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The spread of pathogens from farmed salmon is a conservation concern for wild Pacific salmon in British Columbia (BC), Canada. Three pathogens are prevalent in farmed Atlantic salmon in BC, spill over to wild Pacific salmon, and are linked to negative impacts on wild salmon: Piscine orthoreovirus, Tenacibaculum spp., and sea lice ( Lepeophtheirus salmonis ). Molecular screening of infectious agents in farmed and wild salmon and environmental DNA highlights a further 4 agents that are likely elevated near salmon farms and 37 that co-occur in wild and farmed salmon. Pathogens likely affect wild salmon indirectly by mediating migration, competition, and predation. Current net-pen aquaculture practices pose these risks to numerous populations of all species of wild salmon in BC, most of which are not covered in Government of Canada science and advisory reports. Climate change, pathogen evolution, and changes to disease management and aquaculture regulations will influence future risks.

Spring viremia of carp virus (SVCV) is a rhabdovirus that primarily infects cyprinid finfishes and causes a disease notifiable to the World Organization for Animal Health. Amphibians, which are sympatric with cyprinids in freshwater ecosystems, are considered non-permissive hosts of rhabdoviruses. The potential host range expansion of SVCV in an atypical host species was evaluated by testing the susceptibility of amphibians native to the Pacific Northwest. Larval long-toed salamanders Ambystoma macrodactylum and Pacific tree frog Pseudacris regilla tadpoles were exposed to SVCV strains from genotypes Ia, Ib, Ic, or Id by either intraperitoneal injection, immersion, or cohabitation with virus-infected koi Cyprinus rubrofuscus . Cumulative mortality was 100% for salamanders injected with SVCV, 98-100% for tadpoles exposed to virus via immersion, and 0-100% for tadpoles cohabited with SVCV-infected koi. Many of the animals that died exhibited clinical signs of disease and SVCV RNA was found by in situ hybridization in tissue sections of immersion-exposed tadpoles, particularly in the cells of the gastrointestinal tract and liver. SVCV was also detected by plaque assay and RT-qPCR testing in both amphibian species regardless of the virus exposure method, and viable virus was detected up to 28 days after initial exposure. Recovery of infectious virus from naïve tadpoles cohabited with SVCV-infected koi further demonstrated that SVCV transmission can occur between classes of ectothermic vertebrates. Collectively, these results indicated that SVCV, a fish rhabdovirus, can be transmitted to and cause lethal disease in two amphibian species. Therefore, members of all five of the major vertebrate groups (mammals, birds, reptiles, fish, and amphibians) appear to be vulnerable to rhabdovirus infections. Future research studying potential spillover and spillback infections of aquatic rhabdoviruses between foreign and domestic amphibian and fish species will provide insights into the stressors driving novel interclass virus transmission events.

There are significant commonalities among several pathologies involving fibroblasts, ranging from auto-immune diseases to fibrosis and cancer. Early steps in cancer development and progression are closely linked to fibroblast senescence and transformation into tumor-promoting cancer-associated fibroblasts (CAFs), suppressed by the androgen receptor (AR). Here, we identify ANKRD1 as a mesenchymal-specific transcriptional coregulator under direct AR negative control in human dermal fibroblasts (HDFs) and a key driver of CAF conversion, independent of cellular senescence. ANKRD1 expression in CAFs is associated with poor survival in HNSCC, lung, and cervical SCC patients, and controls a specific gene expression program of myofibroblast CAFs (my-CAFs). ANKRD1 binds to the regulatory region of my-CAF effector genes in concert with AP-1 transcription factors, and promotes c-JUN and FOS association. Targeting ANKRD1 disrupts AP-1 complex formation, reverses CAF activation, and blocks the pro-tumorigenic properties of CAFs in an orthotopic skin cancer model. ANKRD1 thus represents a target for fibroblast-directed therapy in cancer and potentially beyond., (© 2024. The Author(s).)

Skeletal muscle (SkM) lipid composition plays an essential role in physiological muscle maintenance and exercise performance. Thyroid hormones (THs) regulate muscle formation and fuel energy utilization by modulating carbohydrates and lipid and protein metabolism. The best-known effects of THs in SkM include the promotion of mitochondrial biogenesis, the fiber-type switch from oxidative to glycolytic fibers, and enhanced angiogenesis. To assess the role of THs on the lipidic composition of SkM fibers, we performed lipidomic analyses of SkM cells and tissues, glucose tolerance experiments, and exercise performance tests. Our data demonstrated that TH treatment induces remodeling of the lipid profile and changes the proportion of fatty acids in SkM. In brief, THs significantly reduced the ratio of stearic/oleic acid in the muscle similar to what is induced by physical activity. The increased proportion of unsaturated fatty acids was linked to an improvement in insulin sensitivity and endurance exercise. These findings point to THs as critical endocrine factors affecting exercise performance and indicate that homeostatic maintenance of TH signals, by improving cell permeability and receptor stability at the cell membrane, is crucial for muscle physiology.

The early marine life of Pacific salmon is believed to be a critical period limiting population-level survival. Recent evidence suggests that some infectious agents are associated with survival but linkages with underlying physiological mechanisms are lacking. While challenge studies can demonstrate cause and effect relationships between infection and pathological change or mortality, in some cases pathological change may only manifest in the presence of environmental stressors; thus, it is important to gain context from field observations. Herein, we examined physiological correlates with infectious agent loads in Chinook salmon during their first ocean year. We measured physiology at the molecular (gene expression), metabolic (plasma chemistry) and cellular (histopathology) levels. Of 46 assayed infectious agents, 27 were detected, including viruses, bacteria and parasites. This exploratory study identified., a strong molecular response to viral disease and pathological change consistent with jaundice/anemia associated with Piscine orthoreovirus,strong molecular signals of gill inflammation and immune response associated with gill agents ` Candidatus Branchiomonas cysticola' and Parvicapsula pseudobranchicola, a general downregulation of gill immune response associated with Parvicapsula minibicornis complementary to that of P. pseudobranchicola .Importantly, our study provides the first evidence that the molecular activation of viral disease response and the lesions observed during the development of the PRV-related disease jaundice/anemia in farmed Chinook salmon are also observed in wild juvenile Chinook salmon., Competing Interests: The authors have no conflicts to declare., (© The Author(s) 2023. Published by Oxford University Press and the Society for Experimental Biology.)

The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability. Conversely, even partial loss of p53 elevates D2/TH resulting in stimulation and increased fitness of tumor cells by boosting a significant transcriptional program leading to modulation of genes involved in DNA damage and repair and redox signaling. In vivo genetic deletion of D2 significantly reduces cancer progression and suggests that targeting THs may represent a general tool reducing invasiveness in p53-mutated neoplasms., (© 2023. The Author(s).)

The iodothyronine deiodinases constitute a family of three selenoenzymes regulating the intracellular metabolism of Thyroid Hormones (THs, T4 and T3) and impacting on several physiological processes, including energy metabolism, development and cell differentiation. The type 1, 2 and 3 deiodinases (D1, D2, and D3), are sensitive, rate-limiting components within the TH axis, and rapidly control TH action in physiological conditions or disease. Notably, several human pathologies are characterized by deiodinases deregulation (e.g., inflammation, osteoporosis, metabolic syndrome, muscle wasting and cancer). Consequently, these enzymes are golden targets for the identification and development of pharmacological compounds endowed with modulatory activities. However, until now, the portfolio of inhibitors for deiodinases is limited and the few active compounds lack selectivity. Here, we describe the cephalosporin Cefuroxime as a novel D2 specific inhibitor. In both in vivo and in vitro settings, Cefuroxime acts as a selective inhibitor of D2 activity, without altering the enzymatic activity of D1 and D3. By inhibiting TH activation in target tissues, Cefuroxime alters the sensitivity of the hypothalamus-pituitary axis and interferes with the central regulation of THs levels, and is thus eligible as a potential new regulator of hyperthyroid pathologies, which affect thousands of patients worldwide., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer., (© 2023. The Author(s).)

Aim: To estimate hospitalisation rate and investigate the role of age, prematurity and vaccination status in severe pertussis cases., Methods: We retrospectively evaluated 200 children aged 0-14 years, admitted to the emergency rooms of Meyer Hospital of Florence and Pisa Hospital with a diagnosis of pertussis from 1 October 2010 to 31 January 2020., Results: Children younger than 12 months were 63.0%. Preterm infants were 6.5%. The rate of hospitalisation was 49.0%. Among hospitalised cases, 80.6% were younger than 5 months. Overall, 62.0% were unvaccinated; this percentage increased among hospitalised (73.5%) and preterm subsamples (76.9%). Delays in pertussis vaccination were found in 57.7% of term infants and in 80.0% of preterms. Multivariable analysis confirmed the age under 2 months as the variable at higher risk for hospitalisation (OR 4.49, 95% CI 1.85-10.96, p < 0.001). Being fully vaccinated represented a significant protective factor (OR 0.12, 95% CI 0.04-0.35, p < 0.001)., Conclusion: Older classes of age and a complete vaccination, in time with the recommended schedule, are both protective factors for hospitalisation in severe pertussis disease. The widespread vaccination delay frequently observed in preterm children may be the cause for their higher rate of hospitalisation., (© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Skeletal muscle is a key energy-regulating organ, skilled in rapidly boosting the rate of energy production and substrate consumption following increased workload demand. The alteration of skeletal muscle metabolism is directly associated with numerous pathologies and disorders. Thyroid hormones (THs) and their receptors (TRs, namely, TRα and TRβ) exert pleiotropic functions in almost all cells and tissues. Skeletal muscle is a major THs-target tissue and alterations of THs levels have multiple influences on the latter. However, the biological role of THs and TRs in orchestrating metabolic pathways in skeletal muscle has only recently started to be addressed. The purpose of this paper is to investigate the muscle metabolic response to TRs abrogation, by using two different mouse models of global TRα- and TRβKO. In line with the clinical features of resistance to THs syndromes in humans, characterized by THRs gene mutations, both animal models of TRs deficiency exhibit developmental delay and mitochondrial dysfunctions. Moreover, using transcriptomic and metabolomic approaches, we found that the TRs-THs complex regulates the Fatty Acids (FAs)-binding protein GOT2, affecting FAs oxidation and transport in skeletal muscle. In conclusion, these results underline a new metabolic role of THs in governing muscle lipids distribution and metabolism.

Prostate Cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in males and the fifth leading cause of death worldwide. The majority of PCas are androgen-sensitive, with a significant up-regulation of Androgen Receptor (AR) that causes a stimulatory effect on growth and progression of cancer cells. For this reason, the first-line therapy for PCa is androgen ablation, even if it ultimately fails due to the onset of hormone-refractory state, in which the malignant cells do not sense the androgen signal anymore. Besides androgens, a growing number of evidence suggests that Thyroid Hormones (THs) mediate tumor-promoting effects in a variety of human cancers, as Epithelial-to-Mesenchymal Transition (EMT), invasion and metastasis and also stimulation of angiogenesis and tumor metabolism. Moreover, epidemiological studies demonstrated an increased risk for PCa in patients with lower levels of Thyreotropin (TSH). Here, we investigated if intracellular TH metabolism affects Benign Prostatic Hyperplasia (BPH) and PCa formation and progression. We found that the intracellular TH metabolism is a crucial determinant of PCa behavior. We observed that a dynamic stage-specific expression of the THs modulating enzymes, the deiodinases, is required for the progression of BPH to PCa malignancy. By acting simultaneously on epithelial cancer cells and fibroblasts, THs exert a proliferative and pro-inflammatory effect cooperating with androgens. These findings suggest that androgens and THs may interplay and mediate a coordinate effect on human PCa formation and progression. In light of our results, future perspective could be to explore the potential benefits of THs intracellular modulators aimed to counteract PCa progression., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a classical target tissue for TH, which regulates muscle strength and contraction, as well as energetic metabolism of myofibers. Here we address the different contribution of genomic and non-genomic action of TH in skeletal muscle cells by specifically silencing the deiodinase Dio2 or the β3-Integrin expression via CRISPR/Cas9 technology. We found that myoblast proliferation is inversely regulated by integrin signal and the D2-dependent TH activation. Similarly, inhibition of the nuclear receptor action reduced myoblast proliferation, confirming that genomic action of TH attenuates proliferative rates. Contrarily, genomic and non-genomic signals promote muscle differentiation and the regulation of the redox state. Taken together, our data reveal that integration of genomic and non-genomic signal pathways finely regulates skeletal muscle physiology. These findings not only contribute to the understanding of the mechanisms involved in TH modulation of muscle physiology but also add insight into the interplay between different mechanisms of action of TH in muscle cells.

Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and 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 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 were 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.

Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer. Herein, we report that TH coordinates a global program of metabolic reprogramming and induces angiogenesis through up-regulation of the VEGF-A gene, which results in the enhanced proliferation of tumor endothelial cells. In vivo conditional depletion of the TH activating enzyme in a mouse model of cutaneous squamous cell carcinoma (SCC) reduces the concentration of TH in the tumoral cells and results in impaired VEGF-A production and attenuated angiogenesis. In addition, we found that TH induces the expression of the glycolytic genes and fosters lactate production, which are key traits of the Warburg effect. Taken together, our results reveal a TH-VEGF-A-HIF1α regulatory axis leading to enhanced angiogenesis and glycolytic flux, which may represent a target for SCC therapy.

Global expansion of aquaculture and agriculture facilitates disease emergence and catalyzes transmission to sympatric wildlife populations. The health of wild salmon stocks critically concerns Indigenous peoples, commercial and recreational fishers, and the general public. Despite potential impact of viral pathogens such as Piscine orthoreovirus-1 (PRV-1) on endangered wild salmon populations, their epidemiology in wild fish populations remains obscure, as does the role of aquaculture in global and local spread. Our phylogeographic analyses of PRV-1 suggest that development of Atlantic salmon aquaculture facilitated spread from Europe to the North and South East Pacific. Phylogenetic analysis and reverse transcription polymerase chain reaction surveillance further illuminate the circumstances of emergence of PRV-1 in the North East Pacific and provide strong evidence for Atlantic salmon aquaculture as a source of infection in wild Pacific salmon. PRV-1 is now an important infectious agent in critically endangered wild Pacific salmon populations, fueled by aquacultural transmission., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Rapid expansion of salmon aquaculture has resulted in high-density populations that host diverse infectious agents, for which surveillance and monitoring are critical to disease management. Screening can reveal infection diversity from which disease arises, differential patterns of infection in live and dead fish that are difficult to collect in wild populations, and potential risks associated with agent transmission between wild and farmed hosts. We report results from a multi-year infectious-agent screening program of farmed salmon in British Columbia, Canada, using quantitative PCR to assess presence and load of 58 infective agents (viruses, bacteria, and eukaryotes) in 2931 Atlantic salmon (Salmo salar). Our analysis reveals temporal trends, agent correlations within hosts, and agent-associated mortality signatures. Multiple agents, most notably Tenacibaculum maritimum, were elevated in dead and dying salmon. We also report detections of agents only recently shown to infect farmed salmon in BC (Atlantic salmon calicivirus, Cutthroat trout virus-2), detection in freshwater hatcheries of two marine agents (Kudoa thyrsites and Tenacibaculum maritimum), and detection in the ocean of a freshwater agent (Flavobacterium psychrophilum). Our results provide information for farm managers, regulators, and conservationists, and enable further work to explore patterns of multi-agent infection and farm/wild transmission risk.

The emergence of infectious agents poses a continual economic and environmental challenge to aquaculture production, yet the diversity, abundance, and epidemiology of aquatic viruses are poorly characterised. In this study, we applied salmon host transcriptional biomarkers to identify and select fish in a viral disease state, but only those that were negative for known viruses based on RT-PCR screening. These fish were selected for metatranscriptomic sequencing to discover potential viral pathogens of dead and dying farmed Atlantic ( Salmo salar ) and Chinook ( Oncorhynchus tshawytscha ) salmon in British Columbia (BC). We found that the application of the biomarker panel increased the probability of discovering viruses in aquaculture populations. We discovered two viruses that have not previously been characterised in Atlantic salmon farms in BC (Atlantic salmon calicivirus and Cutthroat trout virus-2), as well as partially sequenced three putative novel viruses. To determine the epidemiology of the newly discovered or emerging viruses, we conducted high-throughput reverse transcription polymerase chain reaction (RT-PCR) and screened over 9,000 farmed and wild salmon sampled over one decade. Atlantic salmon calicivirus and Cutthroat trout virus-2 were in more than half of the farmed Atlantic salmon we tested. Importantly we detected some of the viruses we first discovered in farmed Atlantic salmon in Chinook salmon, suggesting a broad host range. Finally, we applied in situ hybridisation to determine infection and found differing cell tropism for each virus tested. Our study demonstrates that continual discovery and surveillance of emerging viruses in these ecologically important salmon will be vital for management of both aquaculture and wild resources in the future., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Thyroid hormones (THs) are key regulators of development, tissue differentiation, and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. Methods: To investigate the function of D3 in a postdevelopmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Results: Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Further, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were upregulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular triiodothyronine levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo , thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. Conclusion: In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin, thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in pathophysiological contexts.

Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mechanisms regulating D2 in cancer. To address this issue, we investigated putative upstream regulators of D2 in keratinocyte carcinomas. We found that the expression of D2 in SCC cells is positively regulated by the NANOG transcription factor, whose expression, besides being causally linked to embryonic stemness, is associated with many human cancers. We also found that NANOG binds to the D2 promoter and enhances D2 transcription. Notably, blockage of D2 activity reduced NANOG-induced cell migration as well as the expression of key genes involved in epithelial-mesenchymal transition in SCC cells. In conclusion, our study reveals a link among endogenous endocrine regulators of cancer, thyroid hormone and its activating enzyme, and the NANOG regulator of cancer biology. These findings could provide the basis for the development of TH inhibitors as context-dependent anti-tumor agents.

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 ( THRA and THRB ), but the discovery of genetic mutations and polymorphisms causing alterations in cell membrane transport (e.g., MCT8 ) and metabolism (e.g., SECISBP2, DIO2 ) 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., (Copyright © 2020 Rurale, Cicco, Dentice, Salvatore, Persani, Marelli and Luongo.)

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.