1,720,980 research outputs found
Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects
No full textPrimary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long lasting progression. Nonetheless, the routinely use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far to be elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These considerations provided the basis for the Fourth Workshop recommendations of a more extensive diagnostic workout about kidney features and of wider criteria for parathyroid surgery including asymptomatic kidney disease. Moreover, kidney involvement in PHPT is likely to be affected by variants of genes coding the key molecules regulating the calcium and ions renal handling; these features might have clinical relevance and should be considered both during diagnostic workout and follow up. Finally, the effects of parathyroid surgery and of medical treatment on kidney involvement of PHPT are reviewed
Epigenetic Alterations in Parathyroid Cancers
Full text linkParathyroid cancers (PCas) are rare malignancies representing approximately 0.005% of all cancers. PCas are a rare cause of primary hyperparathyroidism, which is the third most common endocrine disease, mainly related to parathyroid benign tumors. About 90% of PCas are hormonally active hypersecreting parathormone (PTH); consequently patients present with complications of severe hypercalcemia. Pre-operative diagnosis is often difficult due to clinical features shared with benign parathyroid lesions. Surgery provides the current best chance of cure, though persistent or recurrent disease occurs in about 50% of patients with PCas. Somatic inactivating mutations of CDC73/HRPT2 gene, encoding parafibromin, are the most frequent genetic anomalies occurring in PCas. Recently, the aberrant DNA methylation signature and microRNA expression profile have been identified in PCas, providing evidence that parathyroid malignancies are distinct entities from parathyroid benign lesions, showing an epigenetic signature resembling some embryonic aspects. The present paper reviews data about epigenetic alterations in PCas, up to now limited to DNA methylation, chromatin regulators and microRNA profile
MicroRNAs in parathyroid physiopathology
No full textParathyroid glands regulate calcium homeostasis through synthesis and secretion of parathormone (PTH). They sense the extracellular calcium concentration through the G-protein coupled calcium sensing receptor (CASR) and release PTH in order to preserve calcium concentration in the physiological range. Tumors of the parathyroid glands are common endocrine neoplasia associated with primary or secondary/tertiary hyperparathyroidisms. Small non-coding RNAs are regulators of gene expression able to modulate hormone synthesis, hormone release and endocrine cell proliferation. In this scenario, microRNA (miRNA) expression profiles have been investigated in parathyroid tumors, while miRNAs are involved in hypocalcemia and uremia-induced PTH release from normal parathyroid cells. Here we reviewed data about the role of miRNAs in the regulation of: 1) PTH synthesis and secretion; 2) CASR expression; 3) parathyroid cell tumorigenesis. Though studies about miRNAs in parathyroid gland pathophysiology are limited, they contribute in elucidating regulatory pathways involved in PTH release and parathyroid cell tumorigenesis
Epigenetic alterations in human parathyroid tumors
No full textEpigenetics alterations are involved in tumorigenesis and have been identified in endocrine neoplasia. In particular, DNA methylation, microRNAs deregulations and histone methylation impairment are detected in tumors of the parathyroid glands. Parathyroid tumors are the second most common endocrine neoplasia following thyroid cancer in women, and it is associated with primary hyperparathyroidism, a disease sustained by PTH hypersecretion. Despite the hallmark of global promoter hypomethylations was not detectable in parathyroid tumors, increase of hypermethylation in specific CpG islands was detected in the progression from benign to malignant parathyroid tumors. Furthermore, deregulation of a panel of embryonic-related microRNAs (miRNAs) was documented in parathyroid tumors compared with normal glands. Impaired expression of the histone methyltransferases EZH2, BMI1, and RIZ1 have been described in parathyroid tumors. Moreover, histone methyltransferases have been shown to be modulated by the oncosuppressors HIC1, MEN1, and HRPT2/CDC73 gene products that characterize tumorigenesis of parathyroid adenomas and carcinomas, respectively. The epigenetic scenario in parathyroid tumors have just began to be decoded but emerging data highlight the involvement of an embryonic gene signature in parathyroid tumor development
MicroRNA deregulation in parathyroid tumours suggests an embryonic signature
No full textPrimary hyperparathyroidism is a common endocrine disorder caused by abnormal tumour parathyroid cell proliferation. Parathyroid tumours show a great variability both in clinical features, such as the severity of PTH secretion, the rate and the pattern of cell proliferation, and genetic background. Studies aiming to develop new diagnostic markers and therapeutic approaches need a deeper definition of this variability. Dysregulation of microRNAs (miRNAs) has been shown to play an essential role in the development and progression of cancer. MiRNAs are small noncoding RNAs that inhibit the translation and stability of messenger RNAs (mRNAs). Here, data about the miRNA expression pattern in parathyroid normal and tumour glands were reviewed. Though available data in parathyroid tumours are very limited, the expression pattern of a subset of specific miRNAs clearly discriminated parathyroid carcinomas from normal parathyroid glands and, more clinically relevant, from parathyroid adenomas. Investigation showed that parathyroid tumours were characterized by an embryonic expression pattern of miRNAs such as miR-296, or the miRNA clusters C19MC and miR-371-3, typically in stem cells committed to differentiation or during human embryonic development, respectively. Further, miRNA profiles were correlated with tumour aggressive behaviour. Moreover, the interaction with the oncosuppressor menin suggests that miRNAs might modulate the function of the known oncosuppressors or oncogenes involved in parathyroid tumourigenesis and thus overseeing the tumour phenotype. In conclusion, miRNAs might provide new diagnostic markers and new therapeutic approaches by developing molecular miRNA-targeted therapies for the cure of parathyroid tumours, whose unique option is surgery
Molecular and clinical aspects of the target therapy with the calcimimetic cinacalcet in the treatment of parathyroid tumors
No full textParathyroid tumors are almost invariably associated with parathormone (PTH) hypersecretion resulting in primary (PHPT) or secondary (SHPT) hyperparathyroidism. PHPT is the third most common endocrine disorder with a prevalence of 1-2% in post-menopausal women; SHPT is a major complication of chronic kidney failure, the prevalence of which is increasing. The calciumsensing receptor (CASR) is the key molecule regulating PTH synthesis and release from the parathyroid cells in response to changes in extracellular calcium concentrations. A potent calcimimetic, cinacalcet, has been developed in the last ten years and made available for medical treatment of both PHPT and SHPT. Cinacalcet has been demonstrated to be effective in inhibiting PTH secretion, though the drug fails to normalize PTH release, both in PHPT and SHPT patients with different degrees of disease severity, including patients with parathyroid carcinomas and with MEN1-related parathyroid tumors. Here we reviewed the molecular aspects of CASR target therapy and the effect of the CASR gene single nucleotide polymorphisms. Clinical data concerning the efficacy and safety of cinacalcet in controlling hyperparathyroidism are reported, focusing on the treatment of the different types of parathyroid tumors. Finally, limits of this target therapy are analyzed, pointing out the lack of efficacy in improving kidney and bone morbidities in PHPT and cardiovascular diseases in SHPT. Though cinacalcet is a target therapeutic option for parathyroid tumors, further approaches are warranted to fully control these metabolic disorders and the underlying tumors
Asymptomatic myotonia congenita unmasked by severe hypothyroidism
No full textMyotonia congenita is an inherited muscle disorder sustained by mutations in the skeletal muscle chloride channel gene CLCN1. Symptoms vary from mild to severe and generalized myotonia and worsen with cold, stressful events and hormonal fluctuations. Here we report the case of a young woman who sought medical attention because of subacute onset of diffuse and severe limb myotonia. CLCN1 gene sequencing showed a heterozygous transversion (T550M), two polymorphisms and one silent mutation. Thyroid function screening revealed severe hypothyroidism. She was placed on l-thyroxine replacement therapy which dramatically improved myotonia. We conclude that hypothyroidism unmasked a genetically determined, clinically asymptomatic chloride channelopathy. Diagnostic work-up in patients with clinically isolated myotonia should not be limited to genetic screening of non-dystrophic or dystrophic myotonias. Considering the high prevalence of hypothyroidism in females, systematic thyroid function screening by looking for additional hypothyroid symptoms and serum TSH levels measurement is mandatory in these patients
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Alterations of DNA methylation in parathyroid tumors
No full textParathyroid tumors are common endocrine neoplasias associated with primary hyperparathyroidism, a metabolic disorder characterized by parathormone hypersecretion. Parathyroid neoplasia are frequently benign adenomas or multiple glands hyperplasia, while malignancies are rare. The epigenetic scenario in parathyroid tumors has just begun to be decoded: DNA methylation, histones and chromatin modifiers expression have been investigated so far. The main findings suggest that DNA methylation and chromatin remodeling are active and deregulated in parathyroid tumors, cooperating with genetic alterations to drive the tumor phenotype: the tumor suppressors menin and parafibromin, involved in parathyroid tumorigenesis, interact with chromatin modifiers, defining distinct epigenetic derangements. Many epigenetic alterations identified in parathyroid tumors are common to those in human cancers; moreover, some aspects of the epigenetic profile resemble epigenetic features of embryonic stem cells. Epigenetic profile may contribute to define the heterogeneity of parathyroid tumors and to provide targets for new therapeutic approaches
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