Epigenetic Alterations in Parathyroid Cancers

Parathyroid 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

Serum NT-proBNP Levels Are Not Related to Vitamin D Status in Young Patients with Congenital Heart Defects

Context. Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has been suggested to influence cardiac performance and N-terminal-pro-type B natriuretic peptide (NT-proBNP) release in adults with heart failure. Objectives. To assess the vitamin D status and the impact of hypovitaminosis D on circulating NT-proBNP levels in young patients with congenital heart defects (CHD). Design and Patients. This cross-sectional study included the assessment of serum 25-hydroxyvitamin D (25OHD), parathyroid function markers, and NT-proBNP levels in a series of 230 young in-patients (117 females, 113 males; 6.4 (4.0-9.1) years (median, interquartile range)) with CHD. Results. Serum 25OHD levels 30 ng/mL) occurred in 25% of patients. Serum 25OHD levels inversely correlated with age (r =-0.169, P = 0.013) and height standard deviation score (r =-0.269, P = 0.001). After correction for age, 25OHD negatively correlated with serum PTH levels (\u3b2 =-0.200, P = 0.002). PTH levels above the upper quartile (44 pg/mL) occurred in 32% of hypovitaminosis D patients. Serum NT-proBNP levels were not correlated with 25OHD and PTH levels. Conclusions. Half of the young CHD patients were diagnosed with 25OHD deficiency and a third of hypovitaminosis D patients experienced hyperparathyroidism. Nonetheless, serum NT-proBNP levels were not associated with hypovitaminosis D as well as hyperparathyroidism

Serum NT-proBNP Levels Are Not Related to Vitamin D Status in Young Patients with Congenital Heart Defects

Context. Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has been suggested to influence cardiac performance and N-terminal-pro-type B natriuretic peptide (NT-proBNP) release in adults with heart failure. Objectives. To assess the vitamin D status and the impact of hypovitaminosis D on circulating NT-proBNP levels in young patients with congenital heart defects (CHD). Design and Patients. This cross-sectional study included the assessment of serum 25-hydroxyvitamin D (25OHD), parathyroid function markers, and NT-proBNP levels in a series of 230 young in-patients (117 females, 113 males; 6.4 (4.0-9.1) years (median, interquartile range)) with CHD. Results. Serum 25OHD levels <20 ng/mL were detected in 55.3% of patients. Optimal 25OHD levels (>30 ng/mL) occurred in 25% of patients. Serum 25OHD levels inversely correlated with age ( = −0.169, = 0.013) and height standard deviation score ( = −0.269, = 0.001). After correction for age, 25OHD negatively correlated with serum PTH levels ( = −0.200, = 0.002). PTH levels above the upper quartile (44 pg/mL) occurred in 32% of hypovitaminosis D patients. Serum NT-proBNP levels were not correlated with 25OHD and PTH levels. Conclusions. Half of the young CHD patients were diagnosed with 25OHD deficiency and a third of hypovitaminosis D patients experienced hyperparathyroidism. Nonetheless, serum NT-proBNP levels were not associated with hypovitaminosis D as well as hyperparathyroidism

Polaritonic Chemistry Enabled by Non-Local Metasurfaces

Vibrational strong coupling can modify chemical reaction pathways in unconventional ways. Thus far, Fabry-Perot cavities formed by pairs of facing mirrors have been mostly utilized to achieve vibrational strong coupling. In this study, we demonstrate the application of plasmonic microparticle arrays defining non-local metasurfaces that can sustain surface lattice resonances as a novel tool to enable chemical reactions under vibrational strong coupling. We show that the solvolysis kinetics of \textit{para}-nitrophenyl acetate can be accelerated by a factor of 2.7 by strong coupling to the carbonyl bond of the solvent and the solute with a surface lattice resonance. Our work introduces a new platform to investigate and control polaritonic chemical reactions. In contrast to Fabry-Perot cavities, metasurfaces define open optical cavities with single surfaces, which removes alignment hurdles, facilitating polaritonic chemistry across large areas

Effects of 12-months treatment with zoledronate or teriparatide on intima-media thickness of carotid artery in women with postmenopausal osteoporosis: A pilot study

Atherosclerosis and osteoporosis are interrelated entities and share similar pathogenic mechanisms. Recent studies showed that key proteins of bone metabolism, such as osteoprotegerin (OPG) and osteopontin (OPN), are also involved in vascular atherosclerosis and calcifications. The carotid intima-media thickness (CA-IMT) is an early quantitative marker of generalized atherosclerosis. Aim of study was to investigate whether 12-months treatment with zoledronate (ZLN) or teriparatide (TPT) affects CA-IMT and circulating OPG and OPN levels. In this study, 11 postmenopausal osteoporotic women (aged 73, 70.5\u201374.5 years; median, range interquartile) treated with 5 mg/year iv ZLN; 9 postmenopausal osteoporotic women (aged 70, 62.5\u201373.5 years) treated with 20 \ub5g/day sc TPT; and 10 aged-, body mass index (BMI)-, glycemic, and lipid profiles-matched, free from anti-osteoporotic and hypocholesterolemic drugs, controls were prospectively investigated at baseline and after 12 months. At baseline, median CA-IMT was similar in the three groups and increased after 12 months. CA-IMT increased significantly in TPT-treated patients (1.0, 0.8\u20131.2 vs 1.1, 0.9\u201315 mm, P = 0.04), though the change was minimal. After 12 months of treatment, CA-IMT positively correlated with alkaline phosphatase (ALP) levels (r = 0.767, P = 0.008) and negatively with high-density lipoprotein (HDL) cholesterol levels (r = 120.65, P = 0.03), suggesting interplay between active bone remodeling and lipid profile. At baseline and after 12 months, median serum OPG and OPN levels did not differ among the groups and did not correlate with changes in CA-IMT. In conclusion, ZLN and TPT treatments are safe on carotid walls in osteoporotic women with subclinical atherosclerosis; circulating OPG and OPN are not affected by long-term anti-osteoporotic treatments and do not correlate with CA-IMT

po 450 interplay between coding and non coding genome in human parathyroid tumours

Introduction Parathyroid tumours are the second most common endocrine neoplasia in women, after thyroid cancer. Mutations in the oncosuppressor CDC73 are the key event in most carcinomas whereas alterations in the tumour suppressor MEN1 (located at 11q13.1) occur in up to a third of sporadic adenomas. Although lncRNAs play a regulatory role in endocrine cancer pathogenesis, a lncRNAs profiling in human parathyroid tumours is still missing. Here, we identified a 'molecular signature' able to distinguish among parathyroid histotypes and a new potential epigenetic role of MEN1 in lncRNAs regulation. Material and methods Ninety lncRNAs were investigated in 4 parathyroid carcinomas (PCas), 12 adenomas (PAds) and 2 normal glands (PaNs). Hierarchical clustering (HCL) and Significance Analysis of Microarray (SAM) were performed to identify differences in lncRNAs expression. Significant lncRNAs were validated in additional 7 PCas, 26 PAds, 6 atypical PAds (aPAds) and 4 PaNs. CDC73 and MEN1 genes mutations were detected by Sanger sequencing. PAds genomic characterisation was obtained by array Comparative Genomic Hybridization (aCGH). HEK293 cells were transiently silenced for MEN1 expression to analyse MEN1-lncRNAs correlation. Results and discussions Nine lncRNAs were identified as differentially expressed in parathyroid tissues. Specifically, KCNQ1OT1 and SNHG6 were enriched in PaNs, reduced HAR1B, MEG3, HOXA3as and NEAT1 expression characterised PAds, whereas BC200, HOXA6as and WT1-AS were upregulated in PCas. HCL identified 3 clusters in which PaNs and PCas were distinctly separated, while aPAds were closer to PCas. Moreover, PAds clustered in a highly heterogeneous way. Notably, PCas and aPAds harbouring CDC73-mutations overexpressed the majority of the lncRNAs, compared to CDC73 wild-type samples. Interestingly, BACE1-AS, KCNQ1OT1, NEAT1 and SNHG6 levels in PAds were positively correlated with MEN1 levels. aCGH analysis revealed that Chr11 loss of heterozygosity (LOH) was the main chromosomal aberration in PAds. Of note, Chr11 LOH was associated with significant HAR1B upregulation and these data were confirmed in HEK293 cells knocked-down for MEN1. Conclusion Parathyroid histotypes are characterised by different lncRNAs signatures, suggesting a correlation with tumour aggressiveness and pathogenetic mechanisms. Further, our data highlight that lncRNAs profiles are related to CDC73 gene mutation status, chromosome 11 derangements and MEN1 inactivation

Efficacy and tolerability of tirbanibulin 1% ointment in the treatment of cancerization field: a real-life Italian multicenter observational study of 250 patients

Background: Tirbanibulin 1% ointment is approved for the field treatment of Olsen grade I actinic keratoses (AKs) of the face and scalp. Methods: We performed a multicenter retrospective study involving 15 dermatologic units in Italy to investigate the efficacy and tolerability of tirbanibulin in a real-life setting. 250 patients were enrolled. Tirbanibulin, 1% ointment, was applied daily for five consecutive days. The efficacy of treatment was measured with modifications of the Actinic Keratosis Area and Severity Index (AKASI). A satisfactory response was defined by complete (100% reduction in the number of lesions) or partial clearance (75-99%) of treated AKs. Results: Overall, the AKASI score was significantly reduced in the studied population (mean, from 4.1 ± 2.7 to 1.4 ± 1.5; P < 0.001). A satisfactory response was observed in 222 (88.8%) cases. The proportion of satisfactory responses was higher when follow-up was performed after 8 weeks (34/35, 97.1%). The reduction in AKASI was significant in patients with Olsen grade II or III lesions (from 5.3 ± 2.8 to 1.6 ± 1.6; P < 0.001). A satisfactory response was observed in 91/104 (87.5%) cases. AKASI reduction was also significant in patients with trunk or limb AKs (from 7.0 ± 1.3 to 2.0 ± 1.6; P = 0.018) since a satisfactory response was observed in 7/8 (87.5%) cases. Tirbanibulin was well tolerated; all adverse events (AEs) included transient local reactions at the site of treatment. Overall, 231 patients had at least one AE. Only 7 (2.8%) grade 4 AEs were recorded. Conclusion: Our retrospective study confirmed that tirbanibulin 1% ointment is effective and well tolerated in a real-life setting and is also promising for Olsen grade II and grade III AKs and AKs localized on difficult-to-treat areas

Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects

Primary 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