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Endocrine 08/2011; 40(3):492-4. · 1.42 Impact Factor
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Journal of endocrinological investigation 11/2010; 33(10):767-8. · 1.57 Impact Factor
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M L Sponziello, R Bruno,
C Durante,
M D'Agostino,
R Corradino,
P Giannasio,
E Ciociola,
E Ferretti,
M Maranghi,
A Verrienti,
G De Toma,
S Filetti,
D Russo
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ABSTRACT: Levothyroxine (L-T4)-based suppression of thyrotropin (TSH) secretion is widely used to prevent the growth of benign thyroid nodules, although the effectiveness of this approach has been demonstrated only in a subset of patients. In this study, we analyzed the in vivo effects of L-T4-mediated TSH suppression on elements of insulin/IGF-1-dependent growth-regulating pathways in tissues from patients with benign thyroid nodules. Nodular and non-nodular tissue specimens were collected from 63 patients undergoing thyroidectomy. 32 had received preoperative TSH suppressive therapy with TSH levels consistently below 0.5 mU/l (L-T4 group). TSH suppression had not been used in the other 31, and their TSH levels were normal (0.8-4 mU/l (control group). Quantitative RT-PCR was used to measure mRNA levels for TSH receptor, IGF1, IGF-1 receptor, insulin receptor, insulin receptor substrate 1 in nodular and non-nodular tissues from the 2 groups. Akt and phosphorylated Akt protein levels were detected by Western blot. Mean levels of mRNA for all genes tested were similar in the 2 groups, in both nodular and non-nodular tissues. The 2 groups were also similar in terms of phosphorylated Akt protein levels (measured by densitometric scan in 10 randomly selected nodules from each group). This is the first demonstration based on the study of human thyroid tissues that TSH suppression does not affect the expression of components of the insulin/IGF-1-dependent signaling pathways regulating thyrocyte growth. This may explain the lack of effectiveness of TSH-suppressive therapy in a substantial percentage of benign thyroid nodules.
Hormone and Metabolic Research 09/2010; 43(1):22-5. · 2.19 Impact Factor
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Thyroid 01/2008; 17(12):1307-8. · 4.79 Impact Factor
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C Durante,
E Puxeddu,
E Ferretti,
R Morisi,
S Moretti, R Bruno,
F Barbi,
N Avenia,
A Scipioni,
A Verrienti,
E Tosi,
A Cavaliere,
A Gulino,
S Filetti,
D Russo
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ABSTRACT: BRAF mutations are common in papillary thyroid carcinomas (PTCs). By affecting the expression of genes critically related to the development and differentiation of thyroid cancer, they may influence the prognosis of these tumors.
Our objective was to characterize the expression of thyroid-specific genes associated with BRAF mutation in PTCs. DESIGN/SETTING AND PATIENTS: We examined the expression of key markers of thyrocyte differentiation in 56 PTCs with BRAF mutations (BRAF-mut) and 37 with wild-type BRAF (BRAF-wt). Eight samples of normal thyroid tissue were analyzed as controls. Quantitative PCR was used to measure mRNA levels for the sodium/iodide symporter (NIS), apical iodide transporter (AIT-B), thyroglobulin (Tg), thyroperoxidase (TPO), TSH receptor (TSH-R), the transcription factor PAX8, and glucose transporter type 1 (Glut1). NIS protein expression and localization was also analyzed by immunohistochemistry.
mRNA levels for all thyroid-specific genes were reduced in all PTCs vs. normal thyroid tissues. NIS, AIT-B, Tg, and TPO expression was significantly lower in BRAF-mut tumors than in the BRAF-wt group. Glut-1 transcript levels were increased in all PTCs, and additional increases were noted in BRAF-mut tumors. In both tumor subsets, the NIS protein that was expressed was abnormally retained in the cytoplasm.
BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. This effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mut PTCs.
Journal of Clinical Endocrinology & Metabolism 08/2007; 92(7):2840-3. · 6.50 Impact Factor
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ABSTRACT: In recent years many authors have reported an increase in thyroid cancer (TC) incidence in several countries. The cause of such phenomenon remains unclear.
This study was designed to estimate the incidence of TC in Basilicata, the smallest region of Southern Italy with a population of 596,546 people, between 2001 and 2004.
A total of 302 cases of TC were identified. The annual incidence of TC changed over the years, from 10.0 per 100,000 people in 2001 to 15.7 per 100,000 people in 2004. The number of new TC cases per 100,000 people increased an average of 16% per yr. Median age at diagnosis was 49 yr. The most frequent histotype was papillary TC (PTC) (73.2%). In 20 (6.6%) patients with PTC, we identified at least one first-degree relative affected by differentiated TC.
The present study shows a high incidence of sporadic and familial non-medullary TC in Basilicata. The reason for this finding may be related to several factors discussed in the paper. Further studies evaluating the trends in the incidence of TC in Basilicata in the future could provide some answers for the potential pathogenetic hypothesis.
Journal of endocrinological investigation 07/2007; 30(6):507-12. · 1.57 Impact Factor
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Thyroid 06/2007; 17(5):477-8. · 4.79 Impact Factor
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ABSTRACT: The functional role of the sodium iodide symporter (NIS) in extrathyroidal tissues was investigated by examining its mRNA and protein expression, together with the evidence of radioiodine (131)I uptake in 302 patients who underwent (131)I total body scanning, following the administration of high doses of (131)I for a papillary or follicular thyroid carcinoma. By using a real-time kinetic quantitative RT-PCR and immunohistochemistry, the expression of NIS protein was detected mainly in secretory tissues. In parallel, 1311 uptake was evidenced in the majority of patients in the salivary glands (in 39%) and stomach (in 78%), but was found in breast in only 4 young female patients. These data demonstrate a strong correlation between the organ radioactivity distribution, as observed in vivo, and NIS protein expression. Interestingly, (131)I is rarely concentrated by mammary glands, even when large doses are administered. Moreover, a (131)I transfer in secretion fluids may represent a potential source of contamination responsible for false positive images and diagnostic pitfalls.
Journal of endocrinological investigation 01/2005; 27(11):1010-4. · 1.57 Impact Factor
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M Celano,
F Arturi,
I Presta, R Bruno,
D Scarpelli,
M G Calvagno,
C Cristofaro,
S Bulotta,
P Giannasio,
R Sacco,
S Filetti,
D Russo
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ABSTRACT: Hyperfunctioning thyroid nodules are characterized by the presence of spontaneous somatic mutations responsible for constitutive activation of the cAMP pathway. However, alterations affecting other elements of the cAMP signaling system may counteract the effects of the mutations. In this study, the expression of the adenylyl cyclase (AC) types III and VI was investigated by Western blot in 18 hyperfunctioning thyroid nodules; in 12 samples, we also assessed the presence of TSH receptor (TSHR) or gsp mutations and levels of AC VI and III mRNA. We found that the expression of nodular AC VI (but not AC III) was significantly lower (85.1% of normal, P=0.014) than the expression of both adenylyl cycles types of perinodular tissue from the same patients. Slightly, but not significant differences were detected in nodules with or without mutations and AC protein levels generally showed correlation with the levels of the transcripts detected by RT-PCR. In addition, AC III and AC VI expression levels within a given nodule were characterized by a significant positive correlation. These findings indicate that a diminished expression of AC type VI may be part of the mechanisms occurring in the hyperfunctioning nodules, independently of the presence of TSHR or gsp mutations, which influence the resulting phenotype.
Molecular and Cellular Endocrinology 06/2003; 203(1-2):129-35. · 4.19 Impact Factor
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ABSTRACT: Ten years after the first description of activating mutations in the thyroid stimulating hormone receptor (TSHR) gene in sporadic autonomous hyperfunctioning thyroid adenomas, there is general agreement in assigning a major pathogenic role of this genetic abnormality, acting via the constitutive activation of the cAMP pathway, in both the growth and functional characteristic of these tumours. From the beginning, however, the pathophysiological and clinical relevance of somatic TSHR mutations has been debated and some arguments still exist against a fully causative role of these mutations and the practical value of detecting these mutations for the diagnosis, treatment and prognosis of thyroid hot nodules. Some major issues will be examined herein, including (a) the frequency of TSHR alterations in various reports showing that the genetic abnormality underlying the pathogenesis of a substantial subset of thyroid tumours has yet to be identified; (b) the limitations of the present experimental models, which suggest greater caution in the interpretation of in vitro results; (c) the still unresolved question of absence of genotype-phenotype correlation. Clarification of these issues may hopefully provide new and useful tools for improving the clinical management of this disease.
Thyroid 05/2003; 13(4):341-3. · 4.79 Impact Factor
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ABSTRACT: Apurinic/apyrimidinic endonuclease APE/Ref-1 is a multifunctional protein provided with DNA repair, transcription-factor regulation and anti-apoptotic activities. We have previously reported that, in thyroid cells, TSH regulates both the synthesis and nuclear translocation of APE/Ref-1. We have also shown that nuclear levels of this protein are reduced both in thyroid carcinoma tissues and cell lines. In the present study, APE/Ref-1 expression and cellular localization were analysed by Western blot in hyperfunctioning thyroid nodules from patients with toxic adenoma and/or toxic multinodular goiter. The total content of APE/Ref-1 protein was increased in the majority of the hyperfunctioning tissues with respect to normal adjacent tissue. There was also an increase in the nuclear levels of APE/Ref-1, suggesting enhanced cytoplasm-to-nucleus translocation of the protein in addition to its increased rate of synthesis. These results demonstrate that the phenomenon of nuclear translocation of APE/Ref-1 hypothesized on the basis of cell culture experiments does actually occur in vivo. Together with previous observations in thyroid carcinomas and tumoral cell lines, our findings suggest a two-stage model of APE/Ref-1 behaviour during malignant thyrocyte transformation: an early stage characterized by simple hyperplasia and upregulation of APE/Ref-1 in the nuclear compartment of the cell and a later stage in which nuclear levels of the protein drop to below-normal levels as the cell becomes progressively undifferentiated.
Molecular and Cellular Endocrinology 09/2002; 194(1-2):71-6. · 4.19 Impact Factor
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ABSTRACT: The expression of two iodide transporters, the sodium/iodide symporter (NIS) and pendrin, was analyzed in thyroid tissues of patients with toxic multinodular goiter (TMNG) and non-toxic multinodular goiter (MNG).
The levels of NIS and pendrin proteins were analyzed in total protein extracts from nodular and non-nodular tissues by Western blot.
In tissue samples from TMNG, we found an increased expression of NIS (2.5-fold) in the hot nodules, and similar levels between cold nodules and non-nodular tissues. In contrast, the levels of pendrin were slightly increased in both hot and cold nodules from TMNG, and decreased (about twofold) in cold nodules from MNG. We also noticed that there was no relationship between NIS and pendrin expression.
Our data demonstrate that hot nodules from TMNG express a higher number of iodide transporters (mainly NIS), whereas cold nodules from TMNG, but not from MNG, show levels of the two proteins comparable with normal tissue, suggesting a role in vivo of TSH in maintaining the expression of NIS and pendrin protein in normal thyroid tissue. Finally, different mechanisms are involved in the regulation of NIS and pendrin expression.
European Journal of Endocrinology 12/2001; 145(5):591-7. · 3.42 Impact Factor
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ABSTRACT: Multinodular goiter (MNG) is a common disorder characterized by a nodular enlargement of the thyroid gland and occurring with a female&rcolon;male ratio of 5&rcolon;1. This article reports the analysis of an Italian three-generation pedigree MNG, including 10 affected females and 2 affected males. After linkage to candidate regions previously implicated in various forms of goiter was excluded, a novel MNG locus was searched. Because no male-to-male transmission was present in the study pedigree, an X-linked autosomal dominant pattern of inheritance was hypothesized. Therefore, 18 markers spaced at 10-cM intervals on the X chromosome were examined. A significant LOD score was observed in the Xp22 region, where marker DXS1226 generated a maximum LOD score of 4.73 at a recombination fraction of 0. Analysis of six flanking microsatellites confirmed these data, and haplotype inspection delimited a 9.6-cM interval lying between DXS1052 and DXS8039.
The American Journal of Human Genetics 10/2000; 67(4):1004-7. · 10.60 Impact Factor
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E Chiefari,
D Russo,
D Giuffrida,
G A Zampa,
D Meringolo,
F Arturi,
I Chiodini,
D Bianchi,
M Attard,
V Trischitta, R Bruno,
P Giannasio,
A Pontecorvi,
S Filetti
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ABSTRACT: Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC.
Journal of endocrinological investigation 07/1998; 21(6):358-64. · 1.57 Impact Factor
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ABSTRACT: We report a case of a male patient thyroidectomized for follicular thyroid carcinoma and presenting extremely elevated serum thyrotropin levels under L-T4 suppressive therapy. Administration of L-T3 in increasing amounts resulted in a significant decrease of serum TSH levels. The nature of the possible molecular defects underlying this unusual condition and pitfalls arising from the failure of L-T4 therapy to inhibit TSH secretion in a patient in post-surgical follow-up for follicular carcinoma are discussed.
Journal of endocrinological investigation 28(7):663-6. · 1.57 Impact Factor
