome variable. In parathyroidectomy, possible variability of the AF signal due to composition of a PTG adenoma, secondary/tertiary disease and MEN1 as well as depth-penetration preventing detection of sub-surface PTGs would imply that NIR-AF in its current form is not well-placed to improve cure-rates in hyperparathyroidism, which may already be as high as 98%. Thus far, no study has addressed this. Despite the promising results of NIR-AF, the absence of data demonstrating an improvement in outcomes and the cost of its use currently limit its use in routine clinical practice, especially in a publicly funded healthcare system with budgetary constraints. However, it can be utilised in research settings and this should be undertaken within the context of well-designed and conducted randomised, multi-centre, appropriately powered studies, which will assist in establishing its role in neck endocrine surgery.
| S-EPMC7044090 | biostudies-literature
Project description:We retrospectively evaluated how accurately preoperative imaging localizes parathyroid adenoma in superior versus inferior parathyroids. Over 6 years, 104 patients with primary hyperparathyroidism underwent parathyroid surgery in a single centre. Of these, 103 underwent ultrasound, 97 [99mTc]pertechnetate/MIBI SPECT/CT and 30 [18F]fluorocholine (FCH) PET/CT. One patient with a unilateral double adenoma was excluded from the analysis. Surgical findings with histopathologic confirmation of adenoma were used as the standard. Ultrasound misjudged 5 of 48 detected lower adenomas as upper, but 14 of 29 upper adenomas as lower (error rate 10 vs 48%, p = 0.0002). The corresponding error rates for [99mTc]pertechnetate/MIBI SPECT/CT were 3 versus 55% (p = 0.000014), and for [18F]FCH PET/CT 17 versus 36% (p = 0.26). Our results suggest that about half of the superior parathyroid adenomas which are detected, are erroneously assigned to the inferior position by both ultrasound and SPECT/CT imaging whereas the opposite mistake is significantly less frequent with ultrasound and SPECT/CT.
| S-EPMC10169799 | biostudies-literature
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant humanM-BM- prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1M-CM-^W 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
2012-04-30 | E-GEOD-32387 | biostudies-arrayexpress
Project description:We genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated on in our institution during 2005-2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P <0.001). Further analysis of 21 LPTAs revealed low MIB-1 proliferation index (0.1-1.5%), MEN1 mutations in 5 cases and one HRPT2 mutation. Total or partial loss of parafibromin expression was observed in 10 tumors, two of which also showed loss of APC expression. Using array-CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%) and loss in 11q (33%). Totally 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11 and 15q, and gains in 3q, 5, 7p, 8p, 16q, 17p and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes, most frequently gain of 5 and loss of 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r = 0.48, P = 0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features.
2012-05-09 | GSE36511 | GEO
Project description:Benign parathyroid adenoma is the most common cause of primary hyperparathyroidism, whereas malignant parathyroid carcinoma is exceedingly rare. Distinguishing parathyroid carcinoma from benign adenoma is often difficult, and may be considerably delayed even after surgical resection until the rigorous diagnostic criteria of local invasion of surrounding tissues and/or distant metastases are fulfilled. Thus, new insights into their respective molecular bases may potentially aid in earlier diagnostic discrimination between the two, as well as informing new directions for treatment. In two recent studies, gain-of-function mutations in PIK3CA, a recognized driver oncogene in many human malignancies, have been newly identified in parathyroid carcinoma. To assess the potential specificity for malignant, as opposed to benign parathyroid disease, of PIK3CA hotspot mutations, we PCR-amplified and Sanger sequenced codons 111, 542/545, and 1047 and the immediate flanking regions in genomic DNA from 391 typical, sporadic parathyroid adenomas. Four parathyroid adenomas (1%) had subclonal, somatic, heterozygous, activating PIK3CA mutations. The rarity of PIK3CA activating mutations in benign parathyroid adenomas suggests that tumorigenic activation of PIK3CA is strongly associated with malignant parathyroid neoplasia. However, it does not appear that such mutations, at least in isolation, can be relied upon for definitive molecular diagnosis of parathyroid carcinoma. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
| S-EPMC7285753 | biostudies-literature
Project description:The molecular abnormalities leading to sporadic parathyroid adenomas, a common type of human endocrine neoplasm, are heterogeneous and incompletely understood. Using whole exome and direct sequencing of parathyroid adenoma DNA samples, we identified recurrent somatic mutations in the ZFX gene. ZFX is a member of Krueppel C2H2 type zinc finger protein family, was initially described as a homolog of ZFY, and has been implicated as a transcription factor regulating embryonic stem cell renewal. The ZFX mutations we identified were strikingly specific, focused in each tumor on one encoded residue in a hotspot of two consecutive highly conserved arginine residues (R786/787; arginine to glutamine, threonine or leucine) in a zinc finger domain near the C-terminus of the protein. The intragenic specificity of these recurrently selected mutations, their confirmed expression within the tumors, the absence of loss of heterozygosity, and the absence of these mutations among over 4000 ZFX alleles in the dbSNP137 database, strongly suggest a novel role for ZFX as a human proto-oncogene. Further, these observations highlight the mutated zinc-finger domain as a new focal point for understanding ZFX's normal and tumorigenic functions, and for development of molecularly-targeted therapeutics.
| S-EPMC4278311 | biostudies-literature