Integrated signaling and transcriptome analysis reveals Src family kinase individualities and novel pathways controlled by their constitutive activity

The Src family kinases (SFKs) Lck and Lyn are crucial for lymphocyte development and function. Albeit tissue-restricted expression patterns the two kinases share common functions; the most pronounced one being the phosphorylation of ITAM motifs in the cytoplasmic tails of antigenic receptors. Lck is predominantly expressed in T lymphocytes; however, it can be ectopically found in B-1 cell subsets and numerous pathologies including acute and chronic B-cell leukemias. The exact impact of Lck on the B-cell signaling apparatus remains enigmatic and is followed by the long-lasting question of mechanisms granting selectivity among SFK members. In this work we sought to investigate the mechanistic basis of ectopic Lck function in B-cells and compare it to events elicited by the predominant B-cell SFK, Lyn. Our results reveal substrate promiscuity displayed by the two SFKs, which however, is buffered by their differential susceptibility toward regulatory mechanisms, revealing a so far unappreciated aspect of SFK member-specific fine-tuning. Furthermore, we show that Lck- and Lyn-generated signals suffice to induce transcriptome alterations, reminiscent of B-cell activation, in the absence of receptor/co-receptor engagement. Finally, our analyses revealed a yet unrecognized role of SFKs in tipping the balance of cellular stress responses, by promoting the onset of ER-phagy, an as yet completely uncharacterized process in B lymphocytes

HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy

<p>Abstract</p> <p>Background</p> <p>HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.</p> <p>Methods</p> <p>In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).</p> <p>Results</p> <p>HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.</p> <p>Conclusions</p> <p>This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ACTRN12611000506998">ACTRN12611000506998</a>.</p

Educational resources and digital repositories of open access : an alternative educational method of information access

The European Union after Lisbon summit turned to a digital economy based on knowledge, technologically developed accompanying with relevant goods and services, an alternative economy that will be an imperative power concerning economic evolution, competitiveness and creation of new working positions. This masters thesis is trying to present digital repositories of open access and their principles/values on which are consisted. In addition, this thesis displays several initiatives of open access as well as Budapest Open Access Initiative. However, while the case study of Greece regarding digital repositories of open access and their current circumstances will be also represented. Taking everything into consideration, this masters thesis attempts to present current evolution and long-term targets as regards education repositories of open access its digital environment on-going evolution.151 page(s

The copyright law framework and its interaction with open access repositories in Europe

The paper examines the European copyright framework and its interaction with open access repositories. Access to information resources has become a modern necessity that needs to be met to share equitably the wealth of the European society. The Directives with intellectual property provisions to enhance copyright law policy makers are the foundation of the European copyright regime. This statement helps me to clarify the design and assumptions underlying open access practice in Europe. The paper analyses strengths and short-comings of these Directives in relation to copyright protection and open access practice among European member states

The evolving role of commercial publishers and the future of Open Access Repositories : the potential of corporate social responsibility

Περιέχει το πλήρες κείμενοSince the modes of publishing content have changed in the digital age, Open Access (OA) practice could be an effective response towards the challenges generated by the ongoing technological advancements. It could respond to the competing concerns of copyright protection and equitable access to information, simultaneously. The paper analyzes the interconnections between commercial publishers’ and authors’ interest and argue that Open Access Repositories could be considered as an instrument towards common benefits. In the context of continuous technological growth OA could be also seen as an alternative instrument for the protection of intellectual property to facilitate modern or digital publishing and benefit publisher and intellectual creator, as well. Traditionally, commercial publishers are ‘gatekeepers’ of the standards of merit of academic works even though they get almost all of the profits. However, while they rely on academics’ expertise to remain commercially viable they do not pay for this expertise, appropriately. In contemporary days it is feasible for authors to not rely on commercial publishers. It is therefore in the interests of commercial publishers that academics keep publishing with them. As gatekeepers of standards of merit they can benefit the academic world and remain viable themselves. This claim will be substantiated with examples of relevant licensing forms and other initiatives of OA

Building equitable access to knowledge through open access repositories

Featuring coverage on a broad range of topics such as copyright protection, social justice, and European Copyright Framework, this book is ideally designed for researchers, scientists, policymakers, librarians, IT specialists, authors, ..