Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness.

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid's LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.

The proteomic 2D-DIGE approach reveals the protein voltage-dependent anion channel 2 as a potential therapeutic target in epithelial thyroid tumours.

We investigated the role of VDAC2 in human epithelial thyroid tumours using proteomic 2D-DIGE analysis and qRT-PCR. We found a significant up-regulation of VDAC2 in thyroid tumours and in thyroid tumour cell lines (TPC-1 and CAL-62). We did not detect overexpression of VDAC2 in a normal thyroid cell line (Nthy-ori 3-1). Silico analysis revealed that two proteins, BAK1 and BAX, had a strong relationship with VDAC2. BAK1 gene expression showed down-regulation in thyroid tumours (follicular and papillary tumours) and in TPC-1 and CAL-62 cell lines. Transient knockdown of VDAC2 in TPC-1 and CAL-62 promoted upregulation of the BAK1 gene and protein expression, and increased susceptibility to sorafenib treatment. Overexpression of the BAK1 gene in CAL-62 showed lower sorafenib sensitivity than VDAC2 knockdown cells. We propose the VDAC2 gene as a novel therapeutic target in these tumours.

Thyroglobulin as early prognostic marker to predict remission at 18-24 months in differentiated thyroid carcinoma.

INTRODUCTION: Thyroglobulin (Tg), the most common marker to determine remission of differentiated thyroid carcinoma (DTC), can take 18 months or longer to be undetectable. We hypothesized that Tg stimulated after surgery and immediately before radioiodine treatment (baseline-stimulated Tg) could be a good predictor of remission at 18-24 months. The aim of this study was to evaluate the role of baseline-stimulated Tg as early prognostic marker of DTC. PATIENTS AND METHODS: Retrospective study of 133 patients with DTC from 1998 to 2010 (age at diagnosis 47·4 ± 16·8, follow-up 5·09 ± 3·2 years). Initial subset analysis was performed after excluding patients with positive TgAb, who were later included in the second. Baseline-stimulated Tg was divided into tertiles. Multivariate logistic regression analysis included baseline Tg and other known prognostic markers and receiver operating characteristic (ROC) curve to identify the best cut-off level of baseline Tg were performed. RESULTS: Baseline-stimulated Tg in the highest tertile was the only predictive variable of persistence of disease at 18-24 months in the initial analysis (OR 45·3, P < 0·01). In the second analysis, the predictive variables were baseline-stimulated Tg (OR 39·6, P < 0·001), presence of TgAb (OR 23·4, P < 0·005) and uptake outside of the thyroid bed post-treatment whole body scan (WBS; OR 5·3, P < 0·05) were predictive of persistence of disease. The ROC curve showed that baseline-stimulated Tg below 8·55 µg/l identified 95% of disease-free patients at 18-24 months after initial treatment. CONCLUSIONS: Baseline-stimulated Tg is a good predictor of remission of disease at 18-24 months after initial treatment and could be a useful marker to stratify risk immediately after surgery.

PREDIRCAM eHealth platform for individualized telemedical assistance for lifestyle modification in the treatment of obesity, diabetes, and cardiometabolic risk prevention: a pilot study (PREDIRCAM 1).

BACKGROUND: Healthy diet and regular physical activity are powerful tools in reducing diabetes and cardiometabolic risk. Various international scientific and health organizations have advocated the use of new technologies to solve these problems. The PREDIRCAM project explores the contribution that a technological system could offer for the continuous monitoring of lifestyle habits and individualized treatment of obesity as well as cardiometabolic risk prevention. METHODS: PREDIRCAM is a technological platform for patients and professionals designed to improve the effectiveness of lifestyle behavior modifications through the intensive use of the latest information and communication technologies. The platform consists of a web-based application providing communication interface with monitoring devices of physiological variables, application for monitoring dietary intake, ad hoc electronic medical records, different communication channels, and an intelligent notification system. A 2-week feasibility study was conducted in 15 volunteers to assess the viability of the platform. RESULTS: The website received 244 visits (average time/session: 17 min 45 s). A total of 435 dietary intakes were recorded (average time for each intake registration, 4 min 42 s ± 2 min 30 s), 59 exercises were recorded in 20 heart rate monitor downloads, 43 topics were discussed through a forum, and 11 of the 15 volunteers expressed a favorable opinion toward the platform. Food intake recording was reported as the most laborious task. Ten of the volunteers considered long-term use of the platform to be feasible. CONCLUSIONS: The PREDIRCAM platform is technically ready for clinical evaluation. Training is required to use the platform and, in particular, for registration of dietary food intake.

Are birth weight predictors in diabetic pregnancy the same in boys and girls?

OBJECTIVES: To study the predictors of abnormal fetal growth in diabetic pregnancy, analyzing the role of fetal sex. STUDY DESIGN: Observational retrospective study was carried out in a University hospital. We studied 2833 newborns of diabetic mothers who attended the Diabetes and Pregnancy Clinic and delivered in the center between 1/1/1982 and 31/12/2006 (2370 born to women with gestational diabetes mellitus, 391 to women with type 1 diabetes mellitus (DM), and 72 to women with type 2 DM). Logistic regression analyses were performed with a backward method to predict large for gestational age (LGA), small for gestational age (SGA) and macrosomic newborns using relevant variables and their interaction with fetal sex. We have used as potential predictors of abnormal birth weight: maternal prepregnancy age, weight, height and body mass index, prior pregnancy, prior macrosomia, smoking habit, weight increase during pregnancy, hypertension, gestational age at delivery, twin pregnancy, fetal sex, diabetes type, third trimester HbA1c and interaction of fetal sex with all these variables. RESULTS: Variables predictive of LGA, SGA and macrosomia were as formerly described. Moreover, some predictors of abnormal growth displayed an interaction with fetal sex. In LGA prediction, male sex displayed a positive interaction with delivery week, prior gestation, diabetes type and twin pregnancy and a negative one with weight increase. In SGA prediction, male sex displayed a positive interaction with delivery week and diabetes type. In macrosomia prediction, male sex displayed a negative interaction with weight increase. CONCLUSIONS: In this cohort of diabetic pregnancies, some predictors of abnormal birth weight display interaction with fetal sex. In general, associations were more favorable to female fetuses.

PTEN promoter methylation in sporadic thyroid carcinomas.

The tumor-suppressor gene PTEN/MMAC1, on chromosome 10q23.3, has been implicated in an important number of human tumors, such as thyroid carcinomas. PTEN somatic mutations occur in sporadic tumors of the endometrium, brain, prostate, or melanomas, while germline mutations predispose to development of the multiple hamartoma syndromes (i.e., Cowden's disease and Bannayan-Zonana syndrome). Activation of the two alleles of PTEN is required for its tumor-suppression role. Because the frequency of PTEN suppression in thyroid tumors exceeds that of PTEN mutations or deletions, it is very likely that epigenetic mechanisms, such as promoter hypermethylation, may account for its inactivation in a subset of tumors. The main aim of this study was to assess the frequency of promoter hypermethylation of PTEN in thyroid tumors. We studied frozen tissue samples from 46 papillary carcinomas, 7 follicular carcinomas, 6 follicular adenomas as well as 39 normal thyroid tissue samples. Methylation-specific polymerase-chain reaction (PCR) with three different sets of primers was used. Two of the primer sets were designed to avoid any interference with PTEN pseudogene promoter. PTEN promoter hypermethylation was detected in 21 of 46 (45.7%) papillary carcinomas, 6 of 7 follicular carcinomas, and 5 of 6 follicular adenomas. It was negative in all normal tissues. Negative immunohistochemical staining for PTEN was significantly associated with the presence of promoter hypermethylation (p < 0.001). These results show a high frequency of PTEN promoter hypermethylation, especially in follicular tumors, suggesting its possible role in thyroid tumorigenesis.

Effects of bariatric surgery on vitamin D status and secondary hyperparathyroidism: a prospective study.

BACKGROUND: Morbidly obese patients have been reported to present with vitamin D insufficiency and secondary hyperparathyroidism. Scattered data are available regarding the effects of bariatric surgery on vitamin D status. We studied calcium metabolism and vitamin D status before and after bariatric surgery. METHODS: In this prospective study, 64 patients (M5/F59) fulfilled the inclusion criteria (i.e. 2 calcidiol serum determinations in the winter season) among 457 morbidly obese individuals who underwent Roux-en-Y gastric bypass (RYGBP) a mean of 36 months previously. Laboratory data (serum calcium, phosphorus, creatinine, alkaline phosphatase, albumin, calcidiol, albumin and iPTH) were determined before and after RYGBP. Pre- and postoperative calcidiol levels were categorized as being normal (>50 nmol/L), insufficient (25-50 nmol/L), and deficient (<25 nmol/L). Pre- and postoperative mild secondary hyperparathyroidism was defined as iPTH >7.3 pmol/L with simultaneous normal values for creatinine, calcium and phosphorus. RESULTS: RYGBP produced a significant weight loss coupled with a simultaneous increase in calcidiol (+28%, P<0.0005) and decrements in total alkaline phosphatase (-53%, P<0.0005) and iPTH (-74%, P=0.001). Corrected serum calcium, phosphorus, and creatinine levels were indistinguishable before and after RYGBP. Additionally, 37.5% of the patients maintained their calcidiol category, while 42.2 % improved it and 20.3% lost one category. CONCLUSIONS: RYGBP does not completely correct pre-existing vitamin D deficient states with secondary hyperparathyroidism. Low calcidiol bioavailability and or insufficient sunlight exposure do probably persist after bariatric surgery. While randomized controlled studies are warranted, it seems advisable to support vitamin D supplementation as well as increasing sunlight exposure in the morbidly obese population.

Patients with MEN-1 are more insulin-resistant than their non-affected relatives.

BACKGROUND: Given the clinical impression that patients with type 1 multiple endocrine neoplasia (MEN-1) frequently display abnormal glucose and lipoprotein concentrations, we compared affected subjects followed in our outpatient clinic with their non-affected relatives. METHODS: The clinical histories of 35 members (19 affected) from six families with MEN-1 were reviewed. Total cholesterol, triglycerides, insulin, glucose, and insulin resistance (homeostasis model) were compared in affected and non-affected subjects. RESULTS: The affected subjects displayed higher total cholesterol and triglycerides and more insulin resistance. CONCLUSION: Patients with MEN-1 seem to be more insulin-resistant and to have a higher cardiovascular risk than their non-affected relatives. Three non-exclusive, biologically plausible hypotheses are proposed.

Unchanged hypovitaminosis D and secondary hyperparathyroidism in morbid obesity after bariatric surgery.

BACKGROUND: Morbidly obese patients have been reported to present with vitamin D insufficiency and secondary hyperparathyroidism. We assessed whether bariatric surgery alters the 25-hydroxyvitamin D (calcidiol) and intact parathyroid hormone (iPTH) levels in patients presenting with morbid obesity. METHODS: A cross-sectional survey was conducted on 144 patients of whom 80 had not undergone bariatric surgery, while 64 had bariatric surgery at a mean of 36 months previously. Calcidiol levels were defined as being normal (>50 nmol/L), insufficient (2550 nmol/L) and deficient (<25 nmol/L). Mild secondary hyperparathyroidism was defined as iPTH >7.3 pmol/L with simultaneous normal values for creatinine, calcium and phosphorus. RESULTS: 80% of the patients presented low vitamin D levels and mild secondary hyperparathyroidism. Previous surgery or the presence of diabetes did not influence calcidiol levels. Corrected serum calcium, phosphorus, alkaline phosphatase, iPTH and Calcidiol were similar between subjects with and without surgery. CONCLUSIONS: Vitamin D deficient states with secondary hyperparathyroidism in the morbidly obese precede and are not significantly affected by bariatric surgery. Hypovitaminosis D with secondary hyperparathyroidism due to low calcidiol bio-availability should be added to the crowded list of sequelae of morbid obesity. While further studies are warranted, it seems advisable to support vitamin D supplementation in the morbidly obese population.

Diabetes autoinmune del adulto en diabéticos tipo 2: frecuencia y características / LADA in type 2 diabetics: frequency and characteristics

Se realizó este trabajo para conocer frecuencia, características clínico-bioquímicas, inmunológicas y genéticas de la diabetes autoinmune en adultos (LADA) en 1 000 diabéticos tipo 2 con edades ü 35 años con distintos tiempos de duración de la diabetes. Se les determinó glucemia, anticuerpos antiislotes pancreáticos (ICA), anti-GAD65, anti-ICA512bdc/IA2, antimicrosomales tiroideos (AMT), antigástricos parietales (AGP), antinucleares (AN), microalbuminuria y péptido C en ayunas. Se encuestaron y se registraron algunas características clínicas. Se dividieron en 2 grupos según la presencia de ICA. Todos los diabéticos tipo 2 + para autoanticuerpos antiislotes (ICA y/o anti-GAD65) fueron identificados como LADA. Se detectó el 3,4 (por ciento) de diabético tipo 2 con ICA +, en los diabéticos tipo 2 ICA- el 22,0 (por ciento) presentó anticuerpos anti-GAD65. Se encontró que los diabéticos tipo 2 ICA+ eran más jóvenes, la duración de su diabetes era menor, presentaron menor IMC, disminución de los niveles de péptido C en ayunas, menos antecedentes familiares (padres) de DM2, valores menores en las tensiones arteriales diastólicas y sistólicas, mayor presencia de anticuerpos anti-GAD65, AMT y AGP en comparación con los diabéticos tipo 2 ICA-. Se observó que los diabéticos tipo 2 ICA+ (LADA) tienen características específicas que los asemejan a los diabéticos tipo 1, esto implicaría variaciones importantes en su tratamiento y evolución con respecto a los diabéticos tipo 2 ICA-. Se observó una baja frecuencia de ICA y alta de GAD en los diabéticos tipo 2 cubanos, las cuales fueron diferentes a la encontrada en poblaciones caucasianas. Los anticuerpos anti-GAD65 fueron superiores a los ICA para detectar los LADA. Las características clínicas e inmunológicas de estos pacientes muestran la lenta progresión de la destrucción autoinmune de las células b con implicaciones terapéuticas(AU)

This paper was aimed at knowing the frequency, clinico-biochemical, immunologic and genetic characteristics of autoimmune diabetes in adults (LADA) in 1 000 type 2 diabetic patients aged 35 or over with different times of duration of diabetes. Glycemia, anti-pancreatic islet cell antibodies (ICA), anti-GAD65 antibodies, anti-ICA512bdc/IA2 antibodies, anti-microsomal thyroid antibodies (AMT), anti-gastric parietal antibodies (AGP), antinuclear antibodies (AN), microalbuminuria and peptide C during fasting were determined. These patients were surveyed and some clinical characteristics were registered. They were divided into 2 groups according to the presence of ICA. All the type 2 + diabetics for anti-islet cell autoantibodies (ICA and/or antiGAD65) were identified as LADA. 3.4 percent of type 2 ICA + were detected. 22.0 percent of type 2 ICA - diabetics had anti-GAD65 antibodies. It was found that type 2 ICA + diabetics were younger, that their diabetes was shorter, that they had lower BMI, reduced levels of fasting peptide C, less DM2 history family (parents), lower values of diastolic and systolic arterial pressure, higher presence of anti-GAD65 antibodies, AMT and AGP in comparison with type 2 ICA - diabetics. It was observed that type 2 ICA+ diabetics (LADA) have specific characteristics that make them similar to type 1 diabetics, which would lead to important variations in their treatment and evolution as regards type 2 ICA - diabetics. Among the Cuban type 2 diabetics it was detected a low frequency of ICA and a high frequency of GAD, which were different to those found in the Caucasian populations. The anti-GAD65 antibodies were higher than ICA to detect LADA. The clinical and immunological characteristics of these patients show the slow progression of the autoimmune destruction of b-cells with therapeutic implications(AU)