Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells.

BACKGROUND: The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. However, despite initial successes with these therapies, patients relapse within a year and have to move on to other therapies. Moreover, patients harbouring a wild type BRAF gene (including 25% with NRAS mutations) still require alternative treatment such as chemotherapy. Multiple genetic parameters have been associated with response to chemotherapy, but despite their high frequency in melanoma nothing is known about the impact of BRAF or NRAS mutations on the response to chemotherapeutic agents. METHODS: Using cell proliferation and DNA methylation assays, FACS analysis and quantitative-RT-PCR we have characterised the response of a panel of NRAS and BRAF mutant melanoma cell lines to various chemotherapy drugs, amongst them dacarbazine (DTIC) and temozolomide (TMZ) and DNA synthesis inhibitors. RESULTS: Although both, DTIC and TMZ act as alkylating agents through the same intermediate, NRAS and BRAF mutant cells responded differentially only to DTIC. Further analysis revealed that the growth-inhibitory effects mediated by DTIC were rather due to interference with nucleotide salvaging, and that NRAS mutant melanoma cells exhibit higher activity of the nucleotide synthesis enzymes IMPDH and TK1. Importantly, the enhanced ability of RAS mutant cells to use nucleotide salvaging resulted in resistance to DHFR inhibitors. CONCLUSION: In summary, our data suggest that the genetic background in melanoma cells influences the response to inhibitors blocking de novo DNA synthesis, and that defining the RAS mutation status could be used to stratify patients for the use of antifolate drugs

Alien Registration- Margison, George (Presque Isle, Aroostook County)

https://digitalmaine.com/alien_docs/33835/thumbnail.jp

Alien Registration- Margison, Authora (Presque Isle, Aroostook County)

https://digitalmaine.com/alien_docs/33834/thumbnail.jp

Atl1 Regulates Choice between Global Genome and Transcription-Coupled Repair of O6-Alkylguanines

Nucleotide excision repair (NER) has long been known to remove DNA lesions induced by chemical carcinogens, and the molecular mechanism has been partially elucidated. Here we demonstrate that in Schizosaccharomyces pombe a DNA recognition protein, alkyltransferase-like 1 (Atl1), can play a pivotal role in selecting a specific NER pathway, depending on the nature of the DNA modification. The relative ease of dissociation of Atl1 from DNA containing small O6-alkylguanines allows accurate completion of global genome repair (GGR), whereas strong Atl1 binding to bulky O6-alkylguanines blocks GGR, stalls the transcription machinery, and diverts the damage to transcription-coupled repair. Our findings redraw the initial stages of the NER process in those organisms that express an alkyltransferase-like gene and raise the question of whether or not O6-alkylguanine lesions that are poor substrates for the alkyltransferase proteins in higher eukaryotes might, by analogy, signal such lesions for repair by NER

Liberalizing Career Education: An Aristotelian Approach

Liberal education is traditionally defined in opposition to vocational study. This article proposes an expanded approach to liberal education that encompasses contemporary career preparation programs by implementing an Aristotelian intellectual virtue framework. Although liberal study typically reflects its lineage to theoretical wisdom, or sophia, it virtually ignores the fundamental role played by productive wisdom, or techne, in Aristotelian thought. By applying the intellectual virtue framework to various career education programs, areas of required reform are identified. Two central questions are addressed by the article: (a) how can career education be integrated into secondary school curriculum without compromising student agency and democratic citizenship? and (b) how can secondary school career education prepare students more effectively for the challenges of contemporary working life? The final section offers a series of proposals in response to these two key questions.L'on définit traditionnellement les études en arts libéraux par opposition aux études professionnelles. Cet article propose une interprétation élargie d'une éducation libérale qui englobe les programmes contemporains de formation au choix d'une carrière et ce, en appliquant un cadre aristotélicien de vertu intellectuelle. Bien que les arts libéraux reflètent typiquement leur lien à la sagesse théorique, ou sophia, ils font essentiellement abstraction du rôle fondamental que joue la sagesse productive, ou techne, dans la pensée aristotélicienne. L'application du cadre de vertu intellectuelle aux divers programmes de formation au choix d'une carrière fait ressortir des domaines où la réforme s'avère nécessaire. Cet article aborde deux questions fondamentales : (a) comment les programmes de formation au choix d'une carrière peuvent-ils être intégrés au curriculum du secondaire sans compromettre l'autonomie des élèves et la citoyenneté démocratique? et (b) comment de tels programmes peuvent-ils mieux préparer les élèves au secondaire à faire face aux défis contemporains que pose le monde du travail? La dernière section de l'article propose une série de réponses à ces deux questions clés

The Market Economy Discourse on Education: Interpretation, Impact, and Resistance

This article suggests that the most serious threat posed to contemporary education is the deleterious impact that market economy policies have on current curriculum theory and development. It explores the market economy discourse on education that emerges internationally from the Organization for Economic Cooperation and Development (OECD), and domestically from private institutions such as the Conference Board of Canada (CBOC) and public ministries such as Industry Canada. These various organizations promote the market economy discourse on education by framing discussions on curriculum policy between government and business interests. By referring to the primary sources of the market economy discourse on education, then, this article draws attention to the global economic vision currently shaping Canadian schools and explores its impact on domestic education policy. Further, it proposes a means whereby those teachers holding a less intractable perspective on education might resist the current market economy siege on schools. Ironically, this approach involves using the critical tools appropriated by the market economy discourse on education in a manner entirely unintended and unforeseen by its supporters.Cet article propose que la menace la plus imposante qui plane sur le système éducatif contemporain consiste en l'impact néfaste des politiques d'économie de marché sur la théorie et le développement des programmes scolaires. On y étudie le discours de l'économie de marché sur l'éducation tel qu'il ressort au niveau international de l'Organisation de coopération et de développement économiques (OCDE), au niveau national d'institutions privées comme le Conference Board of Canada (CBOC) et des ministères publics comme Industrie Canada. Ces diverses organisations promeuvent l'application des politiques d'économie de marché sur l'éducation en abordant les discussions sur la politique curriculaire du point de vue des intérêts du gouvernement et des entreprises. En s'appuyant sur les sources primaires du discours d'économie de marché sur l'éducation, cet article fait ressortir la vision économique globale qui dicte actuellement l'orientation des écoles au Canada et étudie l'impact de celle-ci sur les politiques canadiennes sur l'éducation. De plus, l'article propose une façon pour les enseignants dont les perspectives sur l'éducation sont moins arrêtées de résister au siège actuel des écoles par l'économie de marché. Ironiquement, cette technique implique l'utilisation des outils critiques dont s'est approprié le discours d'économie de marché et ce, d'une manière tout à fait inattendue et imprévue par ses adeptes

Principles for Democratic Learning in Career Education

Secondary-level career education, designed to prepare students for their occupational lives, generally adopts a human capital approach to learning. We critique this approach by comparing a range of career-education polices and programs with three key principles for democratic learning. We identify areas that would be enhanced by introducing these principles: avoiding the ahistorical depiction of labour-market and working conditions, expanding current conceptions of lifelong learning, offering students alternative viewpoints on occupationally related issues, respecting moral reasoning in character development, and strengthening critical thinking strategies. L’éducation au choix de carrière au secondaire adopte généralement une approche de l’apprentissage axée sur le capital humain. Les auteurs font la critique de cette approche en comparant un éventail de politiques et de programmes à l’aide de trois principes clés de l’apprentissage démocratique. Ils identifient les aspects qui seraient améliorés par l’introduction de ces principes : la prise en compte du contexte historique dans la description du marché du travail et des conditions de travail, l’élargissement des conceptions actuelles de l’éducation permanente, la diversification des points de vue sur les questions reliées au choix d’une carrière, le respect du raisonnement moral dans le développement du caractère et la consolidation des stratégies en matière de pensée critique.

CRITICAL LITERACY FOR DEMOCRATIC LEARNING IN CAREER EDUCATION

In this article, we explore the models of literacy conveyed by contemporary secondary career education policies, programs, and imperatives in the province of Ontario. The Ontario career education policies we reviewed uniformly advance a functional and socially reproductive model of literacy that undermines the democratic agency of learners. In response to these concerns, we propose that critical literacy should be introduced into Ontario secondary career education initiatives to encourage the democratic participation of students in shaping their vocational experience. Key words: false generosity, critical literacy, democratic learning Dans cet article, les auteurs analysent les modèles de littératie qui ressortent des politiques, programmes et impératifs actuels en matière de formation au choix d’une carrière au secondaire en Ontario. Les politiques ontariennes que les auteurs ont étudiées prônent toutes un modèle de littératie fonctionnel qui privilégie la reproduction sociale, modèle qui entrave l’action démocratique des apprenants. Tenant compte de cette préoccupation, les auteurs proposent l’introduction de la littératie critique dans les initiatives en matière de formation au choix de carrière en vue d’encourager les élèves à participer démocratiquement à leur orientation professionnelle. Mots clés : fausse générosité, littératie critique, apprentissage démocratique