Prognostic value of BRAF mutations in localized cutaneous melanoma

BACKGROUND: BRAF mutations are frequent in melanoma but their prognostic significance remains unclear. OBJECTIVE: We sought to further evaluate the prognostic value of BRAF mutations in localized cutaneous melanoma. METHODS: We undertook an observational retrospective study of 147 patients with localized invasive (stages I and II) cutaneous melanomas to determine the prognostic value of BRAF mutation status. RESULTS: After a median follow-up of 48 months, patients with localized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype (hazard ratio 2.2, 95% confidence interval 1.1-4.3) even after adjustment for Breslow thickness, tumor ulceration, location, age, sex, and tumor mitotic rate. LIMITATIONS: The retrospective design and the small number of events are limitations. CONCLUSIONS: Our findings suggest that reappraisal of clinical treatment approaches for patients with localized melanoma harboring tumors with BRAF mutation might be warranted

Apuntes jurídicos sobre el paisaje lingüístico en Euskal Herria

This paper is a study of place-names and signs in the Basque Country from the point of view of language law. These are matters that relate to both the status and corpus of language and contribute to the formation of the language landscape,» After a brief historical introduction, the author focuses on the factors that bear on signs and the language 1andscape: the cornpetence factor and the language factor. The description of the latter leads the author to a discussion of the existing language system, in which the Spanish and Basque sharing official status does not necessarily entail the obligation to use both languages at the same time. Using this discussion as a frame of reference, the au- thor analyses place-names, traffic signals and signs. As for place-names, the existing rules are deemed rigid and lacking in ambition, in that they do not pursue the dissemination of official Basque forms. In traffic signaIs, Basque has to appear alongside Spanish, which is required by Spanish legislation, although this bilingualism excludes place-names that have an official Basque form only. With regard to signs, the author analyses public premises, companies licensed to provide public services and the private sector. For public premises there is no specific regulation, but the status of Basque as an autochthonous language, together with the identification and informatíon purposes of signs, could support the exclusive use of this language, According to the author , companies licensed to provide public services should observe the same language system as the goverment and therefore promote the use of Basque. Finally, in the private sector, the author upholds the legitimacy of measures to promote Basque language use such as tax allowances and exemptions in advertising and commercial signs.

Avaliação de ligações KK entre perfis tubulares em aço.

Em virtude do elevado grau de desenvolvimento da tecnologia em sua produção, a utilização de perfis tubulares é grandemente difundida em países como, por exemplo, Canadá, Inglaterra, Alemanha e Holanda. A utilização de tais perfis no Brasil era bastante restrita, limitando-se a coberturas espaciais. Atualmente, a situação do mercado brasileiro começa a se alterar em decorrência do significativo aumento da oferta de perfis tubulares estruturais. Este trabalho apresenta uma análise de ligações tipo KK com perfis tubulares circulares (CHS), com o intuito de estabelecer um quadro comparativo entre as formulações analíticas de dimensionamento proposta pelo Eurocode 3 Parte 1.8, 2 edição do guia de projeto de ligações tubulares do CIDECT, ABNT NBR 16239:2013, pelas equações propostas por Paul e Kurobane e critérios de deformação limite. A calibração de um modelo foi feita com dados numéricos e experimentais. Para cada um dos tipos de ligações analisadas, desenvolveu-se um modelo em elementos finitos no programa Ansys. As não-linearidades física e geométrica foram incorporadas aos modelos, a fim de se mobilizar totalmente a capacidade resistente da ligação. A não-linearidade do material foi considerada com o uso do critério de plastificação de Von Mises através de uma lei constitutiva tensão versus deformação bilinear. A não-linearidade geométrica foi introduzida no modelo através da Formulação de Lagrange Atualizado considerando-se a previsão de grandes deformações de forma a permitir a redistribuição de carregamento na ligação após o escoamento inicial. Foi proposto um modelo de uma treliça espacial composta por perfis tubulares de seção circular para comparar os resultados de análises de uma ligação isolada e a resposta desta mesma ligação como parte de uma treliça em escala real.

Sports programs of the Spanish radio in the social network Facebook: compared study (2010-2015)

Social networks have increasingly become a showcase where the media can be promoted. Like many other media, radio stations have made use of social networks to promote themselves in a better way and, sometimes, to keep more feedback with their listeners. But not all programs make the same use and not all of them have managed to reach in the same way his followers. This article discusses the consolidation in the social networks of the major radio sports programs in Spain. Through a comparative analysis between 2010 and 2015, throughout the text, the authors have tried to observe the evolution of the programs and, at the same time, to establish comparisons between the followers that these programs have on social networks and the number of listeners as EGM.

Are they adicctied to college students social networks?

The development of the Internet and in particular of social networks has supposedly given a new view to the different aspects that surround human behavior. It includes those associated with addictions, but specifically the ones that have to do with technologies. Following a correlational descriptive design we present the results of a study, which involved university students from Social and Legal Sciences as participants, about their addiction to the Internet and in particular to social networks. The sample was conformed of 373 participants from the cities of Granada, Sevilla, Málaga, and Córdoba. To gather the data a questionnaire that was design by Young was translated to Spanish. The main research objective was to determine if university students could be considered social network addicts. The most prominent result was that the participants don’t consider themselves to be addicted to the Internet or to social networks; in particular women reflected a major distance from the social networks. It’s important to know that the results differ from those found in the literature review, which opens the question, are the participants in a phase of denial towards the addiction?

Programas iconográficos en "La piel que habito" (Almodóvar, 2011)

Como viene siendo habitual en las últimas películas de Pedro Almodóvar, las imágenes de La piel que habito (2011) se organizan en programas iconográficos que en este caso emanan de operaciones “trans” realizadas tanto en el cuerpo (transexualidad, transgénesis y trasplante), como en el texto (transtextualidad). El presente trabajo se ocupa de la genealogía y formalización de dichos programas así como de cuestiones teóricas surgidas a lo largo del desarrollo de este estudio –la relación entre cuerpo e identidad o el llamado muro de pantallas, entre otras–, de indudable calado en el filme.

Quantification of N-(glucitol)ethanolamine and N-(carboxymethyl)serine:two products of nonenzymatic modification of aminophospholipids formed in vivo

Chemical, nonenzymatic modification of protein and lipids by reducing sugars, such as glucose, is thought to contribute to age-related deterioration in tissue protein and cellular membranes and to the pathogenesis of diabetic complications. This report describes the synthesis and quantification of N-(glucitol)ethanolamine (GE) and N-(carboxymethyl)serine (CMS), two products of nonenzymatic modification of aminophospholipids. GE is the product of reduction and hydrolysis of glycated phosphatidylethanolamine (PE), while CMS is formed through reaction of phosphatidylserine (PS) with products of oxidation of either carbohydrate (glycoxidation) or lipids (lipoxidation). Gas chromatography/mass spectrometry procedures for quantification of the N,O-acetyl methyl ester derivatives of the modified head groups were developed. GE and CMS were quantified in samples of PE and PS, respectively, following incubation with glucose in vitro; CMS formation was dependent on the presence of oxygen during the incubation. Both GE and CMS were detected and quantified in lipid extracts of human red blood cell membranes. The content of GE, but not CMS, was increased in the lipids from diabetic compared to nondiabetic subjects. Measurement of these modified lipids should prove useful for assessing the role of carbonyl-amine reactions of aminophospholipids in aging and age-related diseases.

Carboxymethylethanolamine, a biomarker of phospholipid modification during the maillard reaction in vivo

Nepsilon-(Carboxymethyl)lysine (CML) is a stable chemical modification of proteins formed from both carbohydrates and lipids during autoxidation reactions. We hypothesized that carboxymethyl lipids such as (carboxymethyl)phosphatidylethanolamine (carboxymethyl-PE) would also be formed in these reactions, and we therefore developed a gas chromatography-mass spectrometry assay for quantification of carboxymethylethanolamine (CME) following hydrolysis of phospholipids. In vitro, CME was formed during glycation of dioleoyl-PE under air and from linoleoylpalmitoyl-PE, but not from dioleoyl-PE, in the absence of glucose. In vivo, CME was detected in lipid extracts of red blood cell membranes, approximately 0.14 mmol of CME/mol of ethanolamine, from control and diabetic subjects, (n = 22, p > 0.5). Levels of CML in erythrocyte membrane proteins were approximately 0.2 mmol/mol of lysine for both control and diabetic subjects (p > 0.5). For this group of diabetic subjects there was no indication of increased oxidative modification of either lipid or protein components of red cell membranes. CME was also detected in fasting urine at 2-3 nmol/mg of creatinine in control and diabetic subjects (p = 0.085). CME inhibited detection of advanced glycation end product (AGE)-modified protein in a competitive enzyme-linked immunosorbent assay using an anti-AGE antibody previously shown to recognize CML, suggesting that carboxymethyl-PE may be a component of AGE lipids detected in AGE low density lipoprotein. Measurement of levels of CME in blood, tissues, and urine should be useful for assessing oxidative damage to membrane lipids during aging and in disease.

Quantification of malondialdehyde and 4-hydroxynonenal adducts to lysine residues in native and oxidized human low-density lipoprotein

Malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are major end-products of oxidation of polyunsaturated fatty acids, and are frequently measured as indicators of lipid peroxidation and oxidative stress in vivo. MDA forms Schiff-base adducts with lysine residues and cross-links proteins in vitro; HNE also reacts with lysines, primarily via a Michael addition reaction. We have developed methods using NaBH4 reduction to stabilize these adducts to conditions used for acid hydrolysis of protein, and have prepared reduced forms of lysine-MDA [3-(N epsilon-lysino)propan-1-ol (LM)], the lysine-MDA-lysine iminopropene cross-link [1,3-di(N epsilon-lysino)propane (LML)] and lysine-HNE [3-(N epsilon-lysino)-4-hydroxynonan-l-ol (LHNE)]. Gas chromatography/MS assays have been developed for quantification of the reduced compounds in protein. RNase incubated with MDA or HNE was used as a model for quantification of the adducts by gas chromatography/MS. There was excellent agreement between measurement of MDA bound to RNase as LM and LML, and as thiobarbituric acid-MDA adducts measured by HPLC; these adducts accounted for 70-80% of total lysine loss during the reaction with MDA. LM and LML (0.002-0.12 mmol/ mol of lysine) were also found in freshly isolated low-density lipoprotein (LDL) from healthy subjects. LHNE was measured in RNase treated with HNE, but was not detectable in native LDL. LM, LML and LHNE increased in concert with the formation of conjugated dienes during the copper-catalysed oxidation of LDL, but accounted for modification of <1% of lysine residues in oxidized LDL. These results are the first report of direct chemical measurement of MDA and HNE adducts to lysine residues in LDL. LM, LML and LHNE should be useful as biomarkers of lipid peroxidative modification of protein and of oxidative stress in vitro and in vivo.

The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions

Nepsilon-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was approximately 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML, was also formed during incubation of RNase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.

Lipoxidation products as biomarkers of oxidative damage to proteins during lipid peroxidation reactions

Oxidative stress is implicated in the pathogenesis of numerous disease processes including diabetes mellitus, atherosclerosis, ischaemia reperfusion injury and rheumatoid arthritis. Chemical modification of amino acids in protein during lipid peroxidation results in the formation of lipoxidation products which may serve as indicators of oxidative stress in vivo. The focus of the studies described here was initially to identify chemical modifications of protein derived exclusively from lipids in order to assess the role of lipid peroxidative damage in the pathogenesis of disease. Malondialdehye (MDA) and 4-hydroxynonenal (HNE) are well characterized oxidation products of polyunsaturated fatty acids on low-density lipoprotein (LDL) and adducts of these compounds have been detected by immunological means in atherosclerotic plaque. Thus, we first developed gas chromatography-mass spectrometry assays for the Schiff base adduct of MDA to lysine, the lysine-MDA-lysine diimine cross-link and the Michael addition product of HNE to lysine. Using these assays, we showed that the concentrations of all three compounds increased significantly in LDL during metal-catalysed oxidation in vitro. The concentration of the advanced glycation end-product N epsilon-(carboxymethyl)lysine (CML) also increased during LDL oxidation, while that of its putative carbohydrate precursor the Amadori compound N epsilon-(1-deoxyfructose-1-yl)lysine did not change, demonstrating that CML is a marker of both glycoxidation and lipoxidation reactions. These results suggest that MDA and HNE adducts to lysine residues should serve as biomarkers of lipid modification resulting from lipid peroxidation reactions, while CML may serve as a biomarker of general oxidative stress resulting from both carbohydrate and lipid oxidation reactions.