USG is a convenient, affordable and useful modality to localize abnormal enlarged parathyroid glands in the majority of patients with PHPT. However, when USG is negative, scintigraphy is complementary to it.

Among the 3 imaging techniques tested simultaneously, FCH PET/CT was superior for accurate preoperative localization of parathyroid adenomas, especially for ectopic or small parathyroid lesions.

The presentation of primary hyperparathyroidism (PHPT) is variable throughout the world. The present study explored retrospective data submitted to the Indian PHPT registry ( http://www.indianphptregistry.com ) between July 2005 and June 2015 from 5 centres covering four different geographical regions. The clinical, biochemical, radiological and histopathological characteristics of PHPT patients across India were analysed for similarity and variability across the centres. A total of 464 subjects (137 men and 327 women) with histopathologically proven PHPT were analysed. The mean age was 41 ± 14 years with a female:male ratio of 2.4:1. The majority (95%) of patients were symptomatic. Common clinical manifestations among all the centres were weakness and fatigability (58.7%), bone pain (56%), renal stone disease (31%), pancreatitis (12.3%) and gallstone disease (11%). Mean serum calcium, parathyroid hormone and inorganic phosphorus levels were 11.9 ± 1.6 mg/dL, 752.4 ± 735.2 pg/mL and 2.8 ± 0.9 mg/dL, respectively. Sestamibi scanning had better sensitivity than ultrasonography in the localisation of parathyroid adenoma; however, when these two modalities were combined, 93% of the cases were correctly localised. Mean parathyroid adenoma weight was 5.6 ± 6.5 g (0.1-54 g). It was concluded that the majority of PHPT patients within India are still mainly symptomatic with >50% of patients presenting with bone disease and one-third with renal impairment. Compared to Western countries, Indian patients with PHPT are younger, biochemical abnormalities are more severe, and adenoma weight is higher. As our observation is largely derived from a tertiary care hospital (no routine screening of serum calcium level), the results do not reflect racial differences in susceptibility to PHPT.

Inhibin is a heterodimeric TGFβ family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers; however, its tumor-specific functions remain unknown. Here, we demonstrate that the α subunit of inhibin (INHA), which is critical for the functionality of dimeric inhibin A/B, correlates with microvessel density in human ovarian tissues and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that inhibin-regulated angiogenesis is necessary for metastasis. Although inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis i and Inhibin-induced angiogenesis was abrogated via anti-inhibin α antibodies. The endothelial-specific TGFβ receptor complex comprising ALK1 and endoglin was a crucial mediator of inhibin signaling, offering a molecular mechanism for inhibin-mediated angiogenesis. These results are the first to define a role for inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting inhibin therapeutically. Inhibin is a predictor of poor patient survival in multiple cancers and is a potential target for antiangiogenic therapies. .

There is increased recycling of soluble fibronectin from the cell surface for fibrillogenesis. This recycling is regulated by TGF-β in a transcription- and SMAD-independent manner via specific TβRII and integrin α5β1 interactions. The recycling of fibronectin is Rab11 dependent and is required for TGF-β–induced cell migration.

Edited by Xiao-Fan WangHyperactive Wnt/␤-catenin signaling is linked to cancer progression and developmental abnormalities, making identification of mechanisms controlling Wnt/␤-catenin signaling vital. Transforming growth factor ␤ type III receptor (T␤RIII/betaglycan) is a transmembrane proteoglycan co-receptor that exists with or without heparan and/or chondroitin sulfate glycosaminoglycan (GAG) modifications in cells and has established roles in development and cancer. Our studies here demonstrate that T␤RIII, independent of its TGF␤ co-receptor function, regulates canonical Wnt3a signaling by controlling Wnt3a availability through its sulfated GAG chains. Our findings revealed, for the first time, opposing functions for the different GAG modifications on T␤RIII suggesting that Wnt interactions with the T␤RIII heparan sulfate chains result in inhibition of Wnt signaling, likely via Wnt sequestration, whereas the chondroitin sulfate GAG chains on T␤RIII promote Wnt3a signaling. These studies identify a novel, dual role for T␤RIII/betaglycan and define a key requirement for the balance between chondroitin sulfate and heparan sulfate chains in dictating ligand responses with implications for both development and cancer.Wnt glycoproteins regulate three distinct Wnt signaling pathways to mediate cell fate, proliferation, and apoptosis as well as cancer initiation and progression in multiple cancers, including ovarian (1-9). Activation of the canonical Wnt/␤-catenin pathway begins with the binding of Wnt to its cell surface receptors, Frizzled and LDL receptor-related proteins 5/6 (LRP5/6), 3 followed by phosphorylation of LRP5/6, recruitment of Dishevelled to the plasma membrane to interact with Frizzled, and stabilization of cytosolic ␤-catenin (10). Axin interaction with phosphorylated LRP5/6 and Dishevelled leads to inactivation of the ␤-catenin destruction complex, accumulation of ␤-catenin, and translocation to the nucleus to regulate Wnt target genes by binding to TCF/LEF transcription factors (10, 11). The Wnt signaling cascade is controlled in part by transmembrane proteoglycans, which interact with Wnt signaling components and can either stimulate or inhibit signaling activity. For instance, the HSPG glypican-3 and syndecan-1 stimulate canonical Wnt signaling (12, 13), whereas others, including glypican-1 and glypican-6, suppress Wnt signaling (13,14). Type III TGF-␤ receptor (T␤RIII)/betaglycan is a transmembrane proteoglycan with loss resulting in embryonic lethality in mice (15). Beyond its roles in regulating TGF-␤ signaling, T␤RIII also controls several other pathways to inhibit cell migration, invasion, cell growth, and angiogenesis in both in vitro and in vivo cancer models (16 -22) and regulating differentiation through FGF2 signaling (23). Mechanistically, T␤RIII regulates these pathways either by altering the actin cytoskeleton, via T␤RIII/␤-arrestin2 cytoplasmic interactions (24), or by GAG chain interactions with FGF2 (23). Overall, T␤RIII also acts as a tumor suppressor in prostate (19), lung...

Abstract Aim Reduced 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 normal parathyroid tissues were studied. Real time quantitative polymerase chain reaction (qRT-PCR) 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 qRT-PCR revealed reduced CaSR mRNA expression with a fold reduction of 0.12 (P<0.0001) in parathyroid adenomas. Immunohistochemistry revealed reduced protein expression of CaSR in 85% (34/40) of adenomas. The promoter 2 region of CaSR displayed significant hypermethylation in 45% (18/40) of the adenomas compared to the controls (6.7%;1of 10)(P<0.0001). Bisulphite sequencing analysis revealed maximum methylated CpG at GCM2 binding sites on the CaSR promoter compared to other CpG sites. The methylation status of CaSR correlated directly with plasma iPTH levels in patients with parathyroid adenoma. With ChIP-qPCR analysis, H3K9me3 levels showed increased enrichment by 10-fold in adenomas and correlated with CaSR-mRNA expression (r=0.61; P<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.

Cyclin D1, a G1-S phase regulator, is upregulated in parathyroid adenomas. Since cyclin-dependent kinase (CDK) inhibitors, CDKN2A and CDKN2B, and RASSF1A (Ras-association domain family 1, isoform A) are involved in G1-S phase arrest and act as potential tumor suppressor genes, we aimed to study potential methylation-mediated inactivation of these genes in parathyroid adenomas. Gene expressions of cyclin D1 (CCND1) and regulatory molecules (CDKN2A, CDKN2B and RASSF1A) was analysed in parathyroid adenoma tissues (n = 30). DNA promoter methylation of cyclin D1 regulators were assessed and correlated with clinicopathological features of the patients. Gene expression analysis showed a relative fold reductions of 0.35 for CDKN2A (p = 0.01), 0.45 for CDKN2B (P = 0.02), and 0.39 for RASSF1A (p < 0.01) in adenomatous compared to normal parathyroid tissue. There was an inverse relationship between the expressions of CDKN2A and CDKN2B with CCND1. In addition, the promoter regions of CDKN2A, CDKN2B, and of RASSF1A were significantly hyper-methylated in 50% (n = 15), 47% (n = 14), and 90% (n = 27) of adenomas respectively. In contrast, no such aberrant methylation of these genes was observed in normal parathyroid tissue. So, promoter hypermethylation is associated with down-regulation of CCND1 regulatory genes in sporadic parathyroid adenomas. This dysregulated cell cycle mechanism may contribute to parathyroid tumorigenesis.