Nodules et carcinomes thyroïdiens

Face à l’augmentation des incidentalomes thyroïdiens, la gestion appropriée des nodules thyroïdiens est primordiale afin de permettre la détection des cancers relevants et d’éviter le surdiagnostic et le surtraitement des microcarcinomes papillaires. Cet article décrit les grandes lignes de la prise en charge en tenant compte des nouvelles recommandations

Redox Status and Proteostasis in Ageing and Disease.

Morbidity and mortality from preventable, noncommunicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioral change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centers to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design (HCD) in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet, and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward

Transcriptomic profiling of the response to excess iodide in Keap1 hypomorphic mice reveals new gene-environment interactions in thyroid homeostasis.

Iodide plays a pivotal role in thyroid homeostasis due to its crucial involvement in thyroid hormone biosynthesis. Exposure to pharmacological doses of iodide elicits in the thyroid an autoregulatory response to preserve thyroid function, as well as an antioxidant response that is mediated by the Keap1/Nrf2 signaling pathway. The objective of the present study was to investigate the transcriptional response of the thyroid to excess iodide in a background of enhanced Nrf2 signaling. Keap1 knockdown (Keap1 <sup>KD</sup> ) mice that have activated Nrf2 signaling were exposed or not to excess iodide in their drinking water for seven days and compared to respective wild-type mice. RNA-sequencing of individual mouse thyroids identified distinct transcriptomic patterns in response to iodide, with Keap1 <sup>KD</sup> mice showing an attenuated inflammatory response, altered thyroidal autoregulation, and enhanced cell growth/proliferative signaling, as confirmed also by Western blotting for key proteins involved in antioxidant, autoregulatory and proliferative responses. These findings underscore novel gene-environment interactions between the activation status of the Keap1/Nrf2 antioxidant response system and the dietary iodide intake, which may have implications not only for the goiter phenotype of Keap1 <sup>KD</sup> mice but also for humans harboring genetic variations in KEAP1 or NFE2L2 or treated with Nrf2-modulating drugs

CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma.

Sorafenib is the first-line drug used for patients with advanced hepatocellular carcinoma (HCC). However, acquired sorafenib resistance in cancer patients limits its efficacy. Here, we performed the first genome-wide CRISPR/Cas9-based screening on sorafenib-treated HCC cells to identify essential genes for non-mutational mechanisms related to acquired sorafenib resistance and/or sensitivity in HCC cells. KEAP1 was identified as the top candidate gene by Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK). KEAP1 disrupted HCC cells were less sensitive than wild-type cells in short- and long-term sorafenib treatments. Compared to wild-type cells, KEAP1-disrupted cells showed lower basal and sorafenib-induced reactive oxygen species (ROS) levels and were more resistant to oxidative stress-induced cell death. The absence of KEAP1 led to increased activity of Nrf2, a key transcription factor controlling antioxidant responses, as further evidenced by increased expression of Nrf2-controlled genes including NQO1, GPX2 and TXNRD1, which were positively associated with chemoresistance. In addition, KEAP1 disruption counteracted the reduction of cell viability and the elevation of ROS caused by lenvatinib, a drug that recently showed clinical efficacy as a first-line treatment for unresectable HCC. Finally, Keap1 disruption also increased the resistance of cells to regorafenib, a recently approved drug to treat HCC as a second line therapy. Taken together, our data indicate that deregulation of the KEAP1/Nrf2 pathway following KEAP1 inactivation contributes to sorafenib, lenvatinib, and regorafenib resistance in human HCC cells through up-regulation of Nrf2 downstream genes and decreased ROS levels

Approach to cytological indeterminate thyroid nodules.

The indeterminate thyroid nodules diagnosed by fine-needle aspiration cytology (FNAC)represents a problem for both cytopathologists and clinicians. The former sometimes use this diagnostic category as a sort of basket, putting in cases that they do not know exactly how to classify. The latter are faced with a highly variable risk of malignancy and consequently the management remains a challenge. On the histopathological side, the new WHO classification of tumors of the thyroid introduced the concept of tumors with uncertain and low malignant potential, and the concept of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), whose prognosis and management are still to be completely elucidated. While the risk of malignancy of the indeterminate diagnostic category has decreased due to the re-classification of certain types of papillary thyroid carcinomas of the follicular variant into a low malignant potential form (the NIFTP), cases diagnosed cytologically as indeterminate will probably increase in the future to avoid false positive diagnosis. Thus, the indeterminate thyroid diagnostic category still remains a challenge, both at the diagnostic level and for its management. The new version of the Bethesda system for reporting thyroid cytopathology suggests managing these patients with a repeat FNA, diagnostic lobectomy and/or molecular testing

Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice.

Fibroblast growth factor 21 (Fgf21) is a hormone with emerging beneficial roles in glucose and lipid homeostasis. The interest in Fgf21 as a potential antidiabetic drug and the factors that regulate its production and secretion is growing. Statins are the most widely prescribed drug for the treatment of dyslipidemia. However, the function of statins is not limited to the lowering of cholesterol as they are associated with pleiotropic actions such as antioxidant, anti-inflammatory and cytoprotective effects. The recently described effect of statins on mitochondrial function and the induction of Fgf21 by mitochondrial stress prompted us to investigate the effect of statin treatment on Fgf21 expression in the liver. To this end, C57BL6J male mice and primary mouse hepatocytes were treated with simvastatin, and Fgf21 expression was subsequently assessed by immunoblotting and quantitative real-time PCR. Hepatic Fgf21 protein and mRNA and circulating levels of FGF21significantly decreased in mice that had received simvastatin in their food (0.1% w/w) for 1 week. This effect was also observed with simvastatin doses as low as 0.01% w/w for 1 week or following 2 intraperitoneal injections within a single day. The reduction in Fgf21 mRNA levels was further verified in primary mouse hepatocytes, indicating that the effect of simvastatin is cell autonomous. In conclusion, simvastatin treatment reduced the circulating and hepatic Fgf21 levels and this effect warrants further investigation with reference to its role in metabolism

NFE2L2 (nuclear factor, erythroid 2-like 2)

Review on NFE2L2 (nuclear factor, erythroid 2-like 2

ASIC1a affects hypothalamic signaling and regulates the daily rhythm of body temperature in mice

The body temperature of mice is higher at night than during the day. We show here that global deletion of acid-sensing ion channel 1a (ASIC1a) results in lower body temperature during a part of the night. ASICs are pH sensors that modulate neuronal activity. The deletion of ASIC1a decreased the voluntary activity at night of mice that had access to a running wheel but did not affect their spontaneous activity. Daily rhythms of thyrotropin-releasing hormone mRNA in the hypothalamus and of thyroid-stimulating hormone β mRNA in the pituitary, and of prolactin mRNA in the hypothalamus and pituitary were suppressed in ASIC1a-/- mice. The serum thyroid hormone levels were however not significantly changed by ASIC1a deletion. Our findings indicate that ASIC1a regulates activity and signaling in the hypothalamus and pituitary. This likely leads to the observed changes in body temperature by affecting the metabolism or energy expenditure

NFE2-Related transcription factor 2 coordinates antioxidant defense with thyroglobulin production and iodination in the thyroid gland

Background: The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Antioxidant and detoxification enzymes aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including during exposure to excess iodide, but the factors that coordinate their expression with the cellular redox status are not known. The antioxidant response system comprising the ubiquitously expressed NFE2-related transcription factor 2 (Nrf2) and its redox-sensitive cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) defends tissues against oxidative stress, thereby protecting against pathologies that relate to DNA, protein, and/or lipid oxidative damage. Thus, it was hypothesized that Nrf2 should also have important roles in maintaining thyroid homeostasis. Methods: Ubiquitous and thyroid-specific male C57BL6J Nrf2 knockout (Nrf2-KO) mice were studied. Plasma and thyroids were harvested for evaluation of thyroid function tests by radioimmunoassays and of gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Nrf2-KO and Keap1-KO clones of the PCCL3 rat thyroid follicular cell line were generated using CRISPR/Cas9 technology and were used for gene and protein expression studies. Software-predicted Nrf2 binding sites on the thyroglobulin enhancer were validated by site-directed in vitro mutagenesis and chromatin immunoprecipitation. Results: The study shows that Nrf2 mediates antioxidant transcriptional responses in thyroid cells and protects the thyroid from oxidation induced by iodide overload. Surprisingly, it was also found that Nrf2 has a dramatic impact on both the basal abundance and the thyrotropin-inducible intrathyroidal abundance of thyroglobulin (Tg), the precursor protein of thyroid hormones. This effect is mediated by cell-autonomous regulation of Tg gene expression by Nrf2 via its direct binding to two evolutionarily conserved antioxidant response elements in an upstream enhancer. Yet, despite upregulating Tg levels, Nrf2 limits Tg iodination both under basal conditions and in response to excess iodide. Conclusions: Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.Fil: Ziros, Panos G. Lausanne University; SuizaFil: Habeos, Ioannis. Patras University; GreciaFil: Chartoumpekis, Dionysios V. University of Pittsburgh; Estados UnidosFil: Ntalampyra, Eleni. Universite de Lausanne; SuizaFil: Somm, Emmanuel. Universite de Lausanne; SuizaFil: Renaud, Cédric O.. Universite de Lausanne; SuizaFil: Bongiovanni, Massimo. Institute Of Pathology Locarno; SuizaFil: Trougakos, Ioannis P. Universidad Nacional y Kapodistríaca de Atenas; GreciaFil: Yamamoto, Masayuki. University Of Tohoku; JapónFil: Kensler, Thomas W.. University of Pittsburgh at Johnstown; Estados UnidosFil: Santisteban, Pilar. Universidad Autónoma de Madrid; EspañaFil: Carrasco, Nancy. University of Yale. School of Medicine; Estados UnidosFil: Ris Stalpers, Carrie. Academic Medical Center; Países BajosFil: Amendola, Elena. Universidad de Nápoles; ItaliaFil: Liao, Xiao-Hui. University of Chicago; Estados UnidosFil: Rossich, Luciano Esteban. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Thomasz, Lisa. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Juvenal, Guillermo Juan. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Refetoff, Samuel. University of Chicago; Estados UnidosFil: Sykiotis, Gerasimos P.. Universite de Lausanne; Suiz

Étude des marqueurs génétiques sanguins dans deux races de poneys de pologne

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