Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly

Pituitary adenomas account for 10-15% of primary intracranial tumors. Growth hormone (GH)-secreting adenomas account for 13% of all pituitary adenomas and cause acromegaly. These tumors can be aggressive, invade surrounding structures and are highly recurrent. The objective of this study was to evaluate E-cadherin, Slug and neural cell adhesion molecule (NCAM) expression in GH-secreting pituitary adenomas and its relationship to tumor invasiveness. A cross-sectional study of patients who underwent hypophysectomy due to GH-secreting pituitary adenoma from April 2007 to December 2014 was carried out. The medical records were reviewed to collect clinical data. Immediately after surgery, tumor samples were frozen in liquid nitrogen and stored in a biofreezer at -80°C for assessment of E-cadherin 1 (CDH1), SLUG (SNAI2), and NCAM (NCAM1) by real-time PCR. The samples were fixed in formalin and embedded in paraffin for immunohistochemical analysis of E-cadherin and NCAM. Thirty-five patients with acromegaly were included in the study. Of these, 65.7% had invasive tumors. Immunohistochemically, E-cadherin was expressed in 96.7% of patients, and NCAM in 80% of patients. There was no statistically significant relationship between tumor grade or invasiveness and immunohistochemical expression of these markers. Regarding gene expression, 50% of cases expressed CDH1, none expressed SNAI2, and 53.3% expressed NCAM1. There was no statistically significant relationship between tumor grade or invasiveness and gene expression of CDH1, SNAI2, and NCAM1. The absence of Slug overexpression and of E-cadherin and NCAM suppression suggests that expression of these markers is not associated with tumor invasiveness in GH-secreting pituitary adenomas.

El uso de placebo en ensayos clínicos de fase III en Brasil / The use of placebos in phase III clinical trials in Brazil

El Consejo Federal de Medicina de Brasil (CFM) -órgano normativo y fiscalizador del ejercicio ético de la medicina- prohibió, en 2008, la participación de médicos brasileños en investigaciones que utilizaran placebo para enfermedades con tratamiento eficaz y efectivo, en contraposición a la Declaración de Helsinki, que permite su uso en condiciones metodológicamente justificadas. Con el objetivo de verificar si la normativa ética del CFM modificó el uso de placebo en ensayos clínicos de fase III en Brasil, se analizaron varias características de sus registros en el ClinicalTrials.gov, en los períodos de 2003 a 2007 y de 2009 a 2013. Se concluye que: a) la normativa promulgada por el CFM en 2008 fue ineficaz y prevaleció la posición adoptada por la Declaración de Helsinki; b) el patrocinio de ensayos con placebo por parte de la industria farmacéutica multinacional fue significativo; c) predominaron las investigaciones de fármacos para enfermedades crónicas, y fueron poco significativas para las enfermedades postergadas, de importancia para Brasil.

In 2008, Brazil's Federal Council of Medicine [Conselho Federal de Medicina] (CFM) - regulatory and supervisory agency on the ethical practice of medicine - banned the participation of Brazilian doctors in studies using placebos for diseases with efficient and effective treatment. This position differs with the Helsinki Declaration, which allows the use of placebos in methodologically justified conditions. To ascertain whether the CMF's ethical regulation modified the use of placebos in phase III clinical trials in Brazil, characteristics of the records in ClinicalTrials.gov were researched in the periods from 2003 to 2007 and from 2009 to 2013. The conclusions reached were: a) the regulations issued by the CFM in 2008 were ineffective and the position adopted by the Helsinki Declaration prevails; b) there was significant sponsorship by the multinational pharmaceutical industry of trials with placebos; c) the research was predominantly on new drugs for chronic diseases, with little study done of the neglected diseases which are of great importance to Brazil.

Estudio piloto de marcadores inflamatorios en el sindrome de apnea obstructiva del sueño / Pilot study of inflammatory markers in the syndrome of obstructive sleep apnea

El síndrome de Apnea Obstructiva del Sueño (SAOS), consiste en la aparición repetida de episodios de obstrucción faríngea durante el sueño como consecuencia de un colapso de la vía respiratoria. La respuesta fisiológica a la hipoxia intermitente crónica es la generación de una respuesta inflamatoria local y sistémica. Se han evidenciado cambios importantes a nivel cardiovascular en pacientes con SAOS; sin embargo, se desconocen cuáles marcadores séricos y genéticos pudieran ser de utilidad. En el presente estudio, se presentan 15 marcadores séricos y 3 genéticos (IL-6, IL-1β y TNF-α) en un grupo de cinco pacientes para determinar cuáles pueden ser los marcadores de interés en la aparición y en el desarrollo de esta patología respiratoria. Se proponen como marcadores los niveles séricos: proteína C reactiva, TNFα, IL-6, el receptor soluble de TNF I, sCD62, sCD154, nitrotirosina y anti-oxLDL. Los niveles de IL-1 β, el receptor de TNF soluble II, sCD25, sCD54, nitritos y nitratos no parecieran ser buenos marcadores en SAOS. Los estudios genéticos no fueron concluyentes.

Obstructive sleep apnea syndrome (OSAS) is a repeated sequences of pharynx obstruction during sleep as a consequence of airway collapse. The physiological response to the desaturation is the generation of a local and systemic inflammatory immune response. Important changes at cardiovascular levels in patients with OSAS have been observed; however, it is not know which serum or genetic parameters could be useful. In the present study, we present 15 serum and 3 genetic (IL-6, IL-1β y TNF-α) markers in a group of five patients in order to determine which marker could be useful to study the genesis and progression of this respiratory pathology. The proposed serum markers are C reactive proteín, TNFα, IL-6, soluble de TNF receptor I, sCD62, sCD154, nitrotirosine and anti-oxLDL. The levels of IL-1 β, soluble TNF receptor II, sCD25, sCD54, nitrite y nitrate do not seem to be good markers for OSAS. The genetic studies were not conclusive.

The role of reelin in the development and evolution of the cerebral cortex

Reelin is an extracellular matrix protein that is defective in reeler mutant mice and plays a key role in the organization of architectonic patterns, particularly in the cerebral cortex. In mammals, a "reelin signal" is activated when reelin, secreted by Cajal-Retzius neurons, binds to receptors of the lipoprotein receptor family on the surface of cortical plate cells, and triggers Dab1 phosphorylation. As reelin is a key component of cortical development in mammals, comparative embryological studies of reelin expression were carried out during cortical development in non-mammalian amniotes (turtles, squamates, birds and crocodiles) in order to assess the putative role of reelin during cortical evolution. The data show that reelin is present in the cortical marginal zone in all amniotes, and suggest that reelin has been implicated in the evolution of the radial organization of the cortical plate in the synapsid lineage leading from stem amniotes to mammals, as well as in the lineage leading to squamates, thus providing an example of homoplastic evolution (evolutionary convergence). The mechanisms by which reelin instructs radial cortical organization in these two lineages seem different: in the synapsid lineage, a drastic amplification of reelin production occurred in Cajal-Retzius cells, whereas in squamates, in addition to reelin-secreting cells in the marginal zone, a second layer of reelin-producing cells developed in the subcortex. Altogether, our results suggest that the reelin-signaling pathway has played a significant role in shaping the evolution of cortical development

Functional role of a glycolipid in directional movements of neurons

Migration of neurons from their site of origin to their final destination is a critical and universal step in the formation of the complex structure of the nervous system. The migratory process is thought to be governed in part by genetically and epigenetically defined sequences of signals which are interpreted by migrating cells. The molecular mechanisms that underlie neuronal migration have been the subject of intense investigation. As in other developmental processes, many molecules must participate in neuronal migration. Some molecules, such as cell adhesion molecules and motor proteins, may contribute to discrete steps in the migration act; others, like extracellular signaling molecules, may regulate the activation and/or termination of the migration program. In this article we review findings from our group that demonstrate the functional role(s) of a specific glycolipid in neuronal migration and neurite outgrowth in the developing and adult nervous system

The 9-O-acetyl GD3 gangliosides are expressed by migrating chains of subventricular zone neurons in vitro

Neurons from the anterior subventricular zone (SVZ) of the cerebral cortex migrate tangentially to become interneurons in the olfactory bulb during development and in adult rodents. This migration was defined as neuronophilic, independent of a radial glial substrate. The cortical SVZ and the rostral migratory stream to the olfactory bulb were shown to be rich in 9-O-acetyl GD3 gangliosides (9-O-acGD3), which have been previously shown to be implicated in gliophilic migration in the rodent cerebral cortex and cerebellum. In the present study, we performed SVZ explant cultures using rats during their first postnatal week to analyze the expression of these gangliosides in chain migration of neuronal precursors. We characterized migrating chains of these neuroblasts through morphological analysis and immunocytochemistry for the neural cell adhesion molecule. By using the Jones monoclonal antibody which binds specifically to 9-O-acGD3 we showed that migrating chains from the SVZ explants express 9-O-acGD3 which is distributed in a punctate manner in individual cells. 9-O-acGD3 is also present in migrating chains that form in the absence of radial glia, typical of the neuronophilic chain migration of the SVZ. Our data indicate that 9-O-acetylated gangliosides may participate in neuronophilic as well as gliophilic migration