Publications by authors named "Francesco Frasca"

52 Publications

Recent insights into the pathogenesis of autoimmune hypophysitis.

Expert Rev Clin Immunol 2021 Sep 6:1-11. Epub 2021 Sep 6.

Unit of Endocrinology, University Hospital of Messina, Messina, Italy.

Introduction: Hypophysitis is an inflammation of the pituitary gland and a rare case of hypopituitarism. Despite the expanding spectrum of histological variants and causative agents, its pathogenesis is far to be fully understood. The present review is focused on recent evidence concerning the pathogenesis of autoimmune hypophysitis by searching through online databases like MEDLINE and Scopus up to May 2021.

Areas Covered: Hypophysitis frequently develops in the context of a strong autoimmune background, including a wide spectrum of subtypes ranging from the commonest form of lymphocytic hypophysitis to the newly described and less common IgG4-, anti-PIT-1, and ICI-induced forms. A peculiar combination of genetic predisposition, pituitary damage and immunological setting represents the pathogenetic basis of autoimmune hypophysitis, which is characterized by diffuse infiltration of the gland by lymphocytes and variable degrees of fibrosis followed by pituitary cell destruction. Anti-pituitary antibodies (APA) have been described in sera from patients suffering from autoimmune hypophysitis, though their pathophysiological significance remains largely unknown and their diagnostic value limited.

Expert Opinion: In recent years hypophysitis has gained interest due to the increased number of new diagnoses and the recognition of novel subtypes. Further studies could lead to improvements in biochemical/immunological diagnosis and targeted treatments.
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http://dx.doi.org/10.1080/1744666X.2021.1974297DOI Listing
September 2021

Evidence That Baseline Levels of Low-Density Lipoproteins Cholesterol Affect the Clinical Response of Graves' Ophthalmopathy to Parenteral Corticosteroids.

Front Endocrinol (Lausanne) 2020 22;11:609895. Epub 2020 Dec 22.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

Background: High dose intravenous glucocorticoid (ivGC) therapy is the first line treatment in moderate to severe Graves' ophthalmopathy (GO) and is associated with a clinical response rate ranging from 50% to 80%. Recently, a positive correlation between total cholesterol and low-density lipoproteins cholesterol (LDLc) with GO presentation and activity has been described.

Objective: We aimed at evaluating whether, in patients with moderate to severe active GO treated with ivGC therapy, cholesterol, and LDLc could represent valuable predictive factors of medium-term GO outcome.

Methods: This single center retrospective study was conducted in a consecutive series of 87 patients undergone ivGC therapy because affected by moderate to severe active GO. Clinical outcome of GO was evaluated at week 6 (W6) and 12 (W12) in respect to baseline conditions (week 0) by the seven points CAS according to EUGOGO recommendations. Univariate analysis and binary logistic regression were performed for the outcome variable W12CAS.

Results: In patients with active GO, an early positive clinical response to ivGC therapy (as evaluated by CAS at 6W) was a strong determinant (OR=13) of the clinical outcome at week 12. Moreover, high levels of LDLc at baseline were positively associated with a reduction in the likelihood of being classified as improved at 12W. Patients with LDLc >193.6 mg/dl were very likely to respond negatively to ivGC therapy independently from the response at 6W. Based on these results, we propose a predictive decision-making model to be tested in future prospective studies.

Discussion: We found that, in patients with active GO, both an early clinical response to ivGC therapy and baseline LDLc levels are significant determinants of GO outcome (W12CAS). These data support the need of a cholesterol-lowering treatment before addressing these patients to ivGC therapy.
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http://dx.doi.org/10.3389/fendo.2020.609895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784376PMC
May 2021

Thyroid Cancer and Circadian Clock Disruption.

Cancers (Basel) 2020 Oct 24;12(11). Epub 2020 Oct 24.

Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy.

Thyroid cancer (TC) represents the most common malignancy of the endocrine system, with an increased incidence across continents attributable to both improvement of diagnostic procedures and environmental factors. Among the modifiable risk factors, insulin resistance might influence the development of TC. A relationship between circadian clock machinery disfunction and TC has recently been proposed. The circadian clock machinery comprises a set of rhythmically expressed genes responsible for circadian rhythms. Perturbation of this system contributes to the development of pathological states such as cancer. Several clock genes have been found deregulated upon thyroid nodule malignant transformation. The molecular mechanisms linking circadian clock disruption and TC are still unknown but could include insulin resistance. Circadian misalignment occurring during shift work, jet lag, high fat food intake, is associated with increased insulin resistance. This metabolic alteration, in turn, is associated with a well-known risk factor for TC i.e., hyperthyrotropinemia, which could also be induced by sleep disturbances. In this review, we describe the mechanisms controlling the circadian clock function and its involvement in the cell cycle, stemness and cancer. Moreover, we discuss the evidence supporting the link between circadian clockwork disruption and TC development/progression, highlighting its potential implications for TC prevention, diagnosis and therapy.
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http://dx.doi.org/10.3390/cancers12113109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690860PMC
October 2020

The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer.

Cancers (Basel) 2020 Aug 11;12(8). Epub 2020 Aug 11.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, 95122 Catania, Italy.

Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients.
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http://dx.doi.org/10.3390/cancers12082249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465706PMC
August 2020

Role of selenium and myo-inositol supplementation on autoimmune thyroiditis progression.

Endocr J 2020 Nov 15;67(11):1093-1098. Epub 2020 Jul 15.

Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Via Palermo 636, 95122 Catania, Italy.

Previous reports indicate that selenium supplementation may be useful to reduce cell oxidative stress. In particular, selenium may decrease the level of thyroid autoantibodies in patients with Hashimoto's thyroiditis (HT). Recent studies also indicate that myo-inositol may have beneficial effects on thyroid function in patients with HT. Hence, the aim of the present study is to evaluate whether myo-inositol may enhance the protective effect of selenium on HT progression to hypothyroidism. The study was designed as observational and retrospective. Thyroid hormones were evaluated in patients with HT who were either euthyroid or subclinically hypothyroid. These patients were subdivided into three groups: untreated, treated with selenomethionine alone (Se-meth: 83 μg/day) and treated with Se-meth plus myo-inositol (Se-meth + Myo-I: 83 μg/day + 600 mg/day). Outcome evaluation was performed at baseline and after 6 and 12 months of treatment. High-resolution ultrasound of the thyroid gland was performed to evaluate changes in thyroid echoic pattern during the study. Compared to baseline, levels of thyroid-stimulating hormone (TSH) increased significantly in untreated patients but decreased by 31% and 38%, respectively, in those treated with Se-meth and Se-meth + Myo-I. Moreover, in the latter group the TSH reduction was observed earlier than in the Se-meth-treated group. Densitometric analysis of thyroid ultrasonography showed an echoic pattern improvement in both treated groups compared to untreated patients, although this difference was not statistically significant. Thus, Se-meth treatment is effective in patients with HT and its effect may be improved in combination with Myo-I through earlier achievement of TSH levels closer to physiological concentrations.
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http://dx.doi.org/10.1507/endocrj.EJ20-0062DOI Listing
November 2020

Corticosteroid Pulse Therapy for Graves' Ophthalmopathy Reduces the Relapse Rate of Graves' Hyperthyroidism.

Front Endocrinol (Lausanne) 2020 11;11:367. Epub 2020 Jun 11.

Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, Catania, Italy.

A course of anti-thyroid drugs (ATD) is the most common first line treatment for Graves' hyperthyroidism. However, hyperthyroidism relapse is frequent (30-70%). Due to the autoimmune nature of Graves' disease, the immunosuppressive treatment used for active Graves' orbitopathy (GO) may reduce the relapses after ATD discontinuation. To evaluate the recurrence rate in Graves' patients who, in addition to standard ATD, were treated or not treated with parenteral methylprednisolone (MPDS) for GO. Single-center retrospective study in a continuous series of 162 newly diagnosed Graves' patients, with or without GO, all gone into remission and followed-up until hyperthyroidism recurrence or at least 4 years after ATD discontinuation. Patients with moderate-severe active GO underwent middle dose MPDS treatment according to the EuGoGo guidelines. Cox proportional-hazard model was used to comparatively evaluate the risk of recurrence and the predictive factors in patients treated or not treated with MPDS pulse therapy. MPDS treatment was the most significant factor that independently correlated with a reduced risk of hyperthyroidism relapse (HR = 0.53, 95% C.I. = 0.31-0.89). FT3 and female sex were also independent protective factors, while age almost reached the significance level, = 0.062. The efficacy of MPDS was very high in patients aged <40 years (42.1% decrease in relapses, < 0.01) but it was not significant in older patients. Our study found that after ATD discontinuation the frequency of Graves' hyperthyroidism relapse was reduced in patients treated with MPDS pulse therapy for GO. This effect was more marked in young patients.
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http://dx.doi.org/10.3389/fendo.2020.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301650PMC
May 2021

Onset of Marine-Lenhart syndrome and Graves' ophthalmopathy in a female patient treated with alemtuzumab for multiple sclerosis.

Hormones (Athens) 2021 Mar 5;20(1):161-165. Epub 2020 Jun 5.

Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.

Background: Immune checkpoint blockade therapy may lead to thyroid dysfunction in 3-7% of treated patients. Alemtuzumab is a CD52 inhibitor leading to thyroid dysfunction in approximately 40% of patients. A female patient was affected by multiple sclerosis (MS) and subclinical hyperthyroidism due to an autonomously functioning thyroid nodule (AFTN). After alemtuzumab treatment, she developed aggressive clinical hyperthyroidism consistent with Marine-Lenhart syndrome.

Case Presentation: A 36-year-old woman presented in July 2019 with symptoms of hyperthyroidism and eye complaints. Three years earlier, she was diagnosed with MS. Subclinical hyperthyroidism was diagnosed in April 2017. Thyroid scintigraphy showed an intranodular distribution of Tc-pertechnatate consisting of an AFTN in the right lobe of the thyroid. In June 2018, because of the MS, she was treated with alemtuzumab. In November 2018, she was started on methimazole treatment because of the symptoms of hyperthyroidism. In December 2018, thyroid function was normal under methimazole treatment. In June 2019, the patient received a second round of alemtuzumab administration. One month later, she developed symptoms of hyperthyroidism. These symptoms were accompanied by diplopia. Blood tests showed severe hyperthyroidism. Thyroid scintigraphy showed a diffuse distribution of Tc-pertechnatate and the presence of a "cool" area in the right lobe of the thyroid, confirmed by ultrasonography. The nodule was diagnosed as a low-risk indeterminate lesion.

Conclusion: We present a case of Graves' disease with active, moderate-to-severe Graves' ophthalmopathy in a patient with pre-existing AFTN presenting with a coexisting, rare case of Marine-Lenhart syndrome associated with immune reconstitution after alemtuzumab treatment.
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http://dx.doi.org/10.1007/s42000-020-00215-9DOI Listing
March 2021

Selenium exerts protective effects against oxidative stress and cell damage in human thyrocytes and fibroblasts.

Endocrine 2020 04 30;68(1):151-162. Epub 2019 Dec 30.

Accademia Peloritana dei Pericolanti, University of Messina, Messina, Italy.

Purpose: Selenium, incorporated into specific seleno-enzymes, is essential to proper thyroid function and protect cells from oxidative damage induced by HO during thyroid hormone synthesis. Several studies indicated that low selenium levels are associated with thyroid autoimmunity and related disorders, but real effectiveness of selenium supplementation in such diseases is still controversial. We evaluated the effect of selenium on oxidative damage in human thyrocytes and thyroid fibroblasts in vitro.

Methods: To induce oxidative stress, primary cultures were exposed to HO, in the presence or the absence of selenium, as either selenomethionine or selenite. We performed the following assays: cell viability, caspase-3 activity, BCL-2/BAX gene expression, DNA fragmentation, malondialdehyde levels, and glutathione peroxidase (GPx) activity measurements.

Results: Thyrocytes and thyroid fibroblasts exposed to HO and preincubated with both selenocompounds displayed a significant dose-dependent increase in cell viability compared to cells incubated with HO alone. Pretreatment with selenomethionine and selenite significantly reduced caspase-3 activity and BAX mRNA levels and increased BCL-2 mRNA levels in a dose-dependent manner. Accordingly, HO induced a diffuse pattern of DNA degradation and an increase in malondialdehyde levels, which was prevented by the pretreatment with both selenomethionine and selenite. Both selenocompounds induced an increase in GPx activity, suggesting that these protective effects may be, almost in part, mediated by these selenoproteins.

Conclusion: In human thyrocytes and fibroblasts in vitro, selenium exerts protective effects against HO in a dose-dependent manner, being selenite effective at lower doses than selenomethionine.
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http://dx.doi.org/10.1007/s12020-019-02171-wDOI Listing
April 2020

Curcumin, Hormesis and the Nervous System.

Nutrients 2019 Oct 10;11(10). Epub 2019 Oct 10.

Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia, 97-95125 Catania, Italy.

Curcumin is a polyphenol compound extracted from the rhizome of (family ) commonly used as a spice to color and flavor food. Several preclinical studies have suggested beneficial roles for curcumin as an adjuvant therapy in free radical-based diseases, mainly neurodegenerative disorders. Indeed, curcumin belongs to the family of hormetins and the enhancement of the cell stress response, mainly the heme oxygenase-1 system, is actually considered the common denominator for this dual response. However, evidence-based medicine has clearly demonstrated the lack of any therapeutic effect of curcumin to contrast the onset or progression of neurodegeneration and related diseases. Finally, the curcumin safety profile imposes a careful analysis of the risk/benefit balance prior to proposing chronic supplementation with curcumin.
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http://dx.doi.org/10.3390/nu11102417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835324PMC
October 2019

Challenges in the treatment of parathyroid carcinoma: a case report.

Hormones (Athens) 2019 Sep 23;18(3):325-328. Epub 2019 Mar 23.

Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Via Palermo 636, 95122, Catania, Italy.

Introduction: Parathyroid carcinoma (PC) is a rare neoplasm with a high rate of recurrence and an indolent course. It is frequently functional, causing nearly 1% of the cases of primary hyperparathyroidism (HPT), and in some cases, it may be complicated by brown tumors, mimicking bone metastases. Synchronous parathyroid and papillary thyroid carcinomas are rare.

Case Report: We present a patient with HPT due to PC, misdiagnosed at first evaluation, which exhibited multiple hypermetabolic lytic lesions in the skeleton, suggesting bone metastases. Their regression after PTH reduction suggested the diagnosis of brown tumors due to severe HPT. Given the persistence of HPT, the patient underwent a number of neck surgeries, and a papillary thyroid microcarcinoma with a nodal metastasis was diagnosed. A genetic test discovered a previously unreported mutation of the CDC73 (HRPT2) gene, codifying for parafibromin and resulting in a premature stop codon (c.580A>Tp.Arg194). Because of the persistence of HPT, cinacalcet therapy was started in order to control hypercalcemia.

Conclusion: This is a very unusual patient with a newly discovered variant of the CDC73 gene and a phenotype characterized by recurrent PC, brown tumors, and N1a metastasized thyroid carcinoma. The present case confirms that PC may not exhibit clear malignant properties at first assessment, contributing to inadequate initial surgical treatment. Although infrequently, PC can be associated with papillary thyroid cancer. The diagnosis of brown tumor should be considered in patients with severe HPT and multiple destructive bone lesions mimicking metastases on PET/CT imaging.
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http://dx.doi.org/10.1007/s42000-019-00104-wDOI Listing
September 2019

Effect of Combined Epigenetic Treatments and Ectopic NIS Expression on Undifferentiated Thyroid Cancer Cells.

Anticancer Res 2018 Dec;38(12):6653-6662

Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Background: Poorly differentiated (PDTC) and anaplastic thyroid (ATC) cancer cells are characterized by the acquisition of epigenetic abnormalities, leading to the silencing of both the sodium iodide co-transporter and the Coxsackie adenovirus receptor. As aberrant histone acetylation and DNA methylation represent epigenetic mechanisms involved in neoplastic transformation, our study investigated the anticancer properties of epigenetic modifiers in thyroid carcinoma.

Materials And Methods: The cytotoxicity and gene expression modulation of histone deacetylase and DNA methyltransferase inhibitors were evaluated in both PDTC and ATC.

Results: Epigenetic treatments were cytotoxic to tumor thyrocytes and restored sodium iodide co-transporter and Coxsackie adenovirus receptor, expression as well as radioiodine uptake, in PDTC but not in ATC. However, ectopic expression sodium iodide co-transporter re-activated radioiodine incorporation in ATC.

Conclusion: The ability of epigenetic treatments to interfere with tumor proliferation and induce Coxsackie adenovirus receptor expression, coupled with the ability of ectopic sodium iodide co-transporter to restore radioiodine uptake, raise the possibility that these therapeutic approaches may provide clinical benefit to patients with thyroid carcinoma refractory to radioiodine treatment.
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http://dx.doi.org/10.21873/anticanres.13032DOI Listing
December 2018

Computational modeling reveals MAP3K8 as mediator of resistance to vemurafenib in thyroid cancer stem cells.

Bioinformatics 2019 07;35(13):2267-2275

Department of Drug Sciences, University of Catania, Catania, Italy.

Motivation: Val600Glu (V600E) mutation is the most common BRAF mutation detected in thyroid cancer. Hence, recent research efforts have been performed trying to explore several inhibitors of the V600E mutation-containing BRAF kinase as potential therapeutic options in thyroid cancer refractory to standard interventions. Among them, vemurafenib is a selective BRAF inhibitor approved by Food and Drug Administration for clinical practice. Unfortunately, vemurafenib often displays limited efficacy in poorly differentiated and anaplastic thyroid carcinomas probably because of intrinsic and/or acquired resistance mechanisms. In this view, cancer stem cells (CSCs) may represent a possible mechanism of resistance to vemurafenib, due to their self-renewal and chemo resistance properties.

Results: We present a computational framework to suggest new potential targets to overcome drug resistance. It has been validated with an in vitro model based upon a spheroid-forming method able to isolate thyroid CSCs that may mimic resistance to vemurafenib. Indeed, vemurafenib did not inhibit cell proliferation of BRAF V600E thyroid CSCs, but rather stimulated cell proliferation along with a paradoxical over-activation of ERK and AKT pathways. The computational model identified a fundamental role of mitogen-activated protein kinase 8 (MAP3K8), a serine/threonine kinase expressed in thyroid CSCs, in mediating this drug resistance. To confirm model prediction, we set a suitable in vitro experiment revealing that the treatment with MAP3K8 inhibitor restored the effect of vemurafenib in terms of both DNA fragmentation and poly (ADP-ribose) polymerase cleavage (apoptosis) in thyroid CSCs. Moreover, MAP3K8 expression levels may be a useful marker to predict the response to vemurafenib.

Availability And Implementation: The model is available in GitHub repository visiting the following URL: https://github.com/francescopappalardo/MAP3K8-Thyroid-Spheres-V-3.0.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty969DOI Listing
July 2019

Updates on the Management of Advanced, Metastatic, and Radioiodine Refractory Differentiated Thyroid Cancer.

Front Endocrinol (Lausanne) 2017 20;8:312. Epub 2017 Nov 20.

Clinical Oncology, Royal Marsden NHS Foundation Trust, London, United Kingdom.

Differentiated thyroid cancer (DTC) accounts for 95% of all thyroid cancers and is generally an indolent tumor, treated effectively with surgery, radioactive iodine, and thyroid-stimulating hormone suppressive therapy. However, 5-10% of patients have advanced disease, with aerodigestive tract invasion, distant metastases, or radioiodine refractory disease, with poor prognosis. This review focuses on the approaches for treating advanced DTC, including management of gross extra-thyroidal extension, recurrent loco-regional or distant metastatic disease, the role of external beam radiation therapy and systemic treatment. Locally ablative treatment modalities, including surgery, radiation therapy, and thermal ablation are evolving and can be used in selected patients. In recent years, new therapeutic agents with molecular targets have become available and two multi-kinase inhibitors, Sorafenib and Lenvatinib, have been licensed for iodine refractory DTC showing an advantage in terms of progression-free survival, although an impact on overall survival has not been proven yet. Management of advanced thyroid cancer can be challenging but a multidisciplinary approach can significantly improve outcomes for this patient population.
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http://dx.doi.org/10.3389/fendo.2017.00312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702018PMC
November 2017

Insulin Receptor Isoforms in Physiology and Disease: An Updated View.

Endocr Rev 2017 10;38(5):379-431

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy.

The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to be determined by their different binding affinities for insulin-like growth factors (IGFs), particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues by involving not only different ligand-binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Of note, dysregulation of the IR-A/IR-B ratio is associated with insulin resistance, aging, and increased proliferative activity of normal and neoplastic tissues and appears to sustain detrimental effects. This review discusses novel information that has generated remarkable progress in our understanding of the physiology of IR isoforms and their role in disease. We also focus on novel IR ligands and modulators that should now be considered as an important strategy for better and safer treatment of diabetes and cancer and possibly other IR-related diseases.
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http://dx.doi.org/10.1210/er.2017-00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629070PMC
October 2017

Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy.

Clin Endocrinol (Oxf) 2017 Aug 16;87(2):207-215. Epub 2017 May 16.

Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, Catania, Italy.

Background: Whether serum TSH undergoes seasonal fluctuations in euthyroid and hypothyroid residents of temperate climates is controversial.

Methods: Monthly TSH and thyroid hormone levels were cross-sectionally analysed in a large cohort of euthyroid subjects (n=11 806) and L-thyroxine (L-T4)-treated athyreotic patients (n=3 934). Moreover, in a small group (n=119) of athyreotic patients treated with an unchanged dosage of L-T4 monotherapy, hormones were measured both in the coldest and in the hottest seasons of the same year (longitudinal study).

Results: No seasonal hormone change was observed in the euthyroid subjects except for a small FT3 increase in winter (+2.9%, P<.001). In contrast, the L-T4-treated athyreotic patients had significantly higher serum TSH values in the cold season when the FT4 values were significantly lower. The differences were more notable in the longitudinal series (TSH, 0.80 vs. 0.20 mU/L and FT4, 16.3 vs. 17.8 pmol/L in December-March vs. June-September, respectively). In these patients also serum FT3 values significantly decreased in winter (in the longitudinal series, 3.80 in winter vs 4.07 pmol/L in summer). Regression analysis showed that in athyreotic subjects, a greater FT4 change is required to obtain a TSH change similar to that of euthyroid controls and that this effect is more pronounced in the summer.

Conclusion: Athyreotic patients undergoing L-T4 monotherapy have abnormal seasonal variations in TSH. These changes are secondary to the FT4 and FT3 serum decreases in winter, which occur in spite of the constant treatment. The underlying mechanisms are unclear, but in some cases, these changes may be clinically relevant.
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http://dx.doi.org/10.1111/cen.13351DOI Listing
August 2017

Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism.

Clin Endocrinol (Oxf) 2016 Apr 18;84(4):614-9. Epub 2015 Aug 18.

Department of Experimental and Clinical Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.

Introduction: Mitotane, a steroidogenesis inhibitor with adrenolytic properties used to treat adrenocortical cancer (ACC), can affect thyroid function. A reduction of FT4 levels with normal FT3 and TSH has been described in these patients. Using an in vitro murine model, the secretory capacity of thyrotrophic cells has been shown to be inhibited by mitotane.

Objective: To investigate the pathogenesis of thyroid abnormalities in mitotane-treated patients with ACC.

Patients And Methods: In five female patients with ACC (median age 47; range 31-65) treated with mitotane (dosage 1·5 g/day; 1·0-3·0), we analysed the pattern of TSH and thyroid function index (FT4, FT3 and FT3/FT4 ratio) compared to an age- and gender-matched control group. The in vivo secretory activity of the thyrotrophic cells was evaluated using a standard TRH test (200 μg), and the response was compared to both a group of age-matched female controls (n = 10) and central hypothyroid patients (n = 10).

Results: Basal TSH (median 1·54 mU/l; range 1·20-2·17) was normal and scattered around our median reference value, FT3 levels (median 3·80 pmol/l; 3·30-4·29) were normal but below the median reference value of 4·37 pmol/l and FT4 levels were below the normal range in all patients (median 8·40 pmol/l; 7·6-9·9). FT3/FT4 ratio was in the upper range in 4 patients and higher than normal in one patient. A blunted TSH response to TRH was observed in mitotane-treated patients. ΔTSH (absolute TSH response, peak TSH minus basal TSH) was 3·65 (range 3·53-5·26), 12·37 (range 7·55-19·97) and 1·32 mU/l (range 0·52-4·66) in mitotane-treated patients, controls and central hypothyroid patients, respectively. PRL secretion was normal.

Conclusions: Mitotane-treated patients with ACC showed low FT4, normal FT3 and TSH and impaired TSH response to TRH, characteristic of central hypothyroidism. Furthermore, the elevated FT3/FT4 ratio of these subjects reflects an enhanced T4 to T3 conversion rate, a compensatory mechanism characteristic of thyroid function changes observed in hypothyroid conditions. This finding thus confirms in vitro studies and may have a therapeutic implication for treatment with thyroid hormones, as suggested by current guidelines for this specific condition.
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http://dx.doi.org/10.1111/cen.12868DOI Listing
April 2016

Thyrospheres From Normal or Malignant Thyroid Tissue Have Different Biological, Functional, and Genetic Features.

J Clin Endocrinol Metab 2015 Sep 7;100(9):E1168-78. Epub 2015 Jul 7.

Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy.

Context: Cancer stem cells from several human malignancies, including poorly differentiated thyroid carcinoma and thyroid cancer cell lines, have been cultured in vitro as sphere-forming cells. These thyroid cancer stem cells were proven to be able to reproduce the original tumor in a xenograft orthotopic model.

Objectives: The objective of the study was to characterize papillary thyroid carcinoma (PTC) spheres from well-differentiated thyroid cancer and normal thyroid (NT) spheres obtained from the contralateral thyroid tissue of the same patient.

Design: Thyrospheres from PTCs and NTs were isolated.

Main Outcome Measures: Gene expression analysis by real-time PCR, immunofluorescence studies, and fluorescence-activated cell sorter analysis in thyrospheres from PTCs and NTs have been evaluated.

Conclusions: Compared with NT spheres, PTC spheres are larger, more irregular, and more clonogenic and have a higher rate of symmetric division. Moreover, PTC spheres express higher levels of stem cell markers and lower levels of thyroid-specific genes compared with NT spheres. Under appropriate conditions, NT spheres differentiated into thyrocytes, whereas PTC spheres did not, displaying a defect in the differentiation potential. Immunofluorescence experiments indicated that, in NT spheres, progenitor cells are mainly present in the sphere core, and the sphere periphery contains thyroid precursor cells already committed to differentiation. PTC spheres are not polarized like NT spheres. Unlike cells differentiated from NT spheres, TSH did not significantly stimulate cAMP production in cells differentiated from PTC spheres. A microarray analysis performed in paired samples (NT and PTC spheres from the same patient) indicated that NT and PTC spheres display a gene expression pattern typical of stem/progenitor cells; however, compared with NT spheres, PTC spheres display a unique gene expression pattern that might be involved in PTC progression.
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http://dx.doi.org/10.1210/JC.2014-4163DOI Listing
September 2015

The BRAF(V600E) mutation influences the short- and medium-term outcomes of classic papillary thyroid cancer, but is not an independent predictor of unfavorable outcome.

Thyroid 2014 Aug 11;24(8):1267-74. Epub 2014 Jun 11.

1 Endocrinology, Department of Clinical and Molecular Biomedicine, University of Catania , Catania, Italy .

Introduction: The prognostic usefulness of BRAF(V600E) evaluation in papillary thyroid cancer (PTC) has been analyzed in many studies, with controversial conclusions.

Aim: To analyze the clinical relevance of BRAF(V600E) measurement in a homogenous series of PTC patients followed in a single institution.

Methods: One hundred three classical variant PTC patients who underwent total thyroidectomy in the 3-year period between 2005 and 2008 were retrospectively selected, and BRAF(V600E) assessment was performed using paraffin-embedded archival specimens in 2013. All patients were actively followed at our medical center, with an average follow-up of 55±13 months.

Results: BRAF(V600E) mutation-positive cancers (55.3%) were more frequently associated with lymph node metastasis (p=0.01) and advanced TNM stage (III-IV) (p=0.03). These findings were also confirmed in the subset of 42 microcarcinomas. BRAF(V600E)-positive patients were also at a higher risk of persistent disease (OR 3.5 [95% confidence interval {CI} 1.2-10.3], p=0.03) in univariate but not multivariate analysis (OR 2.8 [CI 0.7-11.8], p=0.2). Lymph node involvement was an independent predictor of persistent disease (OR 30.9 [CI 6.0-159.0], p<0.0001). Kaplan-Meier curves confirmed a higher percentage of persistent/recurrent disease in BRAF(V600E)-positive patients (p=0.02). However, the BRAF(V600E) mutation did not change the recurrence rate of PTC in subgroup analyses on the basis of other established risk factors (p=0.2).

Conclusions: BRAF(V600E)-positive tumors were at higher risk of developing more aggressive behavior and were associated with less favorable outcomes in the short and medium term, but the BRAF(V600E) mutation was not an independent predictor of unfavorable outcome. Therefore, its use as a prognostic marker in clinical practice is not advisable.
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http://dx.doi.org/10.1089/thy.2013.0675DOI Listing
August 2014

Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors.

J Cancer Epidemiol 2013 7;2013:965212. Epub 2013 May 7.

Endocrinology, Garibaldi-Nesima Hospital, Via Palermo, 636, 95122 Catania, Italy.

Background. In the last decades, thyroid cancer incidence has continuously and sharply increased all over the world. This review analyzes the possible reasons of this increase. Summary. Many experts believe that the increased incidence of thyroid cancer is apparent, because of the increased detection of small cancers in the preclinical stage. However, a true increase is also possible, as suggested by the observation that large tumors have also increased and gender differences and birth cohort effects are present. Moreover, thyroid cancer mortality, in spite of earlier diagnosis and better treatment, has not decreased but is rather increasing. Therefore, some environmental carcinogens in the industrialized lifestyle may have specifically affected the thyroid. Among potential carcinogens, the increased exposure to medical radiations is the most likely risk factor. Other factors specific for the thyroid like increased iodine intake and increased prevalence of chronic autoimmune thyroiditis cannot be excluded, while other factors like the increasing prevalence of obesity are not specific for the thyroid. Conclusions. The increased incidence of thyroid cancer is most likely due to a combination of an apparent increase due to more sensitive diagnostic procedures and of a true increase, a possible consequence of increased population exposure to radiation and to other still unrecognized carcinogens.
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http://dx.doi.org/10.1155/2013/965212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664492PMC
June 2013

Thyroid cancer cell resistance to gefitinib depends on the constitutive oncogenic activation of the ERK pathway.

J Clin Endocrinol Metab 2013 Jun 4;98(6):2502-12. Epub 2013 Apr 4.

Endocrinology Unit, Department of Clinical and Molecular Bio-Medicine, University of Catania, Garibaldi-Nesima Medical Center, Via Palermo 636, 95122 Catania, Italy.

Context: Poorly differentiated thyroid carcinomas are refractory to common anticancer therapies, and novel inhibitors are being tested in these deadly malignancies. The epidermal growth factor receptor (EGFR) tyrosine kinase represents an attractive target for treatment because it is up-regulated in thyroid cancer and plays a role in cancer progression. However, EGFR inhibitors have provided poor results in thyroid carcinomas.

Objective: We evaluated the possible mechanism underlying the resistance of thyroid cancer cells to EGFR inhibitors.

Design: We tested the effect of the EGFR tyrosine kinase inhibitor gefitinib in a panel of thyroid cancer cell lines.

Results: We found that in most of the cell lines, although gefitinib inhibited EGFR phosphorylation, it was poorly effective in reducing cell viability. gefitinib, however, was able to inhibit epidermal growth factor-induced cell migration and matrix invasion. In most thyroid cancer cell lines, gefitinib significantly inhibited Akt phosphorylation by inhibiting EGFR activation, but it had limited or no effect on ERK phosphorylation. The poor cell response to gefitinib was associated with genetic alterations, leading to constitutive activation of the ERK pathway, including BRAF(V600E) and HRAS(G12A/Q61R) mutations and RET/PTC1 rearrangement. When BRAF(V600E)-positive thyroid cancer cells were incubated with the specific BRAF inhibitor PLX4032, sensitivity to gefitinib was restored. Similar results were obtained with rat sarcoma and RET/papillary thyroid cancer inhibitors.

Conclusions: These results indicate that thyroid cancer resistance to gefitinib is due to the constitutive activation of the mitogenic pathway by either signals downstream of EGFR or other tyrosine kinase receptors. This resistance can be overcome by the combined use of selective inhibitors.
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http://dx.doi.org/10.1210/jc.2012-3623DOI Listing
June 2013

Update on thyroid cancer treatment.

Future Oncol 2012 Oct;8(10):1331-48

Endocrinology, Department of Clinical & Molecular Biomedicine of the University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.

Surgery and radioiodine therapy are usually effective for most patients with differentiated thyroid cancer. However, poorly differentiated and anaplastic thyroid carcinomas represent a challenge to physicians on the basis of the current cancer treatment modalities. These cancer subtypes are often lethal and refractory to radioiodine therapy as well as most of the common chemotherapy drugs. Several kinase inhibitors are promising targeted therapies for these malignancies; however, clinical trials involving these drugs have provided controversial results and their clinical use is still under debate. Advanced medullary thyroid carcinomas may also be refractory to conventional therapies and novel kinase inhibitors may also be useful to control tumor progression in certain patients. Novel evidence is emerging that thyroid cancer is a stem cell disease, thereby implying that the driving force of thyroid cancers is a subset of undifferentiated cells (thyroid cancer stem cells) with unlimited growth potential and resistance to conventional therapeutic regimens. Thyroid cancer stem cells have been proposed as responsible for tumor invasiveness, metastasis, relapse and differentiation. Therefore, drugs that selectively target these cells could serve as a cornerstone in the treatment of poorly differentiated thyroid cancer.
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http://dx.doi.org/10.2217/fon.12.123DOI Listing
October 2012

Modifications in the papillary thyroid cancer gene profile over the last 15 years.

J Clin Endocrinol Metab 2012 Sep 28;97(9):E1758-65. Epub 2012 Jun 28.

Department of Endocrinology and Metabolism and World Health Organization Collaborating Center for the Study and Treatment of Thyroid Diseases and Other Endocrine and Metabolic Disorders, University of Pisa, 56124 Pisa, Italy.

Background: Evidence for an increased prevalence of BRAF(V600E) mutations has been documented in recent decades. The aim of this study was to evaluate the prevalence of both RET/PTC rearrangements and BRAF(V600E) mutations in an Italian cohort of papillary thyroid carcinoma (PTC) patients followed at the Endocrine Units of Pisa, Milano, and Perugia from 1996-2010.

Patients And Methods: In total, 401 PTC patients were examined and grouped according to the time of surgery: group 1, 1996-2000; group 2, 2001-2005; and group 3, 2006-2010. Patients were analyzed for clinical, pathological, and molecular features. In parallel, the molecular characteristics of 459 PTC from Sicily were studied.

Results: The genetic profiles of the three groups were significantly different (P < 0.0001). In particular, the frequency of RET/PTC rearrangements decreased from 1996-2010, occurring in 33 of 100 (33%) of the patients in group 1, 26 of 148 (17%) in group 2, and 15 of 153 (9.8%) in group 3. The incidence of BRAF(V600E) mutations increased over the same period, from 28% in group 1 (28 of 100) to 48.9% in group 2 (73 of 148) and 58.1% in group 3 (89 of 153). A consistent increase in BRAF(V600E) prevalence was observed in the Sicilian group (P < 0.0001). Moreover, a statistically significant increase in the mean age at diagnosis and decrease in tumor size over the study period was observed.

Conclusion: The genetic profile of PTC changed over the last 15 yr, with a significant decrease in the prevalence of RET/PTC rearrangements and an increase in BRAF(V600E) mutations. In addition, the mean age at diagnosis increased and tumor size decreased over the study period.
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http://dx.doi.org/10.1210/jc.2012-1269DOI Listing
September 2012

IRF5 promotes the proliferation of human thyroid cancer cells.

Mol Cancer 2012 Apr 16;11:21. Epub 2012 Apr 16.

Department of Clinical and Molecular Bio-Medicine, University of Catania, Via Androne, 83-95124 Catania, Italy.

Background: Interferon Regulatory Factor 5 is a transcription factor that regulates the expression of genes involved in the response to viral infection and in the stimulation of the immune system. Moreover, multiple studies have demonstrated that it negatively regulates cell growth and oncogenesis, favoring cell differentiation and apoptosis.Thyroid carcinoma represents 98% of all thyroid malignancies and has shown a steady increase in incidence in both the USA and western European countries.

Findings: We investigated the expression, localization and function of IRF5 in thyroid cancer cells and found that it is highly expressed in both primary and immortalized thyroid carcinomas but not in normal thyrocytes. IRF5 levels were variably modulated by Interferon alpha but IRF5 only localized in the cytoplasmic compartment, thus failing to induce p21 expression as previously reported in different cell models. Furthermore, ectopic IRF5 increased both the proliferation rate and the clonogenic potential of malignant thyroid cells, protecting them from the cytotoxic effects of DNA-damaging agents. These results were directly attributable to IRF5, as demonstrated by the reduction in colony-forming ability of thyroid cancer cells after IRF5 silencing. An IRF5-dependent induction of endogenous B-Raf observed in all thyroid cancer cells might contribute to these unexpected effects.

Conclusions: These findings suggest that, in thyroid malignancies, IRF5 displays tumor-promoting rather than tumor-suppressor activities.
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http://dx.doi.org/10.1186/1476-4598-11-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444366PMC
April 2012

Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients.

PLoS One 2011 1;6(8):e22552. Epub 2011 Aug 1.

Endocrine Unit, Department of Clinical and Molecular Biomedicine, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy.

Context: Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.

Objective: To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback.

Design: Retrospective study.

Setting: Academic hospital.

Patients: 1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.

Measurements: TSH, FT4 and FT3 concentrations by immunoassays.

Results: FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients.

Conclusions: Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148220PMC
December 2011

Levels of histone acetylation in thyroid tumors.

Biochem Biophys Res Commun 2011 Aug 3;411(4):679-83. Epub 2011 Jul 3.

Dipartimento di Scienze Mediche e Biologiche, Università di Udine, Italy.

Histone acetylation is a major mechanism to regulate gene transcription. This post-translational modification is modified in cancer cells. In various tumor types the levels of acetylation at several histone residues are associated to clinical aggressiveness. By using immunohistochemistry we show that acetylated levels of lysines at positions 9-14 of H3 histone (H3K9-K14ac) are significantly higher in follicular adenomas (FA), papillary thyroid carcinomas (PTC), follicular thyroid carcinomas (FTC) and undifferentiated carcinomas (UC) than in normal tissues (NT). Similar data have been obtained when acetylated levels of lysine 18 of H3 histone (H3K18ac) were evaluated. In this case, however, no difference was observed between NT and UC. When acetylated levels of lysine 12 of H4 histone (H4K12ac) were evaluated, only FA showed significantly higher levels in comparison with NT. These data indicate that modification histone acetylation is an early event along thyroid tumor progression and that H3K18 acetylation is switched off in the transition between differentiated and undifferentiated thyroid tumors. By using rat thyroid cell lines that are stably transfected with doxycyclin-inducible oncogenes, we show that the oncoproteins RET-PTC, RAS and BRAF increase levels of H3K9-K14ac and H3K18ac. In the non-tumorigenic rat thyroid cell line FRTL-5, TSH increases levels of H3K18ac. However, this hormone decreases levels of H3K9-K14ac and H4K12ac. In conclusion, our data indicate that neoplastic transformation and hormonal stimulation can modify levels of histone acetylation in thyroid cells.
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http://dx.doi.org/10.1016/j.bbrc.2011.06.182DOI Listing
August 2011

Reactivation of p53 mutants by prima-1 [corrected] in thyroid cancer cells.

Int J Cancer 2012 May 14;130(10):2259-70. Epub 2011 Sep 14.

Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy.

Most undifferentiated thyroid carcinomas express p53 mutants and thereafter, are very resistant to chemotherapy. p53 reactivation and induction of massive apoptosis (Prima-1) is a compound restoring the tumor-suppressor activity of p53 mutants. We tested the effect of Prima-1 in thyroid cancer cells harboring p53 mutations. Increasing doses of Prima-1 reduced viability of thyroid cancer cells at a variable extent (range 20-80%). Prima-1 up-regulated p53 target genes (p21(WAF1) , BCL2-associated X protein (Bax), and murine double minute 2 (MDM2)), in BC-PAP and Hth-74 cells (expressing D259Y/K286E and K286E p53 mutants) but had no effect in SW1736 (p53 null) and TPC-1 (expressing wild-type p53) thyroid cancer cells. Prima-1 also increased the cytotoxic effects of either doxorubicin or cisplatin in thyroid cancer cells, including the chemo-resistant 8305C, Hth-74 and BC-PAP cells. Moreover, real-time PCR and Western blot indicated that Prima-1 increases the mRNA of thyroid-specific differentiation markers in thyroid cancer cells. Fluorescence-activated cell sorting analysis revealed that Prima-1 effect on thyroid cancer cells occurs via the enhancement of both cell cycle arrest and apoptosis. Small interfering RNA experiments indicated that Prima-1 effect is mediated by p53 mutants but not by the p53 paralog p73. Moreover, in C-643 thyroid cancer cells, forced to ectopically express wild-type p53, Prima-1 prevented the dominant negative effect of double K248Q/K286E p53 mutant. Finally, co-IP experiments indicated that in Hth-74 cells Prima-1 prevents the ability of p53 mutants to sequestrate the p53 paralog TAp73. These in vitro studies imply that p53 mutant reactivation by small compounds may become a novel anticancer therapy in undifferentiated thyroid carcinomas.
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http://dx.doi.org/10.1002/ijc.26228DOI Listing
May 2012

In thyroid cancer cell lines expression of periostin gene is controlled by p73 and is not related to epigenetic marks of active transcription.

Cell Oncol (Dordr) 2011 Apr 27;34(2):131-40. Epub 2011 Jan 27.

Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Piazzale Kolbe, 1-33100, Udine, Italy.

Background: Periostin expression is a feature of the epithelial-mesenchymal transition, which occurs during cancer progression. Previous reports indicate that periostin expression is related to tumour aggressiveness.

Methods: In order to identify mechanisms regulating periostin expression in thyroid cancer, a panel of continuous thyroid cancer cell lines was investigated. Levels of posttranslational modifications of the H3 histone were investigated by chromatin immunoprecipitation. Moreover, treatment of cell lines with deacetylase inhibitors and transfection experiments were performed.

Results: Our insights show that levels of H3 histone acetylated at lysines 9 and 14 (which are epigenetic marks of active transcription) are not related to periostin mRNA levels. Moreover, treatment of WRO and FRO thyroid cancer cell lines with the deacetylase inhibitor tricostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) increases levels of acetylated H3 histone to periostin promoter however, unpredictably, reduces periostin mRNA levels. Interestingly, treatment of WRO cells with either TSA or SAHA increases levels of the H3 histone trimethylated at lysine 4, which is a different epigenetic mark of active transcription. Instead, data obtained by cell transfection indicate that ΔNp73, a member of p53 family selectively expressed in thyroid carcinomas, plays a role in activating periostin gene expression.

Conclusions: Levels of epigenetic marks of active transcription do not contribute to regulation of periostin gene expression. The ΔNp73 effects suggest a novel molecular mechanism involved in thyroid cancer progression.
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http://dx.doi.org/10.1007/s13402-011-0009-9DOI Listing
April 2011

Insulin receptor isoforms and insulin-like growth factor receptor in human follicular cell precursors from papillary thyroid cancer and normal thyroid.

J Clin Endocrinol Metab 2011 Mar 1;96(3):766-74. Epub 2010 Dec 1.

Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy.

Context: Factors involved in the biology of normal and cancer stem/precursor cells from the thyroid are unknown. Thyroid cancer cells are responsive to insulin and IGF-I and IGF-II and often overexpress the insulin receptor (IR) and the IGF-I receptor (IGF-IR).

Objective: We investigated the role of IR isoforms (IR-A and IR-B), IGF-IR, and their ligands in thyroid follicular cell precursors both normal and malignant.

Design: We established cultures of follicular cell precursors as thyrospheres from three papillary thyroid cancers and the corresponding nonaffected tissues. The expression of IR, IGF-IR, and their ligands was evaluated by quantitative RT-PCR and, in one case, also by Western blot. The effects of insulin and IGFs on thyrosphere growth and self-renewal were evaluated.

Results: Thyrospheres were characterized by the expression of stem cell markers and low/absent thyroid specific markers. Thyrospheres from normal tissue, but not from cancer tissue, could be induced to differentiate. Both IR isoforms, IGF-IR, IGF-I and IGF-II, were expressed at high levels in thyrospheres and markedly decreased in differentiating cells. IR-A was the predominant isoform in thyrospheres, especially from cancer, while IR-B was predominant in differentiating cells. Cancer thyrosphere growth was stimulated by insulin and IGFs.

Conclusions: Our data suggest that IR isoforms and IGF-IR play a role in the biology of follicular thyroid precursors. Cell differentiation is associated with marked changes in the expression of these receptors and cognate ligands. These data may provide insight for future differentiation therapies in thyroid cancer.
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http://dx.doi.org/10.1210/jc.2010-1255DOI Listing
March 2011

Papillary thyroid cancer incidence in the volcanic area of Sicily.

J Natl Cancer Inst 2009 Nov 5;101(22):1575-83. Epub 2009 Nov 5.

Endocrinology Division, Department of Internal and Specialistic Medicine, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy.

Background: The steadily increasing incidence of thyroid cancer has been attributed mostly to more sensitive thyroid nodule screening. However, various environmental factors, such as those associated with volcanic areas, cannot be excluded as risk factors. We evaluated thyroid cancer incidence in Sicily, which has a homogenous population and a province (Catania) that includes the Mt Etna volcanic area.

Methods: In a register-based epidemiological survey, we collected all incident thyroid cancers in Sicily from January 1, 2002, through December 31, 2004. The age-standardized incidence rate for the world population (ASR(w)) was calculated and expressed as the number of thyroid cancer diagnoses per 100 000 residents per year. The association of thyroid cancer incidence rate with sex, age, tumor histotype, and various environmental factors was evaluated by modeling the variation of the ASR(w). All statistical tests were two-sided.

Results: In 2002-2004, 1950 incident thyroid cancers were identified in Sicily (among women, ASR(w) = 17.8, 95% confidence interval [CI] = 16.9 to 18.7; and among men, ASR(w) = 3.7, 95% CI = 3.3 to 4.1). Although the percentage of thyroid cancers that were microcarcinomas (ie, < or = 10 mm) and ratio of men to women with thyroid cancer were similar in all nine Sicilian provinces, thyroid cancer incidence was statistically significantly higher in the province of Catania (among women, ASR(w) = 31.7, 95% CI = 29.1 to 34.3; and among men, ASR(w) = 6.4, 95% CI = 5.2 to 7.5) than in the rest of Sicily (among women, ASR(w) = 14.1, 95% CI = 13.2 to 15.0; and among men, ASR(w) = 3.0, 95% CI = 2.6 to 3.4) (all P values < .001). Incidence of papillary, but not follicular or medullary, cancers was statistically significantly increased in Catania province, and papillary tumors from patients in Catania more frequently carried the BRAF V600E gene mutation (55 [52%] of 106 tumors) than tumors from patients elsewhere in Sicily (68 [33%] of 205 tumors) (relative risk = 1.7, 95% CI = 1.0 to 2.8, P = .02). Cancer incidence was statistically significantly lower in rural areas than in urban areas of Sicily (P = .003). No association with mild iodine deficiency or industrial installations was found. Levels of many elements (including boron, iron, manganese, and vanadium) in the drinking water of Catania province often exceeded maximum admissible concentrations, in contrast to water in the rest of Sicily.

Conclusion: Residents of Catania province with its volcanic region appear to have a higher incidence of papillary thyroid cancer than elsewhere in Sicily.
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http://dx.doi.org/10.1093/jnci/djp354DOI Listing
November 2009

Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

Endocr Rev 2009 Oct 14;30(6):586-623. Epub 2009 Sep 14.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, 95122 Catania, Italy.

In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.
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http://dx.doi.org/10.1210/er.2008-0047DOI Listing
October 2009
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