Thyroid Hormone Deiodinases and Cancer

Deiodinases constitute a group of thioredoxin fold-containing selenoenzymes that play an important function in thyroid hormone homeostasis and control of thyroid hormone action. There are three known deiodinases: D1 and D2 activate the pro-hormone thyroxine (T4) to T3, the most active form of thyroid hormone, while D3 inactivates thyroid hormone and terminates T3 action. A number of studies indicate that deiodinase expression is altered in several types of cancers, suggesting that (i) they may represent a useful cancer marker and/or (ii) could play a role in modulating cell proliferation – in different settings thyroid hormone modulates cell proliferation. For example, although D2 is minimally expressed in human and rodent skeletal muscle, its expression level in rhabdomyosarcoma (RMS)-13 cells is threefold to fourfold higher. In basal cell carcinoma (BCC) cells, sonic hedgehog (Shh)-induced cell proliferation is accompanied by induction of D3 and inactivation of D2. Interestingly a fivefold reduction in the growth of BCC in nude mice was observed if D3 expression was knocked down. A decrease in D1 activity has been described in renal clear cell carcinoma, primary liver cancer, lung cancer, and some pituitary tumors, while in breast cancer cells and tissue there is an increase in D1 activity. Furthermore D1 mRNA and activity were found to be decreased in papillary thyroid cancer while D1 and D2 activities were significantly higher in follicular thyroid cancer tissue, in follicular adenoma, and in anaplastic thyroid cancer. It is conceivable that understanding how deiodinase dysregulation in tumor cells affect thyroid hormone signaling and possibly interfere with tumor progression could lead to new antineoplastic approaches

Effects of different circuit training protocols on body mass, fat mass and blood parameters among overweight adults

The benefits of regular exercise are known for a long time, but the mechanisms underlying the exercise mode recommendations for specific chronic cardiovascular diseases remains unclear. The aim of this study was to evaluate and compare the effects of different circuit training protocols in sedentary overweight adults

INFLUENCE OF FELDENKRAIS METHOD ON SPINE HEALTH IN PROFESSIONAL ORCHESTRAL MUSICIANS. PILOT STUDY/INFLUENZA DEL METODO FELDENKRAIS SULLA SALUTE DEL RACHIDE IN MUSICISTI ORCHESTRALI PROFESSIONISTI. STUDIO PILOTA

Obiettivo: Lo scopo di questo studio è stato quello di esaminare se il Metodo Feldenkrais fosse utile per migliorare la flessibilità muscolare e ridurre il dolore alla schiena in musicisti orchestrali professionisti. Materiali e metodi: Diciassette partecipanti sono stati reclutati da un orchestra sinfonica di Palermo (Italia) e divisi casualmente in un gruppo di controllo (C, n = 8) e un gruppo Feldenkrais (F, n = 9). Il primo non ha partecipato al protocollo Feldenkrais e a qualsiasi altra attività fisica; mentre il secondo ha preso parte ad un programma costituito da quattro lezioni di gruppo di Consapevolezza Attraverso il Movimento (CAM) eseguito 2 ore alla settimana per 4 settimane. Al fine di valutare lo stato di salute della colonna vertebrale, abbiamo usato il sit-and-reach test ed il trunk lift test. Le differenze all'interno di ogni gruppo e tra il gruppo C e il gruppo F sono state rispettivamente esaminate con il test di Wilcoxon e quello di Mann-Whitney; e considerate significative con p ≤ 0,05. Risultati: La flessibilità muscolare del bicipite femorale e della regione lombare, e la forza, la flessibilità e la resistenza dei muscoli estensori del tronco era leggermente aumentata nel gruppo F rispetto al gruppo C dopo il protocollo Feldenkrais; anche se questa variazione non era statisticamente significativa. Diversamente, il gruppo C ha mostrato una riduzione del 5% in entrambi i test dopo 4 settimane. Dopo il protocollo Feldenkrais, l’altezza del gruppo F era significativamente maggiore rispetto a prima del trattamento. Inoltre, abbiamo trovato che il numero dei partecipanti, che hanno dichiarato di avere dolore forte e frequente alla schiena e agli arti, diminuiva durante il periodo di svolgimento del protocollo Feldenkrais. Questo effetto era maggiore nella regione cervicale rispetto a quella lombare e agli arti superiori. Conclusioni: I nostri risultati mostrano che il Metodo Feldenkrais ha effetti positivi sulla flessibilità muscolare e supporta l'uso di questo metodo per sciogliere le tensioni e le contrazioni muscolari che possono causare dolore nei musicisti orchestrali professionisti.Objectives: The aim of this study was to explore whether Feldenkrais Method was useful for improving muscular flexibility and reducing back pain in professional orchestral musicians. Materials and methods: Seventeen participants were recruited from a symphony orchestra of Palermo (Italy) and randomly divided in a control group (C, n=8) and a Feldenkrais group (F, n=9). The first didn’t participate in the Feldenkrais protocol and any other physical activity; while the second took part into a program consisting of four Awareness through movement (ATM) classes performed 2 hours/week for 4 weeks. In order to assess muscle fitness of spine, we used sit-and-reach and trunk lift test. The differences within each group and between C and F groups were respectively examined with Wilcoxon matched pair test and Mann-Whitney test; and considered significant with p≤0.05. Results: The muscular flexibility of hamstring and low back, and trunk extensor strength, flexibility and endurance slightly increased in F group compared with C group after Feldenkrais protocol even if this variation was not statistically significant. Differently, C group showed a reduction by 5% in both tests after 4 weeks. After Feldenkrais protocol, height of F group was significantly bigger than before treatment. Moreover, we found that the number of participants, who stated to have strong and frequent pain in the back and limbs, decreased during performing the Feldenkrais protocol. This effect was bigger in the cervical than lumbar spine and upper limbs.Conclusion: Our outcomes illustrate that Feldenkrais method has positive effects on muscle flexibility and supports the use of this method for dissolving muscle tensions and contractions that can cause pain in professional orchestral musicians

Disruption of Thyroid Hormone Activation in Type 2 Deiodinase Knockout Mice Causes Obesity With Glucose Intolerance and Liver Steatosis Only at Thermoneutrality

Objective: Thyroid hormone accelerates energy expenditure; thus, hypothyroidism is intuitively associated with obesity. However, studies failed to establish such a connection. In brown adipose tissue (BAT), thyroid hormone activation via type 2 deiodinase (D2) is necessary for adaptive thermogenesis, such that mice lacking D2 (D2KO) exhibit an impaired thermogenic response to cold. Here we investigate whether the impaired thermogenesis of D2KO mice increases their susceptibility to obesity when placed on a high-fat diet. Research Design and Methods: To test this, D2KO mice were admitted to a comprehensive monitoring system acclimatized to room temperature (22$^\circ$C) or thermoneutrality (30$^\circ$C) and kept either on chow or high-fat diet for 60 days. Results: At 22$^\circ$C, D2KO mice preferentially oxidize fat, have a similar sensitivity to diet-induced obesity, and are supertolerant to glucose. However, when thermal stress is eliminated at thermoneutrality (30$^\circ$C), an opposite phenotype is encountered, one that includes obesity, glucose intolerance, and exacerbated hepatic steatosis. We suggest that a compensatory increase in BAT sympathetic activation of the D2KO mice masks metabolic repercussions that they would otherwise exhibit. Conclusions: Thus, upon minimization of thermal stress, high-fat feeding reveals the defective capacity of D2KO mice for diet-induced thermogenesis, provoking a paradigm shift in the understanding of the role of the thyroid hormone in metabolism

An analysis of materials used in the RPC detector and in the closed loop gas system of CMS at the LHC.

The results are reported of the study of materials used in the CERN Closed Loop recirculation gas system currently under test with the RPC muon detectors in the CMS experiment at the LHC. Studies include a sampling campaign in a low-radiation environment (cosmic rays at the CERN ISR test site). We describe the dedicated RPC chamber tests, the chemical analysis of the filters and gas used, and discuss the results of the Closed Loop system

The Type 2 Iodothyronine Deiodinase is Essential for Adaptive Thermogenesis in Brown Adipose Tissue

Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue (BAT). Here we report that despite a normal plasma 3,5,3′-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2–/–) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss. This occurs despite normal basal mitochondrial uncoupling protein 1 (UCP1) concentration. In Dio2–/– brown adipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced increases in lipolysis, UCP1 mRNA, and O2 consumption are all reduced due to impaired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies suggest that UCP1 is primarily dependent on thyroid hormone receptor β (TRβ) while the normal sympathetic response of brown adipocytes requires TRα. Intracellularly generated T3 may be required to saturate the TRα, which has an approximately fourfold lower T3-binding affinity than does TRβ. Thus, D2 is an essential component in the thyroid-sympathetic synergism required for thermal homeostasis in small mammals

Absence of Myocardial Thyroid Hormone Inactivating Deiodinase Results in Restrictive Cardiomyopathy in Mice

Cardiac injury induces myocardial expression of the thyroid hormone inactivating type 3 deiodinase (D3), which in turn dampens local thyroid hormone signaling. Here, we show that the D3 gene (Dio3) is a tissue-specific imprinted gene in the heart, and thus, heterozygous D3 knockout (HtzD3KO) mice constitute a model of cardiac D3 inactivation in an otherwise systemically euthyroid animal. HtzD3KO newborns have normal hearts but later develop restrictive cardiomyopathy due to cardiac-specific increase in thyroid hormone signaling, including myocardial fibrosis, impaired myocardial contractility, and diastolic dysfunction. In wild-type littermates, treatment with isoproterenol-induced myocardial D3 activity and an increase in the left ventricular volumes, typical of cardiac remodeling and dilatation. Remarkably, isoproterenol-treated HtzD3KO mice experienced a further decrease in left ventricular volumes with worsening of the diastolic dysfunction and the restrictive cardiomyopathy, resulting in congestive heart failure and increased mortality. These findings reveal crucial roles for Dio3 in heart function and remodeling, which may have pathophysiologic implications for human restrictive cardiomyopathy

A Novel Pathway Regulates Thyroid Hormone Availability in Rat and Human Hypothalamic Neurosecretory Neurons

Hypothalamic neurosecretory systems are fundamental regulatory circuits influenced by thyroid hormone. Monocarboxylate-transporter-8 (MCT8)-mediated uptake of thyroid hormone followed by type 3 deiodinase (D3)-catalyzed inactivation represent limiting regulatory factors of neuronal T3 availability. In the present study we addressed the localization and subcellular distribution of D3 and MCT8 in neurosecretory neurons and addressed D3 function in their axons. Intense D3-immunoreactivity was observed in axon varicosities in the external zone of the rat median eminence and the neurohaemal zone of the human infundibulum containing axon terminals of hypophysiotropic parvocellular neurons. Immuno-electronmicroscopy localized D3 to dense-core vesicles in hypophysiotropic axon varicosities. N-STORM-superresolution-microscopy detected the active center containing C-terminus of D3 at the outer surface of these organelles. Double-labeling immunofluorescent confocal microscopy revealed that D3 is present in the majority of GnRH, CRH and GHRH axons but only in a minority of TRH axons, while absent from somatostatin-containing neurons. Bimolecular-Fluorescence-Complementation identified D3 homodimers, a prerequisite for D3 activity, in processes of GT1-7 cells. Furthermore, T3-inducible D3 catalytic activity was detected in the rat median eminence. Triple-labeling immunofluorescence and immuno-electronmicroscopy revealed the presence of MCT8 on the surface of the vast majority of all types of hypophysiotropic terminals. The presence of MCT8 was also demonstrated on the axon terminals in the neurohaemal zone of the human infundibulum. The unexpected role of hypophysiotropic axons in fine-tuned regulation of T3 availability in these cells via MCT8-mediated transport and D3-catalyzed inactivation may represent a novel regulatory core mechanism for metabolism, growth, stress and reproduction in rodents and humans

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Background: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment ap-proaches for patients with thyroid disease. Summary: Important clinical practices in use today for the treatment of patients with hypothy-roidism, hyperthyroidism, or thyroid cancer, are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a se-ries of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. Conclusions: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes