Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

Human rearranged RET/PTC3 (papillary thyroid carcinoma) proto-oncogene and high-risk human papillomavirus (HPV) type 16 E7 oncogene induces in the mouse a neoplastic transformation of thyroid follicular cells. We present a detailed immuno-histological study (170 mouse thyroids: RET/PTC3, E7, wild type, 2- to 10-month-old) with cell cycle proliferation and signalling pathway indicators. The characteristics of both models are different. There is an ‘oncogene dependent' cellular signature, maintained at all studied ages in the E7 model, less in the RET/PTC3 model. During tumour development a large heterogeneity occurred in the Tg-RET/PTC3 model within a same tumour or within a same thyroid lobe. The Tg-E7 model was less heterogeneous, with a dominant goitrous pattern. The solid tumour already described in the RET/PTC3 models associated with cribriform patterns, suggested ‘PTC spindle cell changes' as in humans PTC rather than the equivalent of the solid human PTC. Proliferation and apoptosis in the two thyroid models are related to the causal oncogene rather than reflect a general tumorigenic process. The thyroids of RET/PTC3 mice appeared as a partial and transient model of human PTCs, whereas the Tg-E7 mice do not belong to the usual PTC type

Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers

Papillary thyroid cancers (PTCs) incidence dramatically increased in the vicinity of Chernobyl. The cancer-initiating role of radiation elsewhere is debated. Therefore, we searched for a signature distinguishing radio-induced from sporadic cancers. Using microarrays, we compared the expression profiles of PTCs from the Chernobyl Tissue Bank (CTB, n=12) and from French patients with no history of exposure to ionising radiations (n=14). We also compared the transcriptional responses of human lymphocytes to the presumed aetiological agents initiating these tumours, γ-radiation and H2O2. On a global scale, the transcriptomes of CTB and French tumours are indistinguishable, and the transcriptional responses to γ-radiation and H2O2 are similar. On a finer scale, a 118 genes signature discriminated the γ-radiation and H2O2 responses. This signature could be used to classify the tumours as CTB or French with an error of 15–27%. Similar results were obtained with an independent signature of 13 genes involved in homologous recombination. Although sporadic and radio-induced PTCs represent the same disease, they are distinguishable with molecular signatures reflecting specific responses to γ-radiation and H2O2. These signatures in PTCs could reflect the susceptibility profiles of the patients, suggesting the feasibility of a radiation susceptibility test

Increasing the Number of Thyroid Lesions Classes in Microarray Analysis Improves the Relevance of Diagnostic Markers

BackgroundGenetic markers for thyroid cancers identified by microarray analysis have offered limited predictive accuracy so far because of the few classes of thyroid lesions usually taken into account. To improve diagnostic relevance, we have simultaneously analyzed microarray data from six public datasets covering a total of 347 thyroid tissue samples representing 12 histological classes of follicular lesions and normal thyroid tissue. Our own dataset, containing about half the thyroid tissue samples, included all categories of thyroid lesions. Methodology/Principal Findings Classifier predictions were strongly affected by similarities between classes and by the number of classes in the training sets. In each dataset, sample prediction was improved by separating the samples into three groups according to class similarities. The cross-validation of differential genes revealed four clusters with functional enrichments. The analysis of six of these genes (APOD, APOE, CLGN, CRABP1, SDHA and TIMP1) in 49 new samples showed consistent gene and protein profiles with the class similarities observed. Focusing on four subclasses of follicular tumor, we explored the diagnostic potential of 12 selected markers (CASP10, CDH16, CLGN, CRABP1, HMGB2, ALPL2, ADAMTS2, CABIN1, ALDH1A3, USP13, NR2F2, KRTHB5) by real-time quantitative RT-PCR on 32 other new samples. The gene expression profiles of follicular tumors were examined with reference to the mutational status of the Pax8-PPARγ, TSHR, GNAS and NRAS genes. Conclusion/Significance We show that diagnostic tools defined on the basis of microarray data are more relevant when a large number of samples and tissue classes are used. Taking into account the relationships between the thyroid tumor pathologies, together with the main biological functions and pathways involved, improved the diagnostic accuracy of the samples. Our approach was particularly relevant for the classification of microfollicular adenomas

Role of trans-Planckian modes in cosmology

Motivated by the old trans-Planckian (TP) problem of inflationary cosmology, it has been conjectured that any consistent effective field theory should keep TP modes `hidden' behind the Hubble horizon, so as to prevent them from turning classical and thereby affecting macroscopic observations. In this paper we present two arguments against the Hubble horizon being a scale of singular significance as has been put forward in the TP Censorship Conjecture (TCC). First, refinements of TCC are presented that allow for the TP modes to grow beyond the horizon while still keeping the de-Sitter conjecture valid. Second, we show that TP modes can turn classical even well within the Hubble horizon, which, as such, negates this rationale behind keeping them from crossing it. The role of TP modes is known to be less of a problem in warm inflation, because fluctuations start out usually as classical. This allows warm inflation to be more resilient to the TP problem compared to cold inflation. To understand how robust this is, we identity limits where quantum modes can affect the primordial power spectrum in one specific case.Comment: 33 pages, comments welcome; v2: References updated, matches published versio

Le dysfonctionnement thyroïdien : interrelations génétique - environnement

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Stimulation by iodide of H(2)O(2) generation in thyroid slices from several species.

The regulation of thyroid metabolism by iodide involves numerous inhibitory effects. However, in unstimulated dog thyroid slices, a small inconstant stimulatory effect of iodide on H(2)O(2) generation is observed. The only other stimulatory effect reported with iodide is on [1-(14)C]glucose oxidation, i.e. on the pentose phosphate pathway. Because we have recently demonstrated that the pentose phosphate pathway is controlled by H(2)O(2) generation, we study here the effect of iodide on basal H(2)O(2) generation in thyroid slices from several species. Our data show that in sheep, pig, bovine, and to a lesser extent dog thyroid, iodide had a stimulatory effect on H(2)O(2) generation. In horse and human thyroid, an inconstant effect was observed. We demonstrate in dogs that the stimulatory effect of iodide is greater in thyroids deprived of iodide, raising the possibility that differences in thyroid iodide pool may account, at least in part, for the differences between the different species studied. This represents the first demonstration of an activation by iodide of a specialized thyroid function. In comparison with conditions in which an inhibitory effect of iodide on H(2)O(2) generation is observed, the stimulating effect was observed for lower concentrations and for a shorter incubation time with iodide. Such a dual control of H(2)O(2) generation by iodide has the physiological interest of promoting an efficient oxidation of iodide when the substrate is provided to a deficient gland and of avoiding excessive oxidation of iodide and thus synthesis of thyroid hormones when it is in excess. The activation of H(2)O(2) generation may also explain the well described toxic effect of acute administration of iodide on iodine-depleted thyroids.Comparative StudyIn VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe