FMRFamide related peptide ligands activate the Caenorhabditis elegans orphan GPCR Y59H11AL.1

G-protein coupled receptors (GPCRs) are ancient molecules that can sense environmental and physiological signals. Currently, the majority of the predicted Caenorhabditis elegans GPCRs are orphan. Here, we describe the characterization of such an orphan C. elegans GPCR, which is categorized in the tachykinin-like group of receptors. Since the C. elegans genome predicts only one tachykinin-like peptide (SFDRMGGTEFGLM), which could not activate the receptor, we hypothesized that one or some of the numerous FMRFamide related peptides (FaRPs) could be the cognate ligands for this receptor. This hypothesis was based on the suggestion that RFamides may be ancestral neuropeptides, from which a lot of the amidated neuropeptides, including tachykinins, derived. Indeed, we found that the orphan receptor encoded by the Y59H11AL.1 gene is activated by several C. elegans neuropeptides, including SPMERSAMVRFamide. These peptides activate the receptor in a concentration-dependent way.status: publishe

Comparison of Qualitative (COBAS AMPLICOR HCV 2.0 versus VERSANT HCV RNA) and Quantitative (COBAS AMPLICOR HCV Monitor 2.0 versus VERSANT HCV RNA 3.0) Assays for Hepatitis C Virus (HCV) RNA Detection and Quantification: Impact on Diagnosis and Treatment of HCV Infections

Quantitative measurements of serum hepatitis C virus (HCV) RNA are becoming increasingly important in the management of HCV-infected patients. Here we compared two quantitative assays, the COBAS AMPLICOR HCV Monitor 2.0 assay (Roche Diagnostics) and the branched DNA-based VERSANT HCV RNA 3.0 assay (Bayer Diagnostics) for HCV RNA measurement in 344 samples derived from 120 patients with chronic genotype 1 HCV infection. The overall concordance between the results of the two tests was 95%, and the HCV RNA titers within the dynamic ranges of the assays correlated very well (r(2) = 0.86). Furthermore, both tests performed equally well in determining an early viral response at week 1 or 4 during antiviral therapy. We also compared two qualitative HCV RNA detection assays: the COBAS AMPLICOR HCV 2.0 assay versus the transcription-mediated amplification (TMA)-based VERSANT HCV RNA qualitative assay. Stored samples from sustained responders to interferon-ribavirin therapy were retested by the HCV TMA assay and were found to contain no detectable HCV RNA, demonstrating complete concordance between the results of PCR and TMA. However, HCV RNA was detected by the TMA assay in end-of-treatment (ETR) samples from 33% of patients with relapses who were HCV RNA negative according to the COBAS AMPLICOR assay. This observation suggests that a TMA assay can lead to a more correct definition of the ETR response

The Vitamin D Receptor in Thyroid Development and Function

Background and Objective: Vitamin D is known to modulate thyroid neoplastic and autoimmune disease. We investigated the role of the vitamin D receptor (VDR) in normal thyroid development and function (thyrocytes and C cells). Methods: The thyroid phenotype of VDR knockout mice was studied in comparison to wild-type controls. The mice were fed a normal diet or a calcium-rich diet to circumvent effects induced by hypocalcemia. Results: Thyroid morphology was unaltered in VDR knockout mice. Also, expression of different parameters of thyrocyte function was comparable (immunohistochemistry). C cell physiology was, however, affected in the absence of the VDR, resulting in increased thyroidal calcitonin expression (immunohistochemistry), paralleled by increased serum calcitonin levels, but only in normocalcemic mice. To study a possible effect of vitamin D status on basal calcitonin levels in humans, serum calcitonin concentrations were compared between vitamin D-deficient and -sufficient patients (serum 25-OH vitamin D3 ≤10 and ≥40 ng/ml, respectively), but no difference was observed. Conclusions: In mice, the VDR is redundant for normal thyrocyte function, but not for C cell function, where it mediates the negative control of calcitonin by 1,25-dihydroxyvitamin D3. In patients, vitamin D status does not affect basal serum calcitonin levels. A study in healthy individuals is needed to confirm these findings

The vitamin D receptor in thyroid development and function

BACKGROUND AND OBJECTIVE: Vitamin D is known to modulate thyroid neoplastic and autoimmune disease. We investigated the role of the vitamin D receptor (VDR) in normal thyroid development and function (thyrocytes and C cells). METHODS: The thyroid phenotype of VDR knockout mice was studied in comparison to wild-type controls. The mice were fed a normal diet or a calcium-rich diet to circumvent effects induced by hypocalcemia. RESULTS: Thyroid morphology was unaltered in VDR knockout mice. Also, expression of different parameters of thyrocyte function was comparable (immunohistochemistry). C cell physiology was, however, affected in the absence of the VDR, resulting in increased thyroidal calcitonin expression (immunohistochemistry), paralleled by increased serum calcitonin levels, but only in normocalcemic mice. To study a possible effect of vitamin D status on basal calcitonin levels in humans, serum calcitonin concentrations were compared between vitamin D-deficient and -sufficient patients (serum 25-OH vitamin D3 ≤10 and ≥40 ng/ml, respectively), but no difference was observed. CONCLUSIONS: In mice, the VDR is redundant for normal thyrocyte function, but not for C cell function, where it mediates the negative control of calcitonin by 1,25-dihydroxyvitamin D3. In patients, vitamin D status does not affect basal serum calcitonin levels. A study in healthy individuals is needed to confirm these findings.status: publishe

Altered Expression of Key Players in Vitamin D Metabolism and Signaling in Malignant and Benign Thyroid Tumors

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, mediates antitumor effects in various cancers. The expression of key players in vitamin D signaling in thyroid tumors was investigated. Vitamin D receptor (VDR) and CYP27B1 and CYP24A1 (respectively activating and catabolizing vitamin D) expression was studied (RT-PCR, immunohistochemistry) in normal thyroid, follicular adenoma (FA), differentiated thyroid cancer (DTC) consisting of the papillary (PTC) and follicular (FTC) subtype, and anaplastic thyroid cancer (ATC). VDR, CYP27B1, and CYP24A1 expression was increased in FA and DTC compared with normal thyroid. However, in PTC with lymph node metastasis, VDR and CYP24A1 were decreased compared with non-metastasized PTC. In ATC, VDR expression was often lost, whereas CYP27B1/CYP24A1 expression was comparable to DTC. Moreover, ATC with high Ki67 expression (>30%) or distant metastases at diagnosis was characterized by more negative VDR/CYP24A1/CYP27B1 staining. In conclusion, increased expression of key players involved in local 1,25(OH)(2)D(3) signaling was demonstrated in benign and differentiated malignant thyroid tumors, but a decrease was observed for local nodal and especially distant metastasis, suggesting a local antitumor response of 1,25(OH)(2)D(3) in early cancer stages. These findings advocate further studies with 1,25(OH)(2)D(3) and analogs in persistent and recurrent iodine-refractory DTC.status: publishe