The Role of the PAX8/PPARγ Fusion Oncogene in Thyroid Cancer

Thyroid cancer is uncommon and exhibits relatively low mortality rates. However, a subset of patients experience inexorable growth, metastatic spread, and mortality. Unfortunately, for these patients, there have been few significant advances in treatment during the last 50 years. While substantial advances have been made in recent years about the molecular genetic events underlying papillary thyroid cancer, the more aggressive follicular thyroid cancer remains poorly understood. The recent discovery of the PAX8/PPARγ translocation in follicular thyroid carcinoma has promoted progress in the role of PPARγ as a tumor suppressor and potential therapeutic target. The PAX8/PPARγ fusion gene appears to be an oncogene. It is most often expressed in follicular carcinomas and exerts a dominant-negative effect on wild-type PPARγ, and stimulates transcription of PAX8-responsive promoters. PPARγ agonists have shown promising results in vitro, although very few studies have been conducted to assess the clinical impact of these agents

The contribution of X-linked coding variation to severe developmental disorders

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Angle-resolved photoemission spectroscopy of the cuprate superconductors

This paper reviews the most recent ARPES results on the cuprate superconductors and their insulating parent and sister compounds, with the purpose of providing an updated summary of the extensive literature in this field. The low energy excitations are discussed with emphasis on some of the most relevant issues, such as the Fermi surface and remnant Fermi surface, the superconducting gap, the pseudogap and d-wave-like dispersion, evidence of electronic inhomogeneity and nano-scale phase separation, the emergence of coherent quasiparticles through the superconducting transition, and many-body effects in the one-particle spectral function due to the interaction of the charge with magnetic and/or lattice degrees of freedom. The first part of the paper introduces photoemission spectroscopy in the context of strongly interacting systems, along with an update on the state-of-the-art instrumentation. The second part provides a brief overview of the scientific issues relevant to the investigation of the low energy electronic structure by ARPES. The rest of the paper is devoted to the review of experimental results from the cuprates and the discussion is organized along conceptual lines: normal-state electronic structure, interlayer interaction, superconducting gap, coherent superconducting peak, pseudogap, electron self energy and collective modes. Within each topic, ARPES data from the various copper oxides are presented.Comment: Reviews of Modern Physics, in press. A HIGH-QUALITY pdf file is available at http://www.physics.ubc.ca/~damascel/RMP_ARPES.pd

Chromosomal rearrangements and the pathogenesis of differentiated thyroid cancer

The majority of thyroid cancers arise from the follicular cells of the thyroid gland, which yield a wide variety of distinct morphotypes, ranging from relatively indolent lesions to the most malignant forms of cancer known. The remaining primary thyroid cancers arise from C cells within the gland and result primarily from mutations of the RET protooncogene, germ line mutations of which give rise to the various forms of multiple endocrine neoplasia. The most common of the follicular cell-derived cancers are papillary carcinomas, (PTC), followed by follicular carcinomas (FTC) and its Hurthle cell variant (HCC) and finally anaplastic carcinomas (ATC). The pathogenesis of many thyroid cancers, of both PTC and FTC morphotype, involves chromosomal translocations. Rearrangements of the RET protoconcogene are known to be involved in the pathogenesis of ca. 50% of PTC. A similar proportion of FTC have been associated with a t(2;3)(q13;p25) translocation, fusing the thyroid-specific transcription factor PAX8 with the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor, a ubiquitously expressed transcription factor. These rearrangements have analogy with translocations in erythropoetic cells, which form the only other known group of human malignancies that are largely the result of chromosomal translocation events. In this review we compare and contrast the oncogenic properties of thyroid and erythroid chromosomal transformations and speculate on mechanisms leading to their formation