Towards Sustainable Development and Green Economy in European Union

Sustainable development is suggested by environmentalists as the solution for confronting the intense environmental, social and economic problems that emerge globally in the last decades. This study presents the recent features and trends of the associated concepts, like the green economy, green entrepreneurship, green professions and labour-market, with a particular reference to European Union countries. In the course of transforming the current economic model towards a green direction, vocational education appears as a fundamental prerequisite that will prepare the future workforce of green economy. In this respect, a small-scale research is also presented, recording the relevant opinions of senior high-school students in Western Attica (Greece), being an area of acute environmental, social and economic problems

Determining the Opinions of Pupils on Space Professions

The purpose of this study was to plan educational interventions for informing the school population of Western Attica (Greece), an area with acute social and environmental problems (unemployment and natural disasters), about Space professions and their career perspectives. Accordingly, a questionnaire for determining the opinions of senior high-school pupils on the related issues had been designed and used for conducting a limited preliminary survey, to evaluate the entire process. This survey indicated that pupils are not aware of the related career prospects. The recording of the opinions about Space professions revealed that they are strongly associated with the profession of astronaut, although there are many more that can contribute to social welfare and environmental protection. Therefore, an educational intervention should be planned around three main points; these of presenting: Space professions, available career options and motives for pursuing them

Cell-selective labeling using amino acid precursors for proteomic studies of multicellular environments.

We report a technique to selectively and continuously label the proteomes of individual cell types in coculture, named cell type-specific labeling using amino acid precursors (CTAP). Through transgenic expression of exogenous amino acid biosynthesis enzymes, vertebrate cells overcome their dependence on supplemented essential amino acids and can be selectively labeled through metabolic incorporation of amino acids produced from heavy isotope-labeled precursors. When testing CTAP in several human and mouse cell lines, we could differentially label the proteomes of distinct cell populations in coculture and determine the relative expression of proteins by quantitative mass spectrometry. In addition, using CTAP we identified the cell of origin of extracellular proteins secreted from cells in coculture. We believe that this method, which allows linking of proteins to their cell source, will be useful in studies of cell-cell communication and potentially for discovery of biomarkers

Graded Smad2/3 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells

The Transforming Growth Factor (TGF) β signalling family includes morphogens, such as Nodal and Activin, with important functions in vertebrate development. The concentration of the morphogen is critical for fate decisions in the responding cells. Smad2 and Smad3 are effectors of the Nodal/Activin branch of TGFβ signalling: they are activated by receptors, enter the nucleus and directly transcribe target genes. However, there have been no studies correlating levels of Smad2/3 activation with expression patterns of endogenous target genes in a developmental context over time. We used mouse Embryonic Stem (ES) cells to create a system whereby levels of activated Smad2/3 can be manipulated by an inducible constitutively active receptor (Alk4*) and an inhibitor (SB-431542) that blocks specifically Smad2/3 activation. The transcriptional responses were analysed by microarrays at different time points during activation and repression. We identified several genes that follow faithfully and reproducibly the Smad2/3 activation profile. Twenty-seven of these were novel and expressed in the early embryo downstream of Smad2/3 signalling. As they responded to Smad2/3 activation in the absence of protein synthesis, they were considered direct. These immediate responsive genes included negative intracellular feedback factors, like SnoN and I-Smad7, which inhibit the transcriptional activity of Smad2/3. However, their activation did not lead to subsequent repression of target genes over time, suggesting that this type of feedback is inefficient in ES cells or it is counteracted by mechanisms such as ubiquitin-mediated degradation by Arkadia. Here we present an ES cell system along with a database containing the expression profile of thousands of genes downstream of Smad2/3 activation patterns, in the presence or absence of protein synthesis. Furthermore, we identify primary target genes that follow proportionately and with high sensitivity changes in Smad2/3 levels over 15–30 hours. The above system and resource provide tools to study morphogen function in development

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential

Functional analysis of DEF6 and def8 revealed DEF6 as a novel activator of Rac, Cdc42 and Rho GTPases regulating cell morphology

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Collateral loss of MTAP in CDKN2A deleted cancers leads to selective dependence on PRMT5

CDKN2A is frequently deleted in a wide array of human cancers, the majority of which respond poorly to current standard therapies 1-3. Despite this, no therapeutic approaches that selectively target CDNK2A deleted cancers have been identified to date. MTAP is a gene that resides proximal to CDKN2A on chromosome 9p21 and as a result is frequently co-deleted in several cancer types with high unmet medical need. By screening an epigenome-targeted deep coverage shRNA library across a large panel of cell lines from the CCLE 4, we find that the collateral loss of MTAP in CDKN2A deleted tumors leads to increased sensitivity to inhibition of the arginine methyltransferase PRMT5. MTAP is an enzyme in the methionine salvage pathway, and its loss leads to the accumulation of the metabolic byproduct MTA 5-7. Surprisingly, we found that MTA selectively inhibits the catalytic activity of PRMT5 but not other histone methyltransferases. Knockout of MTAP in an MTAP-proficient cell line led to increased MTA levels and rendered them sensitive to PRMT5 depletion. Moreover, reconstitution of MTAP in an MTAP-deficient cell line fully rescued PRMT5 dependence. Collectively, these findings indicate that the collateral loss of MTAP in CDNK2A deleted cancers leads to a hypomorphic PRMT5 state, due to MTA accumulation, that is sensitized towards further PRMT5 inhibition. Intriguingly, although the catalytic activity of PRMT5 is required for this effect, a highly potent SAM-cooperative PRMT5 catalytic inhibitor failed to recapitulate the differential growth inhibition observed by RNAi or by MTA itself. These findings suggest that PRMT5 inhibitors that phenocopy MTA will be required to best exploit the hypomorphic PRMT5 state in cancers with MTAP loss, and present an attractive therapeutic strategy for the wide spectrum of CDKN2A/MTAP deficient tumors

MicroRNAs Mediate Resistance to Tyrosine Kinase Inhibitors in Philadelphia-Positive B-ALL by Down-Regulating Key Tumor Suppressors

Abstract Abstract 2553 The Philadelphia (Ph) chromosome (t(9;22)(q34;q11)) is the most common recurrent cytogenetic abnormality in adult B-cell acute lymphoblastic leukemia (B-ALL). Resulting expression of the BCR-ABL fusion gene product, a constitutively active tyrosine kinase, leads to an extremely poor prognosis when the disease is treated with chemotherapy alone. In recent years targeted therapy with tyrosine kinase inhibitors (TKIs) in combination with chemotherapy has improved outcomes. Therapeutic resistance remains a major clinical problem, however, with less than half of patients surviving three years from initial therapy in most series even with up-front TKI-chemotherapy regimens. TKI resistance in B-ALL may result from acquired mutations of the BRC-ABL protein or from BCR-ABL-independent causes, including feedback activation of BCL6 or activation of other oncogenic signaling pathways through poorly understood mechanisms. In this study, we screened a whole-genome library of microRNAs for ability to produce resistance to TKI therapy in murine pro-B cells transformed with BCR-ABL. Several initial candidates from the screen were individually confirmed to confer TKI resistance, including miR 148/152 and 19, known oncomirs in T-ALL. Computational analysis of the gene targets of validated miRs shows significant overlap at several tumor-suppressor pathways, including down-regulation of PTEN, a known mechanism of TKI resistance in Ph+ B-ALL cell lines. In sum, we have identified a novel mechanism of TKI resistance in Ph+ B-ALL mediated by miRs and leading to down-regulation of specific tumor suppressive intermediates. These findings will allow development of new therapeutic combinations to improve outcomes for B-ALL patients. Disclosures: No relevant conflicts of interest to declare

Mouse models of cancer as biological filters for complex genomic data

Genetically and pathologically accurate mouse models of leukemia and lymphoma have been developed in recent years. Adoptive transfer of genetically modified hematopoietic progenitor cells enables rapid and highly controlled gain- and loss-of-function studies for these types of cancer. In this Commentary, we discuss how these highly versatile experimental approaches can be used as biological filters to pinpoint transformation-relevant activities from complex cancer genome data. We anticipate that the functional identification of genetic ‘drivers’ using mouse models of leukemia and lymphoma will facilitate the development of molecular diagnostics and mechanism-based therapies for patients that suffer from these diseases