Over-Expression of Endothelin 3 Sensitizes Mice to Uv-Induced Melanoma Metastasis

Melanomagenesis is influenced by environmental and genetic factors. In normal cells, ultraviolet (UV) induced photoproducts are successfully repaired by the nucleotide excision repair (NER) pathway. Mice carrying mutations in the xeroderma pigmentosum (Xp) complementation group of genes (Xpa-Xpg) lack the NER pathway and are therefore highly sensitive to UV light; however, they do not develop melanoma after UV exposure. In humans, the Endothelin 3 signaling pathway has been linked to melanoma progression and its metastatic potential. Transgenic mice that over-express Edn3 under the control of the Keratin 5 promoter (K5-Edn3) and exhibit a hyperpigmentation phenotype, were crossed with Xp deficient mice. Because melanoma is highly metastatic and many primary malignancies spread via the lymphatic system, analyzing the lymph nodes may serve useful in assessing the possible spread of tumor cells to other tissues. This study aimed to determine whether the over-expression of Edn3 is sufficient to lead to melanoma metastasis to the lymph nodes. Mice were exposed to UV radiation and analyzed for the presence of skin lesions. Mice presenting skin lesions were sacrificed and the nearest lymph nodes were excised and examined for the presence of metastasis. Mice with melanoma skin lesions presented enlarged and hyperpigmented lymph nodes. Diagnosis of melanoma was established by immunostaining with melanocyte and melanoma cell markers, and while UV radiation caused the development of skin lesions in both K5-Edn3 transgenic and control mice, only those mice carrying the K5-Edn3 transgene were found to develop melanoma metastasis to the lymph nodes. These results indicate that over-expression of Edn3 is sufficient to lead to lymph node metastasis in mice exposed to at least one dose of UV radiation.

UV-induced melanoma mouse model dependent on endothelin 3 over-expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.^

Avaliação de polimorfismos funcionais nos genes de reparo XRCC1, APEX1, XPD e XPF em carcinomas de células escamosas orais

Base excision repair (BER) and nucleotide excision repair (NER) pathways play critical role in maintaining genome integrity. Polymorphisms in BER and NER genes which modulate the DNA repair capacity may affect the susceptibility and prognosis of oral cancer. This study was conducted with genomic DNA from 92 patients with oral squamous cell carcinomas (OSCC) and 130 controls. The cases were followed up to explore the associations between BER and NER genes polymorphisms and the risk and prognosis of OSCC. Four single-nucleotide polymorphisms (SNPs) in XRCC1 (rs25487), APEX1 (rs1130409), XPD (rs13181) and XPF (rs1799797) genes were tested by polymerase chain reaction – quantitative real time method. The GraphPad Prism version 6.0.1 statistical software was applied for statistical analysis of association. Odds ratio (OR), hazard ratio (HR), and their 95 % confidence intervals (CIs) were calculated by logistic regression. Kaplan-Meier curve and Cox proportional hazard model were used for prognostic analysis. The presence of polymorphic variants in XRCC1, APEX1, XPD and XPF genes were not associated with an increased risk of OSCC. Gene-environment interactions with smoking were not significant for any polymorphism. The presence of polymorphic variants of the XPD gene in association with alcohol consumption conferred an increased risk of 1.86 (95% CI: 0.86 – 4.01, p=0.03) for OSCC. Only APEX1 was associated with decreased specific survival (HR 3.94, 95% CI: 1.31 – 11.88, p=0.01). These results suggest an interaction between polymorphic variants of the XPF gene and alcohol consumption. Additionally APEX1 may represent a prognostic marker for OSCC.

UV-Induced Melanoma Mouse Model Dependent on Endothelin 3 Over-Expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.

Social economy, youth and employment

Organizations of the Social Economy in Spain accounted for 13% of employment and 12% of GDP in 2013, according to the Spanish Confederation fo Social Economy. Also, according to various institutions and studies, the role of Social Economy has become relevant due to they represent a model promoting the creation of collective business projects with greater sustainability and potential than models of individual self-employment. However, despite all this, there are few academic studies or sectoral reports analyzing employment in this sector, especially in the case of youth employment. This study aims to fill this gap in the literature analyzing the scared available data in order to show the numbers and characteristics of youth employment in this sector. Results show the weight of youth employment in the Social Economy is higher than the economy overall.

La historia contemporánea en relación con la memoria, los museos y los espacios de memoria Internacionales - pasado, presente y futuro

El artículo examina los conceptos de Monumentos, Sitios y Museos conmemorativos a nivel internacional. Se comienza con la terminología de historia contemporánea como un término que se desarrolló y amplió desde 1950. La historia contemporánea influye también en el campo de las Bellas Artes. Los monumentos conmemorativos o sitios de la memoria en lugares auténticos son de gran importancia para la concienciación. En combinación con los museos tienen la posibilidad de recoger diversos objetos como fuentes escritas, artefactos, fotografías y registros de la historia oral como testimonios de los antiguos acontecimientos. En cuanto a los museos, esto se refleja particularmente en las concepciones de los museos para la Guerra y la Paz, los museos de la Memoria sobre el Genocidio, y los museos de Movimientos de Resistencia. Un artefacto particular del ataque terrorista del 11 de septiembre de 2001 es la Karyatide del famoso artista alemán Fritz Koenig, ahora colocado en el Battery Park al sur de Manhattan. Por último, el Memorial y Museo Nacional 11 de Septiembre se explica junto con su arquitectura, la idea de “Ausencia Reflexionada” y la Misión de la Memoria para el futuro.

Sjuksköterskans upplevelse av humorns betydelse i psykiatrisk omvårdnad - En intervjustudie

Bakgrund: Sjuksköterskan förväntas arbeta med patientens bästa i fokus och hon möter många allvarliga situationer där själva existensen står på spel och där sjuksköterskan behöver härbärgera starka känslor hos patienter och deras närstående, men också upprätthålla sin egen integritet och känslomässiga balans. Humor har visats vara ett kraftfullt men tveeggat verktyg i kommunikation och relationsbyggande. Inom psykiatrin kan detta verktyg förmodas behöva hanteras med särskilt kunskap och omsorg. Syfte: Att beskriva hur sjuksköterskan i psykiatrisk omvårdnad ser på humor som företeelse och hennes upplevelse av positiva respektive negativa effekter av att använda humor. Metod: Undersökningen utfördes med en kvalitativ innehållsanalys av halvstrukturerade intervjuer med fem sjuksköterskor verksamma inom psykiatrisk omvårdnad. Resultat: Humor sågs som ett viktigt verktyg inom psykiatrisk omvårdnad som det krävdes lyhördhet, respekt, fingertoppskänsla och timing för att kunna använda. Den huvudsakliga strategin för att använda humor var öppenhet för spontant humor i mötet men det gavs även exempel på medvetna interventioner. Humor öppnade möjligheter att få se verkligheten från nya perspektiv vilket var verksamt för att förändra negativa tankar samt lätta på ångest och negativa känslor. Humor underlättade kommunikation och kunde användas för att jämna ut maktbalanser. Det fanns risk för negativa effekter om humor användes för att trycka ner andra eller som verklighetsflykt. Psykiatriska patienter uppfattades som mer sårbara och medvetenhet om hur svåra psykiska sjukdomar påverkar förmågan att uppfatta och uppskatta humor var viktig även om ett allmänt bra bemötande ansågs vara grundläggande. Slutsats: Positiva former av humor som används på ett respektfullt och inkännande sätt kan vara är ett viktigt verktyg i omvårdnaden för att möjliggöra nya perspektiv på tillvaron, ge lättnad i ångest, minska negativa känslor och tankar samt höja livskvaliteten för både patienter och personal i en verksamhet med mycket allvar.

Språkintroduktion en dörröppnare till gymnasiet? : Andraspråkselevers upplevelse av språkintroduktion

Syftet med studien är att undersöka nyanlända elevers erfarenhet av introduktionsprogrammet samt att belysa deras upplevelser av kunskapsinlärning på ett andra språk. Vidare är syftet att synliggöra huruvida eleverna upplever IM som en väg in i gymnasieskolan och i samhället. Studien bygger på kvalitativa metoder med intervjuer från fem elever som går på språkintroduktionsprogrammet. Intervjuerna har skrivits ner och bearbetats. Resultatet analyserar utifrån andraspråksforskning som presenteras i inledningen. Studien visar liksom andra undersökningar att andraspråkselever behöver få möjlighet att utveckla så väl sitt språk som ämneskunskaper. Språket är viktigt för såväl det egna identitetsskapande som gemenskapen med andra elever på gymnasiet.

A esquina do povo de alt’lam: aprimoramento racial e moral no movimento espírita natalense

A partir de um conjunto de dados obtidos em pesquisa, o texto deseja salientar uma face pouco examinada pelos estudiosos do espiritismo no Brasil: aquela dos grupos espíritas que cultuam extraterrestres. Examina a narrativa Rebelião de Lúcifer, escrita pelo médium potiguar Jan Val Ellam. Sustenta que esta atualiza noções importantes em relação a narrativas de salvação anteriores construídas pelo espiritismo. Destaca em especial o aprimoramento racial e moral através da reencarnação em distintos corpos humanos e em diferentes planetas. Examina-os a partir das noções de exílio planetário e de evolução racializada. Argumenta que Jan Val Ellam as atualiza através da categoria nativa Povo de Alt’Lam e através de bricolagem com outros campos semânticos, notadamente a ufologia e a fi cção científica

Analysis of a socio-professional group underestimated: officials of notaries in Southern Spain according to the cadastre of Ensenada.

This paper tries to show the reality of one of the trades more important for historians, the officials of the notaries. The work of these officials has allowed us to have great historical sources; we refer to the notarial documentation and documenta-tion of the City Council. They were the executive arm of the pub-lic notaries. Nevertheless, the approach to this figure seems diffi-cult, since we do not find lavish allusions of them or any of their obligations in the documentation preserved. However, we have one of the most important historical sources by middle of Eight-eenth century; this is known as the Cadastre of Ensenada. We have been able to approach this type of job through analysis and study of the Cadastre, so we know who were those men who did this huge undertaking and what was his salary for performing their tasks. In addition, we proceeded to the consultation of doc-umentation kept in local files to have a more accurate understand-ing of the real situation of those officials.

Strävan efter värdighet : En studie av servicearbete

The focus of this study is dignity in low status service work. Using labels such as bad jobs, McJobs and dirty work, these jobs have been described as low-skilled, low-paid, monotonous and physically demanding with lack of voice and no job security. Research on dignity at work is especially relevant in a time when different ambitions for more dignified work, initiated by political parties as well as unions, tend to be forgotten or down-prioritized. This study investigates what conditions are preventing dignity among low status service workers and how they create and maintain dignity for themselves. What briefly has been found is that dignity can be prevented by unreasonable demands, constant control, exposed work and mismanagement. Moreover, customerprerogative can prevent dignity when employees are being mistreated by disrespectful customers. Dignity is also hindered by frightening customers, especially in the case of sexual harassment, threats and violence. In this study theories about working conditions and professional status are brought together to explain experiences of dignity at work. Service workers do not only have managers to deal with, but also customers whose treatment is reflected by the status of the service occupation. Besides, working conditions and professional status are two mechanisms acting together when it comes to experiences of dignity at work and may thus result in double tensions in daily work.   Acts for dignity, meaning different ways in which the service workers create and maintain dignity for themselves, are reactions to the obstacles to dignity at work. Three different categories of acts for dignity can be found. The identity-bolstering acts help the workers maintain their professional identity or self-image when it is threatened by different obstacles to dignity. The justifying acts mean that the workers legitimize different obstacles to dignity. Finally, the compensating acts help the workers to even out different obstacles to dignity.

Étude du comportement de la chromatine, de la régulation de la transcription et réparation des gènes de l’ARNr avant la réplication de l’ADN et assemblage de la réparation par excision de nucléotides chez Saccharomyces cerevisiae

Résumé : Le nucléole est considéré comme étant une « usine » à produire des ribosomes. Cette production est la fonction la plus énergivore de la cellule. Elle met en jeu les trois ARN polymérases et représente 80% de l’activité de transcription au sein d’une cellule. Les trois quarts de cette activité de transcription correspondent à la synthèse des ARNr par l’ARN polymérase I (ARNPI). Ainsi mieux comprendre les mécanismes cellulaires se déroulant à l’intérieur de ce compartiment permettra le développement de nouveaux traitements contre le cancer. La synthèse d’ARNr par l’ARNPI est régulée à trois niveaux : l’initiation de la transcription, l’élongation et le nombre de gènes de l’ARNr en transcription. La plupart des travaux qui se sont intéressés à ces niveaux de régulation ont été réalisés avec des cellules en phase exponentielle de croissance. Au cours de mes travaux, je me suis attardé sur la régulation de la transcription par l’ARNPI au cours de la phase G1 du cycle cellulaire et au début de la phase S. Ainsi mes résultats ont montré que si la chromatine des gènes de l’ARNr est essentiellement dépourvue de nucléosomes, la régulation de l’ARNPI diffère dans des cellules en G1 et au début de la phase S. J’ai pu de ce fait observer qu’en G1, la transcription de l’ARNPI se concentre sur un nombre réduit de gènes en transcription. Dans des cellules arrêtées au début de la phase S avec de l’hydroxyurée, la transcription de l’ARNPI est perturbée par un défaut de maturation de l’ARNR. Fort de ces résultats sur la nature des gènes ribosomaux en phase G1, je me suis attardé à la réparation de ces gènes lors de cette phase. Alors que dans des cellules en phase exponentielle de croissance irradiées avec des UVC, la chromatine des gènes de l’ARNr se ferme ; je n’ai pas observé la formation de nucléosomes suite à l’irradiation de cellules synchronisée en G1. Mes résultats montrent également que la réparation est plus efficace. Parallèlement, j’ai exploré l’assemblage du complexe de réparation par excision de nucléotides. Toutefois, les résultats obtenus sont peu concluants.

Étude de la réparation des lésions induites par les UVs dans les extrémités chromosomiques de la levure Saccharomyces cerevisiae

Résumé : Les télomères sont des structures nucléoprotéiques spécialisées qui assurent la stabilité du génome en protégeant les extrémités chromosomiques. Afin d’empêcher des activités indésirables, la réparation des dommages à l’ADN doit être convenablement régulée au niveau des télomères. Pourtant, il existe peu d’études de la réparation des dommages induits par les ultraviolets (UVs) dans un contexte télomérique. Le mécanisme de réparation par excision de nucléotides (NER pour « Nucleotide Excision Repair ») permet d’éliminer les photoproduits. La NER est un mécanisme très bien conservé de la levure à l’humain. Elle est divisée en deux sous voies : une réparation globale du génome (GG-NER) et une réparation couplée à la transcription (TC-NER) plus rapide et plus efficace. Dans notre modèle d’étude, la levure Saccharomyces cerevisiae, une forme compactée de la chromatine nommée plus fréquemment « hétérochromatine » a été décrite. Cette structure particulière est présente entre autres, au niveau des régions sous-télomériques des extrémités chromosomiques. La formation de cette chromatine particulière implique quatre protéines nommées Sir (« Silent Information Regulator »). Elle présente différentes marques épigénétiques dont l’effet est de réprimer la transcription. L’accès aux dommages par la machinerie de réparation est-il limité par cette chromatine compacte ? Nous avons donc étudié la réparation des lésions induites par les UVs dans différentes régions associées aux télomères, en absence ou en présence de protéines Sir. Nos données ont démontré une modulation de la NER par la chromatine, dépendante des nucléosomes stabilisés par les Sir, dans les régions sous-télomériques. La NER était moins efficace dans les extrémités chromosomiques que dans les régions plus proches du centromère. Cet effet était dépendant du complexe YKu de la coiffe télomérique, mais pas dépendant des protéines Sir. La transcription télomériques pourrait aider la réparation des photoproduits, par l’intermédiaire de la sous-voie de TC-NER, prévenant ainsi la formation de mutations dans les extrémités chromosomiques. Des ARN non codants nommés TERRA sont produits mais leur rôle n’est pas encore clair. Par nos analyses, nous avons confirmé que la transcription des TERRA faciliterait la NER dans les différentes régions sous-télomériques.

A esquina do povo de alt’lam: aprimoramento racial e moral no movimento espírita natalense

A partir de um conjunto de dados obtidos em pesquisa, o texto deseja salientar uma face pouco examinada pelos estudiosos do espiritismo no Brasil: aquela dos grupos espíritas que cultuam extraterrestres. Examina a narrativa Rebelião de Lúcifer, escrita pelo médium potiguar Jan Val Ellam. Sustenta que esta atualiza noções importantes em relação a narrativas de salvação anteriores construídas pelo espiritismo. Destaca em especial o aprimoramento racial e moral através da reencarnação em distintos corpos humanos e em diferentes planetas. Examina-os a partir das noções de exílio planetário e de evolução racializada. Argumenta que Jan Val Ellam as atualiza através da categoria nativa Povo de Alt’Lam e através de bricolagem com outros campos semânticos, notadamente a ufologia e a fi cção científica

Modulação da expressão da proteína XPA em resposta ao tratamento com azul de metileno fotossensibilizado

Reactive oxygen species (ROS) are produced by aerobic metabolism and react with biomolecules, such as lipids, proteins and DNA. In high concentration, they lead to oxidative stress. Among ROS, singlet oxygen (1O2) is one of the main ROS involved in oxidative stress and is one of the most reactive forms of molecular oxygen. The exposure of some dyes, such as methylene blue (MB) to light (MB+VL), is able to generate 1O2 and it is the principle involved in photodynamic therapy (PDT). 1O2 e other ROS have caused toxic and carcinogenic effects and have been associated with ageing, neurodegenerative diseases and cancer. Oxidative DNA damage is mainly repaired by base excision repair (BER) pathway. However, recent studies have observed the involvement of nucleotide excision repair (NER) factors in the repair of this type of injury. One of these factors is the Xeroderma Pigmentosum Complementation Group A (XPA) protein, which acts with other proteins in DNA damage recognition and in the recruitment of other repair factors. Moreover, oxidative agents such as 1O2 can induce gene expression. In this context, this study aimed at evaluating the response of XPA-deficient cells after treatment with photosensitized MB. For this purpose, we analyzed the cell viability and occurrence of oxidative DNA damage in cells lines proficient and deficient in XPA after treatment with MB+VL, and evaluated the expression of this enzyme in proficient and complemented cells. Our results indicate an increased resistance to treatment of complemented cells and a higher level of oxidative damage in the deficient cell lines. Furthermore, the treatment was able to modulate the XPA expression up to 24 hours later. These results indicate a direct evidence for the involvement of NER enzymes in the repair of oxidative damage. Besides, a better understanding of the effects of PDT on the induction of gene expression could be provided