A chemical screen identifies the chemotherapeutic drug topotecan as a specific inhibitor of the B-MYB/MYCN axis in neuroblastoma

The transcription factor MycN is the prototypical neuroblastoma oncogene and a potential therapeutic target. However, its strong expression caused by gene amplification in about 30% of neuroblastoma patients is a considerable obstacle to the development of therapeutic approaches aiming at eliminating its tumourigenic activity. We have previously reported that B-Myb is essentially required for transcription of the MYCN amplicon and have also shown that B-MYB and MYCN are engaged in a feed forward loop promoting the survival/proliferation of neuroblastoma cells. We postulated that pharmacological strategies breaking the B-MYB/MYCN axis should result in clinically desirable effects. Thus, we implemented a high throughput chemical screen, using a curated library of ~1500 compounds from the National Cancer Institute, whose endpoint was the identification of small molecules that inhibited B-Myb. At the end of the screening, we found that the compounds pinafide, ellipticine and camptothecin inhibited B-Myb transcriptional activity in luciferase assays. One of the compounds, the topoisomerase-1 inhibitor camptothecin, is of considerable clinical interest since its derivatives topotecan and irinotecan are currently used as first and second line treatment agents for various types of cancer, including neuroblastoma. We found that neuroblastoma cells with amplification of MYCN are more sensitive than MYCN negative cells to camptothecin and topotecan killing. Campothecin and topotecan caused selective down-regulation of B-Myb and MycN expression in neuroblastoma cells. Notably, forced overexpression of B-Myb could antagonize the killing effect of topotecan and camptothecin, demonstrating that the transcription factor is a key target of the drugs. These results suggest that camptothecin and its analogues should be more effective in patients whose tumours feature amplification of MYCN and/or overexpression of B-MYB

Task-based programming in COMPSs to converge from HPC to big data

Task-based programming has proven to be a suitable model for high-performance computing (HPC) applications. Different implementations have been good demonstrators of this fact and have promoted the acceptance of task-based programming in the OpenMP standard. Furthermore, in recent years, Apache Spark has gained wide popularity in business and research environments as a programming model for addressing emerging big data problems. COMP Superscalar (COMPSs) is a task-based environment that tackles distributed computing (including Clouds) and is a good alternative for a task-based programming model for big data applications. This article describes why we consider that task-based programming models are a good approach for big data applications. The article includes a comparison of Spark and COMPSs in terms of architecture, programming model, and performance. It focuses on the differences that both frameworks have in structural terms, on their programmability interface, and in terms of their efficiency by means of three widely known benchmarking kernels: Wordcount, Kmeans, and Terasort. These kernels enable the evaluation of the more important functionalities of both programming models and analyze different work flows and conditions. The main results achieved from this comparison are (1) COMPSs is able to extract the inherent parallelism from the user code with minimal coding effort as opposed to Spark, which requires the existing algorithms to be adapted and rewritten by explicitly using their predefined functions, (2) it is an improvement in terms of performance when compared with Spark, and (3) COMPSs has shown to scale better than Spark in most cases. Finally, we discuss the advantages and disadvantages of both frameworks, highlighting the differences that make them unique, thereby helping to choose the right framework for each particular objective.This work is supported by the Spanish Government (SEV2015-0493), by the Spanish Ministry of Science and Innovation (contract TIN2015-65316-P), by Generalitat de Catalunya (contracts 2014-SGR-1051 and 2014-SGR-1272). Javier Conejero’s postdoctoral contract is cofinanced by the Ministry of Economy and Competitiveness under the Juan de la Cierva Formación postdoctoral fellowship number FJCI-2015-24651. This work is also supported by the Intel-BSC Exascale Lab. The Human Brain Project receives funding from the EU’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 604102.Peer ReviewedPostprint (author's final draft

Polyphenon E enhances the antitumor immune response in neuroblastoma by inactivating myeloid suppressor cells

This is the author's accepted manuscript. The final published article is available from the link below. Note: In this manuscript as well as in the original published version of this article the word "Polyphenon" was incorrectly spelled in the title as "Polyphenol."Purpose: Neuroblastoma is a rare childhood cancer whose high risk, metastatic form has a dismal outcome in spite of aggressive therapeutic interventions. The toxicity of drug treatments is a major problem in this pediatric setting. In this study, we investigated whether Polyphenon E, a clinical grade mixture of green tea catechins under evaluation in multiple clinical cancer trials run by the National Cancer Institute (Bethesda, MD), has anticancer activity in mouse models of neuroblastoma. Experimental Design: We used three neuroblastoma models: (i) transgenic TH-MYCN mouse developing spontaneous neuroblastomas; (ii) nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenotransplanted with human SHSY5Y cells; and (iii) A/J mice transplanted with syngeneic Neuro 2A cells. Mice were randomized in control and Polyphenon E–drinking groups. Blood from patients with neuroblastoma and normal controls was used to assess the phenotype and function of myeloid cells. Results: Polyphenon E reduced the number of tumor-infiltrating myeloid cells, and inhibited the development of spontaneous neuroblastomas in TH-MYCN transgenic mice. In therapeutic models of neuroblastoma in A/J, but not in immunodeficient NOD/SCID mice, Polyphenon E inhibited tumor growth by acting on myeloid-derived suppressor cells (MDSC) and CD8 T cells. In vitro, Polyphenon E impaired the development and motility of MDSCs and promoted differentiation to more neutrophilic forms through the 67 kDa laminin receptor signaling and induction of granulocyte colony-stimulating factor. The proliferation of T cells infiltrating a patient metastasis was reactivated by Polyphenon E. Conclusions: These findings suggest that the neuroblastoma-promoting activity of MDSCs can be manipulated pharmacologically in vivo and that green tea catechins operate, at least in part, through this mechanism.SPARKS, Research in Childhood Cancer, the CGD Research Trust, and the Wellcome Trust

Guia per treballar la Competència d’Autonomia i Iniciativa Personal

En aquest moment de garbuix educatiu, presentem un escrit que fa referència a la competència d’Autonomia i Iniciativa Personal. La competència d’Autonomia i Iniciativa personal és una competència bàsica on destaca el treball actitudinal i d’autoregulació per part de l’alumnat. És una de les competències de més transversalitat, amb aspectes que s’entrellacen amb les altres competències i en totes les àrees. Es troba estretament lligada a la convivència, els valors i la responsabilitat. Aquests paràmetres fan que sigui complex de poder-la seqüenciar i graduar, tant per al seu desenvolupament com per a la seva avaluació. És una competència relacionada amb les vivències del dia a dia, les relacions personals i socials. Aquests aspectes es creuen: cal conèixer-se a sí mateix per poder conèixer i relacionar-se amb els altres. Gestionar les emocions no es gens fàcil i aprendre-ho encara menys. Però no perquè sigui difícil ho hem d’obviar. De mica en mica aniran sortint formes de treballar-ho, a través d’activitats de vida escolar i extraescolar, parlant-ne, jugant, simulant... Com la resta de competències, aquesta també manifesta una relació molt directa amb la d’aprendre a aprendre i la social i ciutadana. L’article parteix d’una anàlisi de la competència, els elements de fonamentació teòrica, els diferents components que la formen i tracta les metodologies més adients per a assolir-la. L’objectiu principal és suggerir diferents propostes didàctiques (pràctiques) a través de diverses activitats. Es pretén que sigui una guia o ajuda per treballar aquesta competència, partint des del (més general) marc teòric fins al pràctic, de manera gradual, començant des de l’educació infantil (3 anys) i continuant fins al final de l’educació primària (12 anys). També es presenten orientacions per a l’avaluació, amb diferents eines per avaluar i els criteris i indicadors a les activitats exposades. Finalment es proposen orientacions que es poden donar a les famílies per tal que puguin saber quines actuacions solen donar-se en els infants de cada cicle i com poden acompanyar en la vida diària des de casa

Chirality Transfer in a Calixarene-Based Directional Pseudorotaxane Complex

Hexamethoxycalix[6]arene 3 forms a directional pseudorotaxane complex with the chiral axle (S)-(alpha-methyl-benzyl)benzylammonium 2(+). Between the two (endo-chiral)-2(+)@3 and (exo-chiral)-2(+)@3 pseudorotaxane stereoisomers, the former is preferentially formed. This result confirms the validity of the "endo-alpha-methyl-benzyl rule", previously reported by us. DFT calculations suggest that C-H horizontal ellipsis pi interactions between the methyl group of 2(+) and the calixarene aromatic rings, determine the stereoselectivity of the threading process toward the "endo-alpha-methyl-benzyl preference". An amplification of optical rotation is observed upon formation of the pseudorotaxane complex (endo-chiral)-2(+)@3 with respect to free axle 2(+). Thus, the specifical rotation of the 1:1 mixture of chiral 2(+)center dot B(ArF)(4)(-) salt and achiral 3 was augmented upon formation of the pseudorotaxane and DFT calculations were used to rationalize this result