Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes.

AIMS/HYPOTHESIS: MicroRNAs are key regulators of gene expression involved in health and disease. The goal of our study was to investigate the global changes in beta cell microRNA expression occurring in two models of obesity-associated type 2 diabetes and to assess their potential contribution to the development of the disease. METHODS: MicroRNA profiling of pancreatic islets isolated from prediabetic and diabetic db/db mice and from mice fed a high-fat diet was performed by microarray. The functional impact of the changes in microRNA expression was assessed by reproducing them in vitro in primary rat and human beta cells. RESULTS: MicroRNAs differentially expressed in both models of obesity-associated type 2 diabetes fall into two distinct categories. A group including miR-132, miR-184 and miR-338-3p displays expression changes occurring long before the onset of diabetes. Functional studies indicate that these expression changes have positive effects on beta cell activities and mass. In contrast, modifications in the levels of miR-34a, miR-146a, miR-199a-3p, miR-203, miR-210 and miR-383 primarily occur in diabetic mice and result in increased beta cell apoptosis. These results indicate that obesity and insulin resistance trigger adaptations in the levels of particular microRNAs to allow sustained beta cell function, and that additional microRNA deregulation negatively impacting on insulin-secreting cells may cause beta cell demise and diabetes manifestation. CONCLUSIONS/INTERPRETATION: We propose that maintenance of blood glucose homeostasis or progression toward glucose intolerance and type 2 diabetes may be determined by the balance between expression changes of particular microRNAs

Aurora kinases are expressed in medullary thyroid carcinoma (MTC) and their inhibition suppresses in vitro growth and tumorigenicity of the MTC derived cell line TT

International audienceBACKGROUND: The Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation. To date no information on the expression of these proteins in medullary thyroid carcinoma (MTC) are available. We here investigated the expression of the Aurora kinases in human MTC tissues and their potential use as therapeutic targets. METHODS: The expression of the Aurora kinases in 26 MTC tissues at different TNM stages was analyzed at the mRNA level by quantitative RT-PCR. We then evaluated the effects of the Aurora kinase inhibitor MK-0457 on the MTC derived TT cell line proliferation, apoptosis, soft agar colony formation, cell cycle and ploidy. RESULTS: The results showed the absence of correlation between tumor tissue levels of any Aurora kinase and tumor stage indicating the lack of prognostic value for these proteins. Treatment with MK-0457 inhibited TT cell proliferation in a time- and dose-dependent manner with IC50 = 49.8 ± 6.6 nM, as well as Aurora kinases phosphorylation of substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it. Cytofluorimetric analysis confirmed that MK-0457 induced accumulation of cells with ≥ 4N DNA content without inducing apoptosis. Finally, MK-0457 prevented the capability of the TT cells to form colonies in soft agar. CONCLUSIONS: We demonstrate that Aurora kinases inhibition hampered growth and tumorigenicity of TT cells, suggesting its potential therapeutic value for MTC treatment

Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis

Calcitonin (CT) is an important clinical marker for the diagnosis and follow-up of medullary thyroid carcinoma, although it is not absolutely specific. Some authors have reported C-cell hyperplasia in a number of thyroid specimens affected by Hashimoto's thyroiditis. The association between thyroiditis and hypercalcitoninemia is still controversial because some authors have reported low CT levels. The aim of this study is to evaluate the basal CT values in patients with and without thyroid autoimmunity. From May 2005 to February 2010, 1073 patients underwent ultrasonography-guided fine-needle aspiration cytology at the Thyroid Center of Sapienza University of Rome, with evaluation of basal serum FT4, FT3, TSH, and antithyroid peroxidase (anti-TPO) antibodies as well as CT levels. Forty-one patients presented a basal CT level above the reference upper limit. The mean serum CT was significantly lower in women than in men (4.28 +/- 6.63 vs 7.50 +/- 25.50 pg/ml; P0.05). Importantly, the rate of 'suspicious' CT values (above the 10 pg/ml cutoff) was not significantly different between patients with or without thyroid autoimmunity (3.9 vs 3.0%). Patients with hypercalcitoninemia suffering from chronic autoimmune thyroiditis should undergo the same clinical evaluation procedure as patients do without thyroid autoimmunity. Endocrine-Related Cancer (2012) 19 345-34

A clinical-radiological score to diagnose Hashimoto’s thyroiditis: a proposal

Introduction. Early diagnosis of Hashimoto’s thyroiditis (HT) may be difficult. The heterogeneity of criteria used to diagnose HT may prevent strong conclusions from being drawn in studies focusing on clinical aspects of HT. The aim of this study is to design a simple score to diagnose chronic autoimmune thyroiditis. Methods. 1021 consecutive patients that were advised to undergo total thyroidectomy at an University thyroid referral center. Given a dichotomous outcome, a set of 2 demographic (sex and age), 3 biochemical (overt or subclinical hypothyroidism, positive anti-Tg Ab, and positive anti-TPO Ab) and 4 imaging covariates (hypoechogenic parenchyma, heterogeneous thyroid echopattern, color-Doppler pattern and estimated thyroid volume) was analyzed. Results. Analysis showed that anti-TPO Ab [area under the curve (AUC) under the ROC curve, 0.67], and anti-Tg Ab (0.63) were univariate predictors of the diagnosis of HT, which is largely recognized. Combined covariates were then tested using stepwise logistic regression. A model to predict the final diagnosis was calculated by using multivariate logistic regression analysis. The final model included anti-TPO Ab, anti-Tg Ab and thyroid vascularity (AUC 0.72). A second scoring system was developed to diagnose HT, with the addition of heterogeneous echopattern and goiter (AUC 0.76). Conclusions. A simple scoring system for the early diagnosis of HT could easily be applied in clinical practice and research. The better proposed score has been shown to have an overall low degree of sensitivity and speci?city, but higher than the single predictors alone (sensitivity 45.5% and specificity 89.0%, with a cutoff value of 1.7). International multicenter studies can recruit a higher number of patients and provide a sufficient amount of data to integrate all features of HT into a consensus diagnostic score