Publications by authors named "Domenico Salvatore"

72 Publications

The importance of the RET gene in thyroid cancer and therapeutic implications.

Nat Rev Endocrinol 2021 Feb 18. Epub 2021 Feb 18.

Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Since the discovery of the RET receptor tyrosine kinase in 1985, alterations of this protein have been found in diverse thyroid cancer subtypes. RET gene rearrangements are observed in papillary thyroid carcinoma, which result in RET fusion products. By contrast, single amino acid substitutions and small insertions and/or deletions are typical of hereditary and sporadic medullary thyroid carcinoma. RET rearrangements and mutations of extracellular cysteines facilitate dimerization and kinase activation, whereas mutations in the RET kinase coding domain drive dimerization-independent kinase activation. Thus, RET kinase inhibition is an attractive therapeutic target in patients with RET alterations. This approach was initially achieved using multikinase inhibitors, which affect multiple deregulated pathways that include RET kinase. In clinical practice, use of multikinase inhibitors in patients with advanced thyroid cancer resulted in therapeutic efficacy, which was associated with frequent and sometimes severe adverse effects. However, remarkable progress has been achieved with the identification of novel potent and selective RET kinase inhibitors for the treatment of advanced thyroid cancer. Although expanded clinical validation in future trials is needed, the sustained antitumoural activity and the improved safety profile of these novel compounds is opening a new exciting era in precision oncology for RET-driven cancers.
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http://dx.doi.org/10.1038/s41574-021-00470-9DOI Listing
February 2021

Deiodinases and Cancer.

Endocrinology 2021 Apr;162(4)

Department of Public Health, University of Naples "Federico II," Naples, Italy.

Hormones are key drivers of cancer development, and alteration of the intratumoral concentration of thyroid hormone (TH) is a common feature of many human neoplasias. Besides the systemic control of TH levels, the expression and activity of deiodinases constitute a major mechanism for the cell-autonomous, prereceptoral control of TH action. The action of deiodinases ensures tight control of TH availability at intracellular level in a time- and tissue-specific manner, and alterations in deiodinase expression are frequent in tumors. Research over the past decades has shown that in cancer cells, a complex and dynamic expression of deiodinases is orchestrated by a network of growth factors, oncogenic proteins, and miRNA. It has become increasingly evident that this fine regulation exposes cancer cells to a dynamic concentration of TH that is functional to stimulate or inhibit various cellular functions. This review summarizes recent advances in the identification of the complex interplay between deiodinases and cancer and how this family of enzymes is relevant in cancer progression. We also discuss whether deiodinase expression could represent a diagnostic tool with which to define tumor staging in cancer treatment or even a therapeutic tool against cancer.
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http://dx.doi.org/10.1210/endocr/bqab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906444PMC
April 2021

Long-term management of lenvatinib-treated thyroid cancer patients: a real-life experience at a single institution.

Endocrine 2021 Feb 3. Epub 2021 Feb 3.

Department of Public Health, University of Naples "Federico II", 80131, Naples, Italy.

Purpose: The efficacy of lenvatinib for advanced and progressive radioactive iodine refractory differentiated thyroid cancer is well established. Herein, we retrospectively evaluated the long-term safety and efficacy of lenvatinib in 23 patients treated at a single Institution.

Methods: Clinical data of all patients treated for a differentiated thyroid cancer with lenvatinib from April 2015 to September 2020 were retrospectively analyzed.

Results: A total of 23 patients were included. In all, 21 patients received lenvatinib as first-line systemic therapy. Median age at initiation of lenvatinib treatment was 68 (44-90) years. Median duration of the study from initiation of lenvatinib to study end was 23 (2-65) months. The indication for lenvatinib treatment was documented progression of distant metastases in 20 patients and of locally advanced disease in the other 3 and median duration of lenvatinib therapy was 15 (2-64) months. Best treatment responses were: partial response in 6 patients, stable disease in 14, progressive disease in 1, and not evaluable in 2. Median progression-free survival was 25 months (95% CI: 12-40) and median overall survival was 46 months (95% CI: 28-65). Three patients had to discontinue lenvatinib treatment due to serious adverse events and no drug-related death was observed. Ten patients continued lenvatinib for more than 24 months and the only newly registered adverse event after this period of time was one case of G2 proteinuria. Six patients continued lenvatinib treatment beyond documented tumor progression due to oligoprogression or slowly progressive disease (median time 18.5 months, 8-42 months). A total of 14 patients were alive at the end of the study: 11 showed partial response/stable disease on lenvatinib, including 3 who had a stable disease after local ablative therapy for oligoprogressive metastases; 3 had to change treatment, including 2 for lenvatinib-related serious adverse events and 1 for progressive disease.

Conclusions: Long-term lenvatinib treatment is safe and some patients may experience persistent long-term control of the disease. Late treatment-related AEs rarely occurred. Oligoprogressive and slowly progressive disease can be managed without treatment withdrawal as long as there are some clinical benefits.
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http://dx.doi.org/10.1007/s12020-021-02634-zDOI Listing
February 2021

Germline mutations in the thyroid hormone receptor alpha gene predispose to cutaneous tags and melanocytic nevi.

Thyroid 2021 Jan 28. Epub 2021 Jan 28.

University of Naples , Molecular and Clinical Endocrinology and Oncology, Via S. Pansini, 5, Naples, Italy, 80131;

Background Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (thyroid hormone receptor α and β, TRα, TRβ) to regulate transcription of target genes. Heterozygous, dominant negative, mutations in human TRα mediate Resistance to Thyroid Hormone alpha (RTHα), characterized by features of hypothyroidism (e.g. skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods RTHα cases (n=10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had both highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, Cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n=2 cases) and melanoma (c-kit, MAGE, CDK4, n=1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients was markedly increased. Conclusions Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHα patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted.
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http://dx.doi.org/10.1089/thy.2020.0391DOI Listing
January 2021

Thyroid fine-needle aspiration trends before, during, and after the lockdown: what we have learned so far from the COVID-19 pandemic.

Endocrine 2021 01 7;71(1):20-25. Epub 2020 Dec 7.

Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.

Purpose: Nowadays, the clinical management of thyroid nodules needs to be multi-disciplinary. In particular, the crosstalk between endocrinologists and cytopathologists is key. When FNAs are properly requested by endocrinologists for nodules characterised by relevant clinical and ultrasound features, cytopathologists play a pivotal role in the diagnostic work-up. Conversely, improper FNA requests can lead to questionable diagnostic efficiency. Recently, recommendations to delay all non-urgent diagnostic procedures, such as thyroid FNAs, to contain the spread of COVID-19 infection, have made the interplay between endocrinologists and cytopathologists even more essential. The objective of this study was to assess the impact of COVID-19 pandemic on our practice by evaluating the total number of FNAs performed and the distribution of the Bethesda Categories before, during, and after the lockdown.

Methods: We analysed the FNA trends before (1st January 2019 to March 13th 2020), during (March 14th to May 15th), and after (May 16th to July 7th) the lockdown.

Results: Although the total number of weekly FNAs dropped from 62.1 to 23.1, our referring endocrinologists managed to prioritise patients with high-risk nodules. In fact, in the post-lockdown, the weekly proportion of benign diagnoses dropped on average by 12% and that of high-risk diagnoses increased by 6%.

Conclusions: The lesson we have learned so far from this pandemic is that by applying safety protocols to avoid contagion and by increasing the threshold for FNA requests for thyroid nodules, we can continue to guarantee our services to high-risk patients even in times of a health crisis.
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http://dx.doi.org/10.1007/s12020-020-02559-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719849PMC
January 2021

Safety and Quality-of-Life Data from an Italian Expanded Access Program of Lenvatinib for Treatment of Thyroid Cancer.

Thyroid 2021 Feb 22;31(2):224-232. Epub 2020 Oct 22.

Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.
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http://dx.doi.org/10.1089/thy.2020.0276DOI Listing
February 2021

A Type 2 Deiodinase-Dependent Increase in Mediates Myoblast-Endothelial Cell Crosstalk During Skeletal Muscle Regeneration.

Thyroid 2021 Jan 9;31(1):115-127. Epub 2020 Sep 9.

Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

The type 2 deiodinase (DIO2) converts thyroxine to 3,3',5-triiodothyronine (T3), modulating intracellular T3. An increase in DIO2 within muscle stem cells during skeletal muscle regeneration leads to T3-dependent potentiation of differentiation. The muscle stem cell niche comprises numerous cell types, which coordinate the regeneration process. For example, muscle stem cells provide secretory signals stimulating endothelial cell-mediated vascular repair, and, in turn, endothelial cells promote muscle stem differentiation. We hypothesized that loss in muscle stem cells directly impairs muscle stem cell-endothelial cell communication, leading to downstream disruption of endothelial cell function. We assessed the production of proangiogenic factors in differentiated C2C12 cells and in a C2C12 cell line without (D2KO C2C12) by real-time quantitative-polymerase chain reaction and enzyme-linked immunosorbent assay. Conditioned medium (CM) was collected daily in parallel to evaluate its effects on human umbilical vein endothelial cell (HUVEC) proliferation, migration and chemotaxis, and vascular network formation. The effects of T3-treatment on vascular endothelial growth factor () mRNA expression in C2C12 cells and mouse muscle were assessed. Chromatin immunoprecipitation (ChIP) identified thyroid hormone receptor (TR) binding to the gene. Using mice with a targeted disruption of (D2KO mice), we determined endothelial cell number by immunohistochemistry/flow cytometry and evaluated related gene expression in both uninjured and injured skeletal muscle. In differentiated D2KO C2C12 cells, expression was 46% of wildtype (WT) C2C12 cells, while secreted VEGF was 45%. D2KO C2C12 CM exhibited significantly less proangiogenic effects on HUVECs. and T3 treatment of C2C12 cells and WT mice, and ChIP using antibodies against TRα, indicated that is a direct genomic T3 target. In uninjured D2KO soleus muscle, expression was decreased by 28% compared with WT mice, while endothelial cell numbers were decreased by 48%. Seven days after skeletal muscle injury, D2KO mice had 36% fewer endothelial cells, coinciding with an 83% decrease in expression in fluorescence-activated cell sorting purified muscle stem cells. loss in the muscle stem cell impairs muscle stem cell-endothelial cell crosstalk via changes in the T3-responsive gene , leading to downstream impairment of endothelial cell function both and .
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http://dx.doi.org/10.1089/thy.2020.0291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840309PMC
January 2021

Targeting the right population for T3 + T4 combined therapy: where are we now and where to next?

Endocrine 2020 08 22;69(2):244-248. Epub 2020 Jun 22.

Department of Public Health, University of Naples Federico II, Naples, Italy.

The universal applicability of levothyroxine (LT4) monotherapy for the treatment of hypothyroidism has been questioned in recent years. Indeed, it is now clear that about 10-15% of LT4-treated hypothyroid patients are dissatisfied with their treatment. It is plausible that this subset of hypothyroid patients may need T3 + T4 combined therapy to restore peripheral euthyroidism. To address this issue, many clinical trials have investigated the effect of T3 + T4 combinations versus standard LT4-based therapy. However, to date, results have been inconclusive, mainly due to the lack of markers that identify candidates for combination therapy. A breakthrough in this field came with the recent finding that several single-nucleotide polymorphisms in the deiodinase genes are associated with the persistence of hypothyroid symptoms in biochemically euthyroid LT4-treated patients, and are thus markers of candidates for combination therapy. In addition, whole-genome association studies are expanding our knowledge of other genes of the thyroid hormone (TH) pathway that affect serum TH levels. To target the right population for the T3 + T4 combined therapy, the next step is to translate these new findings into prospective trials. Hopefully, this will pave the way to personalized therapy for each hypothyroid patient.
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http://dx.doi.org/10.1007/s12020-020-02391-5DOI Listing
August 2020

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Thyroid 2021 Feb 1;31(2):264-271. Epub 2020 Jul 1.

Department of Translational and Precision Medicine, Pathological and Oncological Sciences, Sapienza University of Rome, Rome, Italy.

One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as in 1109 patients (53.6%), in 796 (38.4%), and in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.
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http://dx.doi.org/10.1089/thy.2020.0272DOI Listing
February 2021

Thyroid Hormone Hyposensitivity: From Genotype to Phenotype and Back.

Front Endocrinol (Lausanne) 2019 24;10:912. Epub 2020 Jan 24.

Department of Public Health, University of Naples Federico II, Naples, Italy.

Thyroid hormone action defects (THADs) have been classically considered conditions of impaired sensitivity to thyroid hormone (TH). They were originally referring to alterations in TH receptor genes ( and ), but the discovery of genetic mutations and polymorphisms causing alterations in cell membrane transport (e.g., ) and metabolism (e.g., ) led recently to a new and broader definition of TH hyposensitivity (THH), including not only THADs but all defects that could interfere with the activity of TH. Due to the different functions and tissue-specific expression of these genes, affected patients exhibit highly variable phenotypes. Some of them are characterized by a tissue hypothyroidism or well-recognizable alterations in the thyroid function tests (TFTs), whereas others display a combination of hypo- and hyperthyroid manifestations with normal or only subtle biochemical defects. The huge effort of basic research has greatly aided the comprehension of the molecular mechanisms underlying THADs, dissecting the morphological and functional alterations on target tissues, and defining the related-changes in the biochemical profile. In this review, we describe different pictures in which a specific alteration in the TFTs (TSH, T4, and T3 levels) is caused by defects in a specific gene. Altogether these findings can help clinicians to early recognize and diagnose THH and to perform a more precise genetic screening and therapeutic intervention. On the other hand, the identification of new genetic variants will allow the generation of cell-based and animal models to give novel insight into thyroid physiology and establish new therapeutic interventions.
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http://dx.doi.org/10.3389/fendo.2019.00912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992580PMC
January 2020

Evaluation of BRAF, RAS, RET/PTC, and PAX8/PPARg alterations in different Bethesda diagnostic categories: A multicentric prospective study on the validity of the 7-gene panel test in 1172 thyroid FNAs deriving from different hospitals in South Italy.

Cancer Cytopathol 2020 02 10;128(2):107-118. Epub 2019 Dec 10.

Department of Public Health, University of Naples Federico II, Naples, Italy.

Background: Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated, using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, the most frequent genomic alterations occurring during thyroid oncogenesis.

Methods: In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up.

Results: In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories.

Conclusions: The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class.
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http://dx.doi.org/10.1002/cncy.22217DOI Listing
February 2020

Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch.

Nat Commun 2019 11 27;10(1):5410. Epub 2019 Nov 27.

Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.

Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH signaling may suppress the metastatic proclivity of SCC.
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http://dx.doi.org/10.1038/s41467-019-13140-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881453PMC
November 2019

Management of one patient with oligoprogressive thyroid cancer during treatment with lenvatinib.

Future Oncol 2019 Aug 14;15(24s):21-25. Epub 2019 Aug 14.

Department of Public Health, University of Naples "Federico II", Naples, Italy.

Recent thyroid cancer guidelines found it reasonable to use local therapies during treatment with tyrosine kinase inhibitors (TKIs) in selected patients with oligoprogressive disease, namely, in the presence of a single progressing lesion in an otherwise TKI-responsive metastatic cancer. However, there is a lack of experience in the management of oligoprogressive thyroid cancers. This report illustrates the case of one patient with oligoprogressive thyroid cancer during therapy with lenvatinib. We found that the application of local ablative therapy in oligoprogressive disease prolonged the progression-free survival and thus extended the time to therapy interruption. However, the optimal care for TKI-treated oligoprogressive cancers remains unclear and needs to be investigated in prospective trials.
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http://dx.doi.org/10.2217/fon-2019-0110DOI Listing
August 2019

Thyroid hormone availability in the human fetal brain: novel entry pathways and role of radial glia.

Brain Struct Funct 2019 Jul 4;224(6):2103-2119. Epub 2019 Jun 4.

Department of Endocrine and Nervous System Pathophysiology, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain.

Thyroid hormones (TH) are crucial for brain development; their deficiency during neurodevelopment impairs neural cell differentiation and causes irreversible neurological alterations. Understanding TH action, and in particular the mechanisms regulating TH availability in the prenatal human brain is essential to design therapeutic strategies for neurological diseases due to impaired TH signaling during neurodevelopment. We aimed at the identification of cells involved in the regulation of TH availability in the human brain at fetal stages. To this end, we studied the distribution of the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1), as well as the TH-metabolizing enzymes types 2 and 3 deiodinases (DIO2 and DIO3). Paraffin-embedded human brain sections obtained from necropsies of thirteen fetuses from 14 to 38 gestational weeks were analyzed by immunohistochemistry and in situ hybridization. We found these proteins localized along radial glial cells, in brain barriers, in Cajal-Retzius cells, in migrating fibers of the brainstem and in some neurons and glial cells with particular and complex spatiotemporal patterns. Our findings point to an important role of radial glia in controlling TH delivery and metabolism and suggest two additional novel pathways for TH availability in the prenatal human brain: the outer, and the inner cerebrospinal fluid-brain barriers. Based on our data we propose a model of TH availability for neural cells in the human prenatal brain in which several cell types have the ability to autonomously control the required TH content.
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http://dx.doi.org/10.1007/s00429-019-01896-8DOI Listing
July 2019

Deiodinases and their intricate role in thyroid hormone homeostasis.

Nat Rev Endocrinol 2019 08;15(8):479-488

Department of Public Health, University of Naples "Federico II", Naples, Italy.

The deiodinase family of enzymes mediates the activation and inactivation of thyroid hormone. The role of these enzymes in the regulation of the systemic concentrations of thyroid hormone is well established and underpins the treatment of common thyroid diseases. Interest in this field has increased in the past 10 years as the deiodinases became implicated in tissue development and homeostasis, as well as in the pathogenesis of a wide range of human diseases. Three deiodinases have been identified, namely, types 1, 2 and 3 iodothyronine deiodinases, which differ in their catalytic properties and tissue distribution. Notably, the expression of these enzymes changes during the lifetime of an individual in relation to the different needs of each organ and to ageing. The systemic homeostatic role of deiodinases clearly emerges during changes in serum concentrations of thyroid hormone, as seen in patients with thyroid dysfunction. By contrast, the role of deiodinases at the tissue level allows thyroid hormone signalling to be finely tuned within a given cell in a precise time-space window without perturbing serum concentrations of thyroid hormone. This Review maps the overall functional role of the deiodinases and explores challenges and novel opportunities arising from the expanding knowledge of these 'master' components of the thyroid homeostatic system.
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http://dx.doi.org/10.1038/s41574-019-0218-2DOI Listing
August 2019

The thyroid hormone activating enzyme, type 2 deiodinase, induces myogenic differentiation by regulating mitochondrial metabolism and reducing oxidative stress.

Redox Biol 2019 06 22;24:101228. Epub 2019 May 22.

Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. Electronic address:

Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short- and long-term energy needs. Accordingly, significant metabolic changes are observed depending on thyroid status. Although it is established that hyperthyroidism augments basal energy consumption, thus resulting in an enhanced metabolic state, the net effects on cellular respiration and generation of reactive oxygen species (ROS) remain unclear. To elucidate the effects of augmented TH signal in muscle cells, we generated a doxycycline-inducible cell line in which the expression of the TH-activating enzyme, type 2 deiodinase (D2), is reversibly turned on by the "Tet-ON" system. Interestingly, increased intracellular TH caused a net shift from oxidative phosphorylation to glycolysis and a consequent increase in the extracellular acidification rate. As a result, mitochondrial ROS production, and both the basal and doxorubicin-induced production of cellular ROS were reduced. Importantly, the expression of a set of antioxidant genes was up-regulated, and, among them, the mitochondrial scavenger Sod2 was specifically induced at transcriptional level by D2-mediated TH activation. Finally, we observed that attenuation of oxidative stress and increased levels of SOD2 are key elements of the differentiating cascade triggered by TH and D2, thereby establishing that D2 is essential in coordinating metabolic reprogramming of myocytes during myogenic differentiation. In conclusion, our findings indicate that TH plays a key role in oxidative stress dynamics by regulating ROS generation. Our novel finding that TH and its intracellular metabolism act as mitochondrial detoxifying agents sheds new light on metabolic processes relevant to muscle physiology.
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http://dx.doi.org/10.1016/j.redox.2019.101228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543119PMC
June 2019

A Global Loss of Dio2 Leads to Unexpected Changes in Function and Fiber Types of Slow Skeletal Muscle in Male Mice.

Endocrinology 2019 05;160(5):1205-1222

Brigham and Women's Hospital, Boston, Massachusetts.

The type 2 iodothyronine-deiodinase (D2) enzyme converts T4 to T3, and mice deficient in this enzyme [D2 knockout (D2KO) mice] have decreased T3 derived from T4 in skeletal muscle despite normal circulating T3 levels. Because slow skeletal muscle is particularly susceptible to changes in T3 levels, we expected D2 inactivation to result in more pronounced slow-muscle characteristics in the soleus muscle, mirroring hypothyroidism. However, ex vivo studies of D2KO soleus revealed higher rates of twitch contraction and relaxation and reduced resistance to fatigue. Immunostaining of D2KO soleus showed that these properties were associated with changes in muscle fiber type composition, including a marked increase in the number of fast, glycolytic type IIB fibers. D2KO soleus muscle fibers had a larger cross-sectional area, and this correlated with increased myonuclear accretion in myotubes formed from D2KO skeletal muscle precursor cells differentiated in vitro. Consistent with our functional findings, D2KO soleus gene expression was markedly different from that in hypothyroid wild-type (WT) mice. Comparison of gene expression between euthyroid WT and D2KO mice indicated that PGC-1α, a T3-dependent regulator of slow muscle fiber type, was decreased by ∼50% in D2KO soleus. Disruption of Dio2 in the C2C12 myoblast cell line led to a significant decrease in PGC-1α expression and a faster muscle phenotype upon differentiation. These results indicate that D2 loss leads to significant changes in soleus contractile function and fiber type composition that are inconsistent with local hypothyroidism and suggest that reduced levels of PCG-1α may contribute to the observed phenotypical changes.
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http://dx.doi.org/10.1210/en.2019-00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482039PMC
May 2019

Local hyperthyroidism promotes pancreatic acinar cell proliferation during acute pancreatitis.

J Pathol 2019 06 4;248(2):217-229. Epub 2019 Apr 4.

Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.

Proliferation of pancreatic acinar cells is a critical process in the pathophysiology of pancreatic diseases, because limited or defective proliferation is associated with organ dysfunction and patient morbidity. In this context, elucidating the signalling pathways that trigger and sustain acinar proliferation is pivotal to develop therapeutic interventions promoting the regenerative process of the organ. In this study we used genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones to elucidate their role in acinar proliferation following caerulein-mediated acute pancreatitis in mice. In addition, molecular mechanisms mediating the effects of thyroid hormones were identified by genetic and pharmacological inactivation of selected signalling pathways.In this study we demonstrated that levels of the thyroid hormone 3,3',5-triiodo-l-thyronine (T3) transiently increased in the pancreas during acute pancreatitis. Moreover, by using genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones, we showed that T3 was required to promote proliferation of pancreatic acinar cells, without affecting the extent of tissue damage or inflammatory infiltration.Finally, upon genetic and pharmacological inactivation of selected signalling pathways, we demonstrated that T3 exerted its mitogenic effect on acinar cells via a tightly controlled action on different molecular effectors, including histone deacetylase, AKT, and TGFβ signalling.In conclusion, our data suggest that local availability of T3 in the pancreas is required to promote acinar cell proliferation and provide the rationale to exploit thyroid hormone signalling to enhance pancreatic regeneration. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5247DOI Listing
June 2019

Physicians' professional autonomy and their organizational identification with their hospital.

BMC Health Serv Res 2018 Oct 12;18(1):775. Epub 2018 Oct 12.

Bocconi University, Via Roentgen 1, 20136, Milan, Italy.

Background: Managing medical professionals is challenging because professionals tend to adhere to a set of professional norms and enjoy autonomy from supervision. The aim of this paper is to study the interplay of physicians' professional identity, their organizational identity, and the role of professional autonomy in these processes of social identification.

Methods: We test hypotheses generated according to social identity theory using a survey of physicians working in public hospitals in Italy in 2013.

Results: Higher degrees of organizational and economic professional autonomy are correlated with higher organizational identification. Identification with the profession is positively correlated with identification with the organization.

Conclusions: Although the generalizability of our results is limited, this study suggests that organizations should support the organizational and economic autonomy of their physicians to project an organizational identity that preserves the continuity of a doctor's self-concept and that is evaluated as positive by doctors. As a result, organizations will be able to foster organizational identification, which is potentially capable of inducing pro-social organizational behavior.
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http://dx.doi.org/10.1186/s12913-018-3582-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186093PMC
October 2018

Teriparatide Replacement Therapy for Hypoparathyroidism During Treatment With Lenvatinib for Advanced Thyroid Cancer: A Case Report.

Front Endocrinol (Lausanne) 2018 17;9:244. Epub 2018 May 17.

Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Thyroid cancer metastasizes in 4% of cases. Approximately two-thirds of these patients are refractory to radioactive iodine-131 (RAI) therapy and have a poor 10-year survival prognosis. Treatment with tyrosine kinase inhibitors (TKIs) may be administered in selected RAI-refractory patients. However, these agents are often associated with adverse events, including vomiting. We report the case of a patient affected by RAI-refractory thyroid cancer with lung and intracranial metastases undergoing treatment with the antiangiogenic TKI lenvatinib, and with teriparatide replacement therapy for postsurgical hypoparathyroidism. Due to lenvatinib-related vomiting, which did not respond to therapy, conventional oral calcium supplementation failed to maintain normal serum calcium levels and the patient had repeated episodes of hypocalcemia. Subcutaneous teriparatide injections restored serum calcium levels, and thus lenvatinib therapy could be continued. This experience indicates that hormone replacement with teriparatide is a feasible option for cancer patients affected by hypoparathyroidism not treatable with oral calcium supplementation.
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http://dx.doi.org/10.3389/fendo.2018.00244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966541PMC
May 2018

Using overbooking to manage no-shows in an Italian healthcare center.

BMC Health Serv Res 2018 03 15;18(1):185. Epub 2018 Mar 15.

Department of Statistics, Informatics and Applications (DiSIA) G. Parenti, University of Florence, Viale Giovanni Battista Morgagni, 59, 50134, Florence, Italy.

Background: In almost all healthcare systems, no-shows (scheduled appointments missed without any notice from patients) have a negative impact on waiting lists, costs and resource utilization, impairing the quality and quantity of cares that could be provided, as well as the revenues from the corresponding activity. Overbooking is a tool healthcare providers can resort to reduce the impact of no-shows.

Methods: We develop an overbooking algorithm, and we assess its effectiveness using two methods: an analysis of the data coming from a practical implementation in an healthcare center; a simulation experiment to check the robustness and the potential of the strategy under different conditions. The data of the study, which includes personal and administrative information of patients, together with their scheduled and attended examinations, was taken from the electronic database of a big outpatient center. The attention was focused on the Magnetic Resonance (MR) ward because it uses expensive equipment, its services need long execution times, and the center has actually used it to implement an overbooking strategy aimed at reducing the impact of no-shows. We propose a statistical model for the patient's show/no-show behavior and we evaluate the ensuing overbooking procedure implemented in the MR ward. Finally, a simulation study investigates the effects of the overbooking strategy under different scenarios.

Results: The first contribution is a list of variables to identify the factors performing the best to predict no-shows. We classified the variables in three groups: "Patient's intrinsic factors", "Exogenous factors" and "Factors associated with the examination". The second contribution is a predictive model of no-shows, which is estimated on context-specific data using the variables just discussed. Such a model represents a fundamental ingredient of the overbooking strategy we propose to reduce the negative effects of no-shows. The third contribution is the assessment of that strategy by means of a simulation study under different scenarios in terms of number of resources and no-show rates. The same overbooking strategy was also implemented in practice (giving the opportunity to consider it as a quasi-experiment) to reduce the negative impact caused by non attendance in the MR ward. Both the quasi-experiment and the simulation study demonstrated that the strategy improved the center's productivity and reduced idle time of resources, although it increased slightly the patient's waiting time and the staff's overtime. This represents an evidence that overbooking can be suitable to improve the management of healthcare centers without adversely affecting their costs and the quality of cares offered.

Conclusions: We shown that a well designed overbooking procedure can improve the management of medical centers, in terms of a significant increase of revenue, while keeping patient's waiting time and overtime under control. This was demonstrated by the results of a quasi-experiment (practical implementation of the strategy in the MR ward) and a simulation study (under different scenarios). Such positive results took advantage from a predictive model of no-show carefully designed around the medical center data.
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http://dx.doi.org/10.1186/s12913-018-2979-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856203PMC
March 2018

Are Evidence-Based Guidelines Reflected in Clinical Practice? An Analysis of Prospectively Collected Data of the Italian Thyroid Cancer Observatory.

Thyroid 2017 12 10;27(12):1490-1497. Epub 2017 Nov 10.

1 Department of Internal Medicine and Medical Specialties, University of Rome Sapienza , Rome, Italy .

Objectives: The goal of evidence-based practice guidelines is to optimize the management of emerging diseases, such as differentiated thyroid cancer (DTC). The aim of this study was to assess therapeutic approaches for DTC in Italy and to see how closely these practices conformed to those recommended in the 2009 American Thyroid Association (ATA) guidelines.

Methods: The Italian Thyroid Cancer Observatory was established to collect data prospectively on thyroid cancers consecutively diagnosed in participating centers (uniformly distributed across the nation). Data on the initial treatment of all pathologically confirmed DTC cases present in the database from January 1, 2013 (database creation) to January 31, 2016, were analyzed.

Results: A total of 1748 patients (77.2% females; median age 48.1 years [range 10-85 years]) were enrolled in the study. Most (n = 1640; 93.8%) were papillary carcinomas (including 84 poorly differentiated/aggressive variants); 6.2% (n = 108) were follicular and Hürthle cell carcinomas. The median tumor diameter was 11 mm (range 1-93 mm). Tumors were multifocal in 613 (35%) and presented extrathyroidal extension in 492 (28%) cases. Initial treatments included total thyroidectomy (involving one or two procedures; n = 726; 98.8%) and lobectomy (n = 22; 1.2%). A quarter of the patients who underwent total thyroidectomy had unifocal, intrathyroidal tumors ≤1 cm (n = 408; 23.6%). Neck dissection was performed in 40.4% of the patients (29.5% had central compartment dissection). Radioiodine remnant ablation (RRA) was performed in 1057 (61.2%) of the 1726 patients who underwent total thyroidectomy: 460 (41.2%) of the 983 classified by 2009 ATA guideline criteria as low-risk, 570 (87.1%) of the 655 as intermediate-risk, and 82 (93.1%) of the 88 as high-risk patients (p < 0.001). RRA was performed in 44% of the cases involving multifocal DTCs measuring ≤1 cm.

Conclusions: The treatment approaches for DTCs used in Italy display areas of inconsistency with those recommended by the 2009 ATA guidelines. Italian practices were characterized by underuse of thyroid lobectomy in intrathyroidal, unifocal DTCs ≤1 cm. The use of RRA was generally consistent with risk-stratified recommendations. However, its frequent use in small DTCs (≤1 cm) that are multifocal persists, despite the lack of evidence of benefit. These data provide a baseline for future assessments of the impact of international guidelines on DTC management in Italy. These findings also illustrate that the dissemination and implementation of guideline recommendations, and the change in practice patterns, require ongoing education and time.
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http://dx.doi.org/10.1089/thy.2017.0299DOI Listing
December 2017

Thyroid hormone signaling and deiodinase actions in muscle stem/progenitor cells.

Mol Cell Endocrinol 2017 Dec 16;459:79-83. Epub 2017 Jun 16.

Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. Electronic address:

Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development and metabolism of nearly all vertebrate tissues. In skeletal muscle, TH plays a critical role in regulating the function of satellite cells, the bona fide skeletal muscle stem cells. Deiodinases (D2 and D3) have been found to modulate the expression of various TH target genes in satellite cells. Regulation of the expression and activity of the deiodinases constitutes a cell-autonomous, pre-receptor mechanism that controls crucial steps during the various phases of myogenesis. Here, we review the roles of deiodinases in skeletal muscle stem cells, particularly in muscle homeostasis and upon regeneration. We focus on the role of T3 in stem cell functions and in commitment towards lineage progression. We also discuss how deiodinases might be therapeutically exploited to improve satellite-cell-mediated muscle repair in skeletal muscle disorders or injury.
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http://dx.doi.org/10.1016/j.mce.2017.06.014DOI Listing
December 2017

DIO2 Thr92Ala Reduces Deiodinase-2 Activity and Serum-T3 Levels in Thyroid-Deficient Patients.

J Clin Endocrinol Metab 2017 05;102(5):1623-1630

Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy.

Context: A substantial proportion of athyreotic levothyroxine (LT4)-treated patients experience hypothyroid-like symptoms. During LT4 replacement, levels of the active hormone triiodothyronine (T3) strictly depend on type 2-deiodinase (D2)-mediated activation of LT4. The Thr92Ala polymorphism and the 258 G/A in the DIO2 gene have been associated with various clinical conditions.

Objectives: To investigate the effects of DIO2 polymorphisms in thyroid hormone homeostasis.

Design: We compared the presurgical hormonal status of thyroidectomized LT4-treated patients who had a similar thyroid-stimulating hormone (TSH) level with their postsurgery status and analyzed their DIO2 genotype in a subgroup of 102/140 (72.8%) of patients. We measured the enzymatic properties of Thr92Ala in living cells and in relevant generated mouse models.

Subjects And Methods: A total of 140 thyroidectomized subjects were included. Serum free T3 (FT3), free thyroxine, and TSH levels were directly measured. Immunohistochemistry and immunoblotting were performed for D2 protein.

Results: The DIO2 genotyping revealed an association between low FT3 values and Thr92Ala. Specifically, the mean postsurgery FT3 levels were significantly lower in patients carrying the mutated allele(s) than in wild-type patients, in whom FT3 postsurgical levels were similar to presurgery levels. The -258 G/A variation was not associated with hormonal alteration. We found that endogenous wild-type D2 and Thr92Ala share the same subcellular localization but differ in protein stability. Importantly, Thr92Ala reduced D2-mediated thyroxine to T3 conversion.

Conclusions: Thyroidectomized patients carrying Thr92Ala are at increased risk of reduced intracellular and serum T3 concentrations that are not adequately compensated for by LT4, thus providing evidence in favor of customized treatment of hypothyroidism in athyreotic patients.
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http://dx.doi.org/10.1210/jc.2016-2587DOI Listing
May 2017

The Concerted Action of Type 2 and Type 3 Deiodinases Regulates the Cell Cycle and Survival of Basal Cell Carcinoma Cells.

Thyroid 2017 04 22;27(4):567-576. Epub 2017 Feb 22.

1 Department of Clinical Medicine and Surgery, University of Naples "Federico II" , Napoli, Italy .

Background: Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation, and differentiation. The intracellular hormonal environment can be tailored by the type 1 and 2 deiodinase enzymes D2 and D3, which catalyze TH activation and inactivation respectively. In many cellular systems, THs exert well-documented stimulatory or inhibitory effects on cell proliferation; however, the molecular mechanisms by which they control rates of cell cycle progression have not yet been entirely clarified. We previously showed that D3 depletion or TH treatment influences the proliferation and survival of basal cell carcinoma (BCC) cells. Surprisingly, we also found that BCC cells express not only sustained levels of D3 but also robust levels of D2. The aim of the present study was to dissect the contribution of D2 to TH metabolism in the BCC context, and to identify the molecular changes associated with cell proliferation and survival induced by TH and mediated by D2 and D3.

Methods: We used the CRISPR/Cas9 technology to genetically deplete D2 and D3 in BCC cells and studied the consequences of depletion on cell cycle progression and on cell death. Cell cycle progression was analyzed by fluorescence activated cell sorting analysis of synchronized cells, and the apoptosis rate by annexin V incorporation.

Results: Mechanistic investigations revealed that D2 inactivation accelerates cell cycle progression thereby enhancing the proportion of S-phase cells and cyclin D1 expression. Conversely, D3 mutagenesis drastically suppressed cell proliferation and enhanced apoptosis of BCC cells. Furthermore, the basal apoptotic rate was oppositely regulated in D2- and D3-depleted cells.

Conclusion: Our results indicate that BCC cells constitute an example in which the TH signal is finely tuned by the concerted expression of opposite-acting deiodinases. The dual regulation of D2 and D3 expression plays a critical role in cell cycle progression and cell death by influencing cyclin D1-mediated entry into the G1-S phase. These findings reinforce the concept that TH is a potential therapeutic target in human BCC.
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http://dx.doi.org/10.1089/thy.2016.0532DOI Listing
April 2017

The Thyroid Hormone Inactivating Enzyme Type 3 Deiodinase is Present in Bactericidal Granules and the Cytoplasm of Human Neutrophils.

Endocrinology 2016 08 29;157(8):3293-305. Epub 2016 Jun 29.

Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.

Neutrophils are important effector cells of the innate immune system. Thyroid hormone (TH) is thought to play an important role in their function. Intracellular TH levels are regulated by the deiodinating enzymes. The TH-inactivating type 3 deiodinase (D3) is expressed in infiltrating murine neutrophils, and D3 knockout mice show impaired bacterial killing upon infection. This suggests that D3 plays an important role in the bacterial killing capacity of neutrophils. The mechanism behind this effect is unknown. We aimed to assess the presence of D3 in human neutrophils, and determine its subcellular localization using confocal and electron microscopy, because this could give important clues about its function in these cells. D3 appeared to be present in the cytoplasm and in myeloperoxidase containing azurophilic granules and as well as lactoferrin containing specific granules within human neutrophils. This subcellular localization did not change upon activation of the cells. D3 is observed intracellularly during neutrophil extracellular trap formation, followed by a reduction of D3 staining after release of the neutrophil extracellular traps into the extracellular space. At the transcriptional level, human neutrophils expressed additional essential elements of TH metabolism, including TH transporters and TH receptors. Here, we demonstrate the presence and subcellular location of D3 in human neutrophils for the first time and propose a model, in which D3 plays a role in the bacterial killing capacity of neutrophils either through generation of iodide for the myeloperoxidase system or through modulation of intracellular TH bioavailability.
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http://dx.doi.org/10.1210/en.2016-1103DOI Listing
August 2016

Reciprocal interplay between thyroid hormone and microRNA-21 regulates hedgehog pathway-driven skin tumorigenesis.

J Clin Invest 2016 06 9;126(6):2308-20. Epub 2016 May 9.

The thyroid hormone-inactivating (TH-inactivating) enzyme type 3 iodothyronine deiodinase (D3) is an oncofetal protein that is rarely expressed in adult life but has been shown to be reactivated in the context of proliferation and neoplasms. D3 terminates TH action within the tumor microenvironment, thereby enhancing cancer cell proliferation. However, the pathological role of D3 and the contribution of TH metabolism in cancer have yet to be fully explored. Here, we describe a reciprocal regulation between TH action and the cancer-associated microRNA-21 (miR21) in basal cell carcinoma (BCC) skin tumors. We found that, besides being negatively regulated by TH at the transcriptional level, miR21 attenuates the TH signal by increasing D3 levels. The ability of miR21 to positively regulate D3 was mediated by the tumor suppressor gene GRHL3, a hitherto unrecognized D3 transcriptional inhibitor. Finally, in a BCC mouse model, keratinocyte-specific D3 depletion markedly reduced tumor growth. Together, our results establish TH action as a critical hub of multiple oncogenic pathways and provide functional and mechanistic evidence of the involvement of TH metabolism in BCC tumorigenesis. Moreover, our results identify a miR21/GRHL3/D3 axis that reduces TH in the tumor microenvironment and has potential to be targeted as a therapeutic approach to BCC.
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http://dx.doi.org/10.1172/JCI84465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887175PMC
June 2016

Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling.

Cancer Res 2016 Mar 16;76(5):1237-44. Epub 2015 Dec 16.

Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. CEINGE-Biotecnologie Avanzate, Naples, Italy.

Thyroid hormone is a pleiotropic factor that controls many cellular processes in multiple cell types such as cancer stem cells (CSC). Thyroid hormone concentrations in the blood are stable, but the action of the deiodinases (D2-D3) provides cell-specific regulation of thyroid hormone activity. Deregulation of deiodinase function and thyroid hormone status has been implicated in tumorigenesis. Therefore, we investigated the role of thyroid hormone metabolism and signaling in colorectal CSCs (CR-CSC), where deiodinases control cell division and chemosensitivity. We found that increased intracellular thyroid hormone concentration through D3 depletion induced cell differentiation and sharply mitigated tumor formation. Upregulated BMP4 expression and concomitantly attenuated Wnt signaling accompanied these effects. Furthermore, we demonstrate that BMP4 is a direct thyroid hormone target and is involved in a positive autoregulatory feedback loop that modulates thyroid hormone signaling. Collectively, our findings highlight a cell-autonomous metabolic mechanism by which CR-CSCs exploit thyroid hormone signaling to facilitate their self-renewal potential and suggest that drug-induced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1542DOI Listing
March 2016