Global MicroRNA Expression Profiling Identifies MiR-210 Associated with Tumor Proliferation, Invasion and Poor Clinical Outcome in Breast Cancer

Aberrant microRNA (miRNA) expression is associated with cancer and has potential diagnostic and prognostic value in various malignancies. In this study, we investigated miRNA profiling as a complementary tool to improve our understanding of breast cancer (BC) biology and to assess whether miRNA expression could predict clinical outcome of BC patients.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Modeling of miRNA and Drug Action in the EGFR Signaling Pathway

MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR) signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs) on this pathway and propose that the embedded miRNA-network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer

Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype

Background: Dicer, a ribonuclease, is the key enzyme required for the biogenesis of microRNAs and small interfering RNAs and is essential for both mammalian development and cell differentiation. Recent evidence indicates that Dicer may also be involved in tumourigenesis. However, no studies have examined the clinical significance of Dicer at both the RNA and the protein levels in breast cancer.Methods: In this study, the biological and prognostic value of Dicer expression was assessed in breast cancer cell lines, breast cancer progression cellular models, and in two well-characterised sets of breast carcinoma samples obtained from patients with long-term follow-up using tissue microarrays and quantitative reverse transcription-PCR.Results: We have found that Dicer protein expression is significantly associated with hormone receptor status and cancer subtype in breast tumours (ER P=0.008; PR P=0.019; cancer subtype P=0.023, luminal A P=0.0174). Dicer mRNA expression appeared to have an independent prognostic impact in metastatic disease (hazard ratio=3.36, P=0.0032). In the breast cancer cell lines, lower Dicer expression was found in cells harbouring a mesenchymal phenotype and in metastatic bone derivatives of a breast cancer cell line. These findings suggest that the downregulation of Dicer expression may be related to the metastatic spread of tumours.Conclusion: Assessment of Dicer expression may facilitate prediction of distant metastases for patients suffering from breast cancer

Breast Cancer Epigenetics: From DNA Methylation to microRNAs

Both appropriate DNA methylation and histone modifications play a crucial role in the maintenance of normal cell function and cellular identity. In cancerous cells these “epigenetic belts” become massively perturbed, leading to significant changes in expression profiles which confer advantage to the development of a malignant phenotype. DNA (cytosine-5)-methyltransferase 1 (Dnmt1), Dnmt3a and Dnmt3b are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells. Intriguingly, DNMTs were found to be overexpressed in cancerous cells, which is believed to partly explain the hypermethylation phenomenon commonly observed in tumors. However, several lines of evidence indicate that further layers of gene regulation are critical coordinators of DNMT expression, catalytic activity and target specificity. Splice variants of DNMT transcripts have been detected which seem to modulate methyltransferase activity. Also, the DNMT mRNA 3′UTR as well as the coding sequence harbors multiple binding sites for trans-acting factors guiding post-transcriptional regulation and transcript stabilization. Moreover, microRNAs targeting DNMT transcripts have recently been discovered in normal cells, yet expression of these microRNAs was found to be diminished in breast cancer tissues. In this review we summarize the current knowledge on mechanisms which potentially lead to the establishment of a DNA hypermethylome in cancer cells

Operating a full tungsten actively cooled tokamak: overview of WEST first phase of operation

WEST is an MA class superconducting, actively cooled, full tungsten (W) tokamak, designed to operate in long pulses up to 1000 s. In support of ITER operation and DEMO conceptual activities, key missions of WEST are: (i) qualification of high heat flux plasma-facing components in integrating both technological and physics aspects in relevant heat and particle exhaust conditions, particularly for the tungsten monoblocks foreseen in ITER divertor; (ii) integrated steady-state operation at high confinement, with a focus on power exhaust issues. During the phase 1 of operation (2017–2020), a set of actively cooled ITER-grade plasma facing unit prototypes was integrated into the inertially cooled W coated startup lower divertor. Up to 8.8 MW of RF power has been coupled to the plasma and divertor heat flux of up to 6 MW m−2 were reached. Long pulse operation was started, using the upper actively cooled divertor, with a discharge of about 1 min achieved. This paper gives an overview of the results achieved in phase 1. Perspectives for phase 2, operating with the full capability of the device with the complete ITER-grade actively cooled lower divertor, are also described

Experimental confirmation of efficient island divertor operation and successful neoclassical transport optimization in Wendelstein 7-X

We present recent highlights from the most recent operation phases of Wendelstein 7-X, the most advanced stellarator in the world. Stable detachment with good particle exhaust, low impurity content, and energy confinement times exceeding 100 ms, have been maintained for tens of seconds. Pellet fueling allows for plasma phases with reduced ion-temperature-gradient turbulence, and during such phases, the overall confinement is so good (energy confinement times often exceeding 200 ms) that the attained density and temperature profiles would not have been possible in less optimized devices, since they would have had neoclassical transport losses exceeding the heating applied in W7-X. This provides proof that the reduction of neoclassical transport through magnetic field optimization is successful. W7-X plasmas generally show good impurity screening and high plasma purity, but there is evidence of longer impurity confinement times during turbulence-suppressed phases.EC/H2020/633053/EU/Implementation of activities described in the Roadmap to Fusion during Horizon 2020 through a Joint programme of the members of the EUROfusion consortium/ EUROfusio

Maximum Clique in Disk-Like Intersection Graphs

We study the complexity of Maximum Clique in intersection graphs of convex objects in the plane. On the algorithmic side, we extend the polynomial-time algorithm for unit disks [Clark '90, Raghavan and Spinrad '03] to translates of any fixed convex set. We also generalize the efficient polynomial-time approximation scheme (EPTAS) and subexponential algorithm for disks [Bonnet et al. '18, Bonamy et al. '18] to homothets of a fixed centrally symmetric convex set. The main open question on that topic is the complexity of Maximum Clique in disk graphs. It is not known whether this problem is NP-hard. We observe that, so far, all the hardness proofs for Maximum Clique in intersection graph classes I follow the same road. They show that, for every graph G of a large-enough class C, the complement of an even subdivision of G belongs to the intersection class I. Then they conclude by invoking the hardness of Maximum Independent Set on the class C, and the fact that the even subdivision preserves that hardness. However there is a strong evidence that this approach cannot work for disk graphs [Bonnet et al. '18]. We suggest a new approach, based on a problem that we dub Max Interval Permutation Avoidance, which we prove unlikely to have a subexponential-time approximation scheme. We transfer that hardness to Maximum Clique in intersection graphs of objects which can be either half-planes (or unit disks) or axis-parallel rectangles. That problem is not amenable to the previous approach. We hope that a scaled down (merely NP-hard) variant of Max Interval Permutation Avoidance could help making progress on the disk case, for instance by showing the NP-hardness for (convex) pseudo-disks

Maximum Clique in Disk-Like Intersection Graphs

We study the complexity of Maximum Clique in intersection graphs of convex objects in the plane. On the algorithmic side, we extend the polynomial-time algorithm for unit disks [Clark '90, Raghavan and Spinrad '03] to translates of any fixed convex set. We also generalize the efficient polynomial-time approximation scheme (EPTAS) and subexponential algorithm for disks [Bonnet et al. '18, Bonamy et al. '18] to homothets of a fixed centrally symmetric convex set. The main open question on that topic is the complexity of Maximum Clique in disk graphs. It is not known whether this problem is NP-hard. We observe that, so far, all the hardness proofs for Maximum Clique in intersection graph classes I follow the same road. They show that, for every graph G of a large-enough class C, the complement of an even subdivision of G belongs to the intersection class I. Then they conclude by invoking the hardness of Maximum Independent Set on the class C, and the fact that the even subdivision preserves that hardness. However there is a strong evidence that this approach cannot work for disk graphs [Bonnet et al. '18]. We suggest a new approach, based on a problem that we dub Max Interval Permutation Avoidance, which we prove unlikely to have a subexponential-time approximation scheme. We transfer that hardness to Maximum Clique in intersection graphs of objects which can be either half-planes (or unit disks) or axis-parallel rectangles. That problem is not amenable to the previous approach. We hope that a scaled down (merely NP-hard) variant of Max Interval Permutation Avoidance could help making progress on the disk case, for instance by showing the NP-hardness for (convex) pseudo-disks