Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly.

CYP27B1 encodes mitochondrial 1α-hydroxylase, which converts 25-hydroxyvitamin D to its active 1,25-dihydroxylated metabolite. We tested the hypothesis that common variants in the CYP27B1 promoter are associated with fracture risk. The study was designed as a population-based genetic association study, which involved 153 men and 596 women aged 65-101 years, who had been followed for 2.

Medullary thyroid carcinoma presenting with an initial CEA elevation.

Background: Carcinoembryonic antigen (CEA) is a tumour marker commonly associated with gastrointestinal malignancy. Patients presenting with an elevated CEA will therefore often undergo extensive investigations in order to elucidate an underlying gastrointestinal malignancy that may not be clinically apparent. However the GI tract is not the only source of CEA elevation.

MicroRNA profiling of benign and malignant pheochromocytomas identifies novel diagnostic and therapeutic targets.

MicroRNAs (miRNAs) are small RNAs ( approximately 22 bp) that post-transcriptionally regulate protein expression and are found to be differentially expressed in a number of human cancers. There is increasing evidence to suggest that miRNAs could be useful in cancer diagnosis, prognosis, and therapy. We performed miRNA microarray expression profiling on a cohort of 12 benign and 12 malignant pheochromocytomas and identified a number of differentially expressed miRNAs.

Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types.

The Carney triad (CT) is gastrointestinal stromal tumor (GIST), paraganglioma, and pulmonary chondroma. The GISTs of CT show different clinical, molecular, and morphologic features to usual adult GISTs but are similar to the majority of pediatric GISTs. We postulated that these GISTs would show negative staining for succinate dehydrogenase B (SDHB).

Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes.

Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET, Von Hippel-Lindau (VHL), neurofibromatosis type I (NF1), and succinate dehydrogenase subunits (SDHB, SDHC, and SDHD) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy (SDHB mutations) or significant multiorgan disease (RET, VHL, or NF1). However, conventional genetic testing for all loci is burdensome and costly.

Identification of Wnt family inhibitors: a pituitary tumor directed whole genome approach.

Wnt signaling pathways are important regulators of normal embryological development including that of the pituitary gland. Altered Wnt pathway expression is common in many human tumors however until recently the role of these pathways in human pituitary tumorigenesis has received little attention. The advent of microarray analysis has identified several Wnt pathway inhibitors that are frequently perturbed in pituitary tumors.

miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer.

PURPOSE: Adrenocortical adenomas are common, whereas adrenocortical carcinomas are rare. Discriminating between benign and malignant adrenocortical tumors using conventional histology can be difficult. In addition, adrenocortical carcinomas generally have poor prognosis and limited treatment options.

The glucocorticoid receptor is overexpressed in malignant adrenocortical tumors.

Context: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. The Weiss score is the most widely accepted method for distinguishing an ACC from an adrenocortical adenoma (ACA); however, in borderline cases, accurate diagnosis remains problematic. We recently discovered that the glucocorticoid receptor (GR) gene NR3C1 is significantly up-regulated in ACCs compared with ACAs in global gene expression studies.

Neonatal hypercalcemia due to polymorphisms of the calcium sensing receptor.

Familial hypocalciuric hypercalcemia (FHH) is known to be caused by heterozygous inactivating mutations of the calcium sensing receptor (CaSR) gene. We report an infant with transient neonatal hypercalcemia who was found to be homozygous for a polymorphism at A986S of the CaSR.

Outcomes of minimally invasive surgery for phaeochromocytoma.

Laparoscopic adrenalectomy is now accepted as the procedure of choice for the resection of benign adrenocortical tumours, but few studies have assessed whether the outcomes of laparoscopic adrenalectomy for adrenal phaeochromocytoma are similar to that of other adrenal tumour types. This is a retrospective cohort study. Clinical and operative data were obtained from an adrenal tumour database and hospital records.

Familial pituitary tumor syndromes.

The vast majority of pituitary tumors are benign and occur sporadically; however, they can still result in significant morbidity and even premature mortality through mass effects and hormone dysfunction. The etiology of sporadic tumors is still poorly understood; by contrast, advances have been made in our understanding of familial pituitary adenoma syndromes in the past decade. Currently, four genes are known to be associated with familial pituitary tumor syndromes: MEN1, CDKN1B, PRKAR1A and AIP.

Nuclear accumulation of e-cadherin correlates with loss of cytoplasmic membrane staining and invasion in pituitary adenomas.

Context: Loss of the cell adhesion protein E-cadherin is associated with invasion and metastasis in a number of malignancies. Recent studies have highlighted that loss of E-cadherin cell membrane expression may be accompanied by its detection in the nucleus, suggesting cellular redistribution during neoplasia. Pituitary tumors, although typically benign, may be locally invasive, and loss of membranous E-cadherin has been reported as a marker of invasion in prolactinomas.

Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours.

Context: Recent case reports detail the successful use of temozolomide in the management of aggressive pituitary tumours. O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that counteracts the effect of temozolomide.

Objective: To study MGMT expression in pituitary tumours and consider whether MGMT expression is associated with response to temozolomide therapy in aggressive pituitary tumours.

Headache of a diagnosis: frontotemporal pain and inflammation associated with osteolysis.

A 62-year-old woman presented with left frontotemporal pain, scalp tenderness and raised levels of inflammatory markers. Temporal arteritis was considered likely, and symptoms resolved with prednisone therapy. This delayed diagnostic bone biopsy until a soft tissue abscess formed, and Pott's puffy tumour associated with Prevotella osteomyelitis of the frontal bone was diagnosed.

Array-CGH identifies cyclin D1 and UBCH10 amplicons in anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive disease with largely unexplained etiology and molecular pathogenesis. In this study, we analyzed genome-wide copy number changes, BRAF (V-raf sarcoma viral oncogene homolog B1) mutations, and p16 and cyclin D1 expressions in a panel of ATC primary tumors. Three ATCs harbored the common BRAF mutation V600E.

Maternal vitamin D deficiency, ethnicity and gestational diabetes.

Aims: Vitamin D deficiency has been linked to impaired glucose metabolism. We determined whether serum 25-hydroxyvitamin D (25OHD) is associated with glucose metabolism in pregnant women and the effect of ethnicity on this relationship.

Methods: We analysed serum 25OHD concentrations in 307 pregnant women attending a metropolitan obstetric clinic between October 2003 and May 2005.

Wnt pathway inhibitors are strongly down-regulated in pituitary tumors.

The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.

A case of oncogenic osteomalacia with preoperative secondary hyperparathyroidism: description of the biochemical response of FGF23 to octreotide therapy and surgery.

Oncogenic osteomalacia is a rare condition characterized by a low serum phosphate, reduced tubular reabsorption of phosphate and a low or inappropriately normal 1,25 dihydroxyvitamin D and is usually secondary to a phosphaturic mesenchymal tumor. Complete tumor resection results in resolution of all features. We report a patient with oncogenic osteomalacia and concurrent secondary hyperparathyroidism.

Elevated serum FGF23 concentrations in plasma cell dyscrasias.

Fibroblast growth factor 23 (FGF23) is now recognized as a key regulator of phosphate metabolism. Numerous reports have found elevated serum FGF23 concentrations in oncogenic osteomalacia associated with mesenchymal tumors. Hypophosphatemic osteomalacia more rarely occurs in non-mesenchymal tumors.

Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation.

A subset of follicular thyroid carcinomas contains a balanced translocation, t(2;3)(q13;p25), that results in fusion of the paired box gene 8 (PAX8) and peroxisome proliferator-activated receptor gamma (PPARG) genes with concomitant expression of a PAX8-PPARgamma fusion protein, PPFP. PPFP is thought to contribute to neoplasia through a mechanism in which it acts as a dominant-negative inhibitor of wild-type PPARgamma. To better understand this type of follicular carcinoma, we generated global gene expression profiles using DNA microarrays of a cohort of follicular carcinomas along with other common thyroid tumors and used the data to derive a gene expression profile characteristic of PPFP-positive tumors.

The Ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPARgamma fusion.

Context: The Ras effector NORE1A (RASSF5A) is a putative tumor suppressor and is inactivated in several human cancers. NORE1A has not been studied in thyroid cancer.

Objective: The objective of this study was to investigate whether NORE1A is involved in follicular thyroid cancer (FTC) development.

PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth.

Follicular thyroid carcinomas are associated with a chromosomal translocation that fuses the thyroid-specific transcription factor paired box gene 8 (PAX8) with the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). This study investigated the transcriptional mechanisms by which PAX8-PPARgamma regulates follicular thyroid cells. In HeLa cells, rat follicular thyroid (FRTL-5) cells, or immortalized human thyroid cells, PAX8-PPARgamma stimulated transcription from PAX8-responsive thyroperoxidase and sodium-iodide symporter promoters in a manner at least comparable with wild-type PAX8.

Leukocyte matrix metalloproteinase-9 is elevated and contributes to lymphocyte activation in type I diabetes.

Degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs) is integral to cell migration and tissue remodeling in diabetes mellitus and its complications. MMPs also regulate the function of leukocytes via proteolytic processing of cytokines/chemokines. In this study, we measured the production of MMP-9 and its natural tissue inhibitor (TIMP)-1 by leukocytes isolated from human type I diabetic patients.

A double mutation in the extracellular Ca2+-sensing receptor's venus flytrap domain that selectively disables L-amino acid sensing.

The extracellular Ca(2+)-sensing receptor is activated allosterically by l-amino acids, and recent molecular analysis indicates that amino acids are likely to bind in the receptor's Venus flytrap domain. In the current study we set out to identify residues in the VFT domain that specifically support amino acid binding and/or amino acid-dependent receptor activation. Herein we describe two mutations of the Ca(2+)-sensing receptor (CaR) Venus Flytrap domain, T145A and S170T, that specifically impair amino acid sensing, leaving Ca2+ sensing intact, as determined by receptor-dependent activation of intracellular Ca2+ mobilization in fura-2-loaded HEK293 cells.