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Cascon A.,Hereditary Endocrine Cancer Group | Cascon A.,Center for Biomedical Research on Rare Diseases | Tennant D.A.,University of Birmingham
Endocrine Pathology | Year: 2012

This review summarizes the way in which inherited mutations define global gene expression in pheochromocytoma (PCC) and paraganglioma (PGL), and how the use of gene expression analysis has advanced our understanding of these diseases. The biology of PCC and PGL tumors is diverse and it has become clear that there is no apparent single biology that defines these tumors. However, over the last 20 years, our understanding of the biology of PGL and PCC has been considerably advanced by the discovery of inherited mutations that predispose individuals to developing the disease. More recently, the use of transcriptomics to stratify tumors based on their gene expression profiles has, in particular, played a vital role in delineating novel mutations involved in the pathogenesis of these tumors. In this review, we describe our current understanding of the biology of cluster 1 (pseudohypoxic) tumors and how mutations that result in the pseudohypoxic phenotype that leads to changes in global gene expression. We also review the advances in our understanding of cluster 2 tumors, and in particular, focus on the newly described MAX tumors. © 2012 Springer Science+Business Media, LLC.


Bernal J.,Autonomous University of Madrid | Bernal J.,Center for Biomedical Research on Rare Diseases
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2011

Purpose of Review: To discuss the recent advances on thyroid hormone transport in the brain. A special attention is paid to the X-linked thyroid hormone cell transport (THCT) defect (also known as the Allan-Herndon-Dudley syndrome), caused by mutations of the specific thyroid hormone transporter MCT8 gene. Recent Findings: MCT8 is involved in thyroid hormone transport in the brain. MRI of patients with THCT defect showed myelination delays, probably related to impaired thyroid hormone action on oligodendrocytes. MCT8 is also expressed in the thyroid and has an important role in thyroid hormone secretion. The altered circulating concentrations of thyroid hormone in the patients are partly because of impaired secretion and altered peripheral metabolism. Increased deiodinase activity is important in the pathophysiology of the syndrome. High D1 activity in liver and kidney increases T4 and r T3 deiodination, and contributes to the increased serum T3. High D2 activity in the brain contributes to compensate the deficient T3 transport by increasing local T3 production. Summary: Patients with suspected X-linked leukoencephalopathy should be screened for MCT8 gene mutations. Research on the brain pathophysiology of the THCT defect should focus on the specific role of Mct8 on oligodendrocytes and myelination. Copyright © Lippincott Williams & Wilkins.


Bernal J.,Autonomous University of Madrid | Morte B.,Center for Biomedical Research on Rare Diseases
Biochimica et Biophysica Acta - General Subjects | Year: 2013

Background: The transcriptional activity of the thyroid hormone receptors is modulated by the ligand, T3, but they have also activity as aporeceptors, in the unliganded state. Aporeceptor activity is thought to contribute to the severity of profound hypothyroidism. During development thyroid hormone receptors are expressed before onset of thyroid gland function and are present therefore in many tissues mainly as aporeceptors. The question we address is whether thyroid hormone aporeceptors are involved in physiological and/or developmental processes. Scope of review: The scope of this article is to review the evidence for a role of thyroid hormone aporeceptors in physiology and development. Related to this topic is the activity of mutant receptors unable to bind hormone. These receptors usually have dominant negative activity. This review focuses on the wild type receptors, and does not discuss the properties of mutant receptors. Major conclusions: Unliganded thyroid hormone receptors influence the timing and control certain aspects of amphibian pre-metamorphosis. In mammals they are likely to influence maturational processes in the brain and other organs before onset of thyroid gland function. Expression of types 2 and 3 deiodinases which control the local tissue concentration of T3 regulates the fractional receptor occupancy and therefore the relative proportion of aporeceptors. This article is part of a Special Issue entitled Thyroid hormone signalling. © 2012 Elsevier B.V. All rights reserved.


Martin-Higueras C.,Center for Biomedical Research on Rare Diseases
Molecular Therapy | Year: 2015

Primary hyperoxaluria type 1 (PH1) is caused by deficient alanine-glyoxylate aminotransferase, the human peroxisomal enzyme that detoxifies glyoxylate. Glycolate is one of the best-known substrates leading to glyoxylate production, via peroxisomal glycolate oxidase (GO). Using genetically modified mice, we herein report GO as a safe and efficient target for substrate reduction therapy (SRT) in PH1. We first generated a GO-deficient mouse (Hao1-/-) that presented high urine glycolate levels but no additional phenotype. Next, we produced double KO mice (Agxt1-/- Hao1-/-) that showed low levels of oxalate excretion compared with hyperoxaluric mice model (Agxt1-/-). Previous studies have identified some GO inhibitors, such as 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1,2,3-thiadiazole (CCPST). We herein report that CCPST inhibits GO in Agxt1-/- hepatocytes and significantly reduces their oxalate production, starting at 25 µM. We also tested the ability of orally administered CCPST to reduce oxalate excretion in Agxt1-/- mice, showing that 30–50% reduction in urine oxalate can be achieved. In summary, we present proof-of-concept evidence for SRT in PH1. These encouraging results should be followed by a medicinal chemistry programme that might yield more potent GO inhibitors and eventually could result in a pharmacological treatment for this rare and severe inborn error of metabolism.Molecular Therapy (2016); doi:10.1038/mt.2015.224. © 2015 American Society of Gene & Cell Therapy


Rodriguez-Antona C.,Hereditary Endocrine Cancer Group | Rodriguez-Antona C.,Center for Biomedical Research on Rare Diseases | Taron M.,Quiron Dexeus Universitary Hospital
Journal of Internal Medicine | Year: 2015

Personalized medicine involves the selection of the safest and most effective pharmacological treatment based on the molecular characteristics of the patient. In the case of anticancer drugs, tumour cell alterations can have a great impact on drug activity and, in fact, most biomarkers predicting response originate from these cells. On the other hand, the risk of developing severe toxicity may be related to the genetic background of the patient. Thus, understanding the molecular characteristics of both the tumour and the patient, and establishing their relation with drug outcomes will be critical for the identification of predictive biomarkers and to provide the basis for individualized treatments. This is a complex scenario where multiple genes as well as pathophysiological and environmental factors are important; in addition, tumours exhibit large inter- and intraindividual variability in space and time. Against this background, the huge amounts of biological and genetic data generated by the high-throughput technologies will facilitate pharmacogenomic progress, suggest novel druggable molecules and support the design of future strategies aimed at disease control. Here, we will review the current challenges and opportunities for pharmacogenomic studies in oncology, as well as the clinically established biomarkers. Lung and renal cancer, two areas in which huge progress has been made in the last decade, will be used to illustrate advances in personalized cancer treatment; we will review EGFR mutation as the paradigm of targeted therapies in lung cancer, and discuss the dissection of lung cancer into clinically relevant molecular subsets and novel advances that suggest an important role of single nucleotide polymorphisms in the response to antiangiogenic agents, as well as the challenges that remain in these fields. Finally, we will present new approaches and future prospects for personalizing medicine in oncology. © 2014 The Association for the Publication of the Journal of Internal Medicine.

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