The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

[Feminizing adrenal tumours in Spain: report of a case and review of the five previously published patients]. / Tumores suprarrenales feminizantes en España: aportación de un caso y revisión de los cinco pacientes descritos.

Feminizing adrenal tumours are very rare. We report the clinical and hormonal study of a case, a 49 years old male, since his first consultation until his death 6 years after the initial diagnosis, and a review of the other 5 Spanish patients previously published. His initial symptoms were gynecomastia and libido decrease, with increase of plasmatic and urinary oestrogen levels, plasma testosterone near low normal level and a right adrenal gland tumour that, after its removal, showed a benign histology and was classified as an adrenocortical adenoma. Three years after, initial symptoms returned, with oestrogen, glucocorticoid and androgen hypersecretion, tumour local relapse and peritoneal, liver and lung metastasis. After mitotane and aminoglutethimide therapy, hormonal concentrations fell temporary and then raised again until his death 3 years later. The main special feature of this case is the apparently benign initial adrenal tumour with only oestrogen hypersecretion, and its relapse 3 years later with secretion of several steroid hormones, generalized metastasis and no response to medical therapy.

Response of ACTH to octreotide in a probable corticotropic adenoma associated with Addison's disease.

BACKGROUND: Our patient was a 65-year-old woman previously diagnosed with Addison's disease. She presented an empty sella turcica and, at the age of 47, was discovered to have autonomous hypersecretion of adrenocorticotropic hormone (ACTH), suggesting a corticotropic adenoma secondary to Addison's disease, with a lack of response to high levels of dexamethasone. She maintained high ACTH levels despite corticosteroid treatment. METHODS: The patient underwent a CRH stimulation test using an intravenous bolus (100 microg) with samples every 30 minutes for 3 hours and, the day after, an octreotide infusion (0.1 mg/200 cc saline) for 2 hours with measurements every 30 minutes for 3 hours. The following month she received subcutaneous octreotide 0.1 mg tid., and samples were taken every week. RESULTS: Thirty minutes after the corticotropic-releasing-hormone (CRH) stimulation test, baseline ACTH levels (1 063 pg/ml) increased to 1530, the other values lying between 1 020-862. After octreotide infusion, baseline ACTH (1 212 pg/ml) was 946-643-1 630-4 600-1 730 at 30-60-90-120-180 minutes. The following month, with octreotide treatment, serum ACTH levels were 454-768-1233-429 pg/ml each week. DISCUSSION: Octreotide acts mainly on somatostatin type 2 receptors (SSTR2) and has no effect in Cushing's syndrome, although a suppressor effect in some ACTH ectopic hypersecretions and in Nelson's syndrome has been demonstrated. It has been observed that SSTR5 appear more frequently than SSTR2 in corticotropic adenomas and corticosteroids downregulate octreotide sensitivity. CONCLUSIONS: Octreotide did not suppress secretion of ACTH in suspected corticotropic adenoma. Newer somatostatin analogues, acting mainly on SSTR5, may be able to control ACTH hypersecretion in cases such as this.

Hepatic cells via cava vein can influence allogenic islet rat transplantation.

We have reported, previously, some effect of allogenic hepatic cells for islet tolerance when they are injected mixed (hepatic cells and islets) in different proportions via portal vein, in diabetic Wistar rats. Now we have studied the role of allogenic hepatic cells injected sequentially 15 min before islets, comparing via the portal vein (A and B groups) and via the cava vein (C and D groups) with a control group of islets alone. The allogenic islets were always injected via portal vein, in similar conditions, while the ratio of hepatic cells/islets was 100:1 (A, C groups) or 200:1 (B, D groups). Islets and hepatic cells were obtained from several different rats. The transplanted rats were observed during 30 days and results compared among the different rat groups: porta-porta (P/P), cava-porta (C/P), and control group. Statistically, a significant interaction between type of transplant and proportion of hepatic cells was observed. Also, C plus D groups showed statistical difference with the control group (p < 0.017) and also all the groups together (p < 0.047). These results suggest that hepatic cells can induce, in some cases, islet graft prolongation in Wistar rats. Better results were obtained when hepatic cells were injected via the cava vein than via the portal vein. Because we used a liver cell suspension integrated for several kinds of cells, the study does not clarify if this effect can be related to some specific hepatic cell subpopulation. To confirm the results and to determine if the hypothetical mechanism can be attributed to a block of the immune system or to some factor secreted by hepatic cells, more studies must be performed.

Long-term evolution and outcomes of microprolactinoma with medical treatment.

INTRODUCTION: Prolactinoma is the most frequent functioning pituitary adenoma. Most commonly occurs as microprolactinoma (less than 1cm in size), which may be cured with medical therapy, but few long-term studies are available about optimal duration of treatment with dopamine agonists to ensure cure after drug discontinuation and its withdrawal without recurrence are do not report consistent results. OBJECTIVE: To establish criteria for cure of microprolactinoma with medical treatment and to analyze the potential predictors involved. PATIENTS: A retrospective study was conducted on 47adult women with microprolactinoma followed up between 1975 and 2010; none of them had undergone prior surgery or radiotherapy, and all of them received treatment with a dopamine agonist for at least 4years. They were divided into two groups for analysis: cured patients with at least 4years with normal prolactin levels after drug discontinuation, and not cured patients. RESULTS: Cure was achieved in 57.4% of patients. Only age at diagnosis was a significant predictor: there were more young patients in the cured group and youngest patients needed less time to cure. Development of empty sella turcica or normal MRI were similar regarding time to cure. CONCLUSIONS: Microprolactinoma may be cured with dopamine agonists, and life-long treatment is not required, although more than 10years may be required to achieve cure, 11,6±5,3 years in our experience.

Empty sella and primary autoimmune hypothyroidism.

In order to assess the association between empty sella (ES) and primary autoimmune hypothyroidism, and the possibility of a common pathogenesis. We retrospectively studied all patients with presumed ES diagnosed in the last 20 years, most of whom were treated by our Endocrinology Department. Subjects with a known etiology were excluded. Incomplete records or those with a doubtful diagnosis were also excluded. A total of 56 subjects were included in the study. ES was diagnosed by pituitary MRI. The measurement of free T4, TSH, and antithyroid antibodies (TPOAb and TgAb) was assayed using commercial kits. The cases of hypothyroidism obtained were compared with those in another group of similar patients, diagnosed with diabetes mellitus type 2, through chi2 test. A total of 15 (26.78%) patients of 56 with ES had autoimmune thyroid disease (subclinical or clinical hypothyroidism). Primary hypothyroidism with negative antithyroid autoantibodies was found in a further 13 patients (23.21%). The 46.42% of ES had primary hypothyroidism; this result had obtained a statistically significant difference when compared to the ratio obtained in the group of diabetes mellitus type 2 (P < 0.0029). There is an important association between ES and autoimmune thyroid disease, which reached 26.78% in our series. We suggest the possibility of a common pathogenesis for certain cases of ES and autoimmune thyroid disease, with the end point of ES in the pituitary, and atrophy in the thyroid gland.

A new approach for bone marrow-derived stem cells intrapancreatic autotransplantation in diabetic rats.

PURPOSE: A new technique for stem cells intrapancreatic autotransplantation in rats. BASIC PROCEDURES: Section of a femoral diaphysis and aspirations of the bone marrow in both femoral segments were performed. A Kirschner needle was placed into the femur. Cells were isolated in Ficoll gradients and preserved at 4-6 degrees C. The second day, cells were injected, via aortic celiac trunk, into the pancreas of the same rat. RESULTS: Femoral surgery were well tolerated. Intrapancreatic homing of the injected cells was suggested with methylene blue injection that stained the pancreas, and proved by labeled cells in pancreas sections. Cell counts after Ficoll isolation were 1 x 10(6) +/- 2 x 10(5) ES. CONCLUSIONS: A technique is described for stem cell autotransplantation in rats. First we obtain autologous bone marrow-derived stem cells. Second, we inject the cells in the pancreas of the donor rat. This approach can be applied to experimental diabetes and other pancreatic processes.