Search

Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application. Significance: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501

While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress. Moreover, this C/EBPα-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application.SIGNIFICANCEThe transcription factor C/EBPα is as a master regulator of normal and leukemic myeloid differentiation. Here, we discovered that C/EBPα regulates fatty acid biosynthesis and metabolic adaptation to redox imbalance in leukemic cells. This confers a vulnerability to lipid oxidative stress to FLT3-mutant cells and supports novel therapeutic opportunities for patients.

The role of RNA modifications in biological processes has been the focus of an increasing number of studies in the last few years and is known nowadays as epitranscriptomics. Among others, N6-methyladenosine (m

The study of RNA modifications, today known as epitranscriptomics, is of growing interest. The N6-methyladenosine (m6A) and 5-methylcytosine (m5C) RNA modifications are abundantly present on mRNA molecules, and impact RNA interactions with other proteins or molecules, thereby affecting cellular processes, such as RNA splicing, export, stability, and translation. Recently m6A and m5C marks were found to be present on human immunodeficiency (HIV) transcripts as well and affect viral replication. Therefore, the discovery of RNA methylation provides a new layer of regulation of HIV expression and replication, and thus offers novel array of opportunities to inhibit replication. However, no study has been performed to date to investigate the impact of HIV replication on the transcript methylation level in the infected cell. We used a productive HIV infection model, consisting of the CD4+ SupT1 T cell line infected with a VSV-G pseudotyped HIVeGFP-based vector, to explore the temporal landscape of m6A and m5C epitranscriptomic marks upon HIV infection, and to compare it to mock-treated cells. Cells were collected at 12, 24, and 36 h post-infection for mRNA extraction and FACS analysis. M6A RNA modifications were investigated by methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-Seq). M5C RNA modifications were investigated using a bisulfite conversion approach followed by high-throughput sequencing (BS-Seq). Our data suggest that HIV infection impacted the methylation landscape of HIV-infected cells, inducing mostly increased methylation of cellular transcripts upon infection. Indeed, differential methylation (DM) analysis identified 59 m6A hypermethylated and only 2 hypomethylated transcripts and 14 m5C hypermethylated transcripts and 7 hypomethylated ones. All data and analyses are also freely accessible on an interactive web resource (http://sib-pc17.unil.ch/HIVmain.html). Furthermore, both m6A and m5C methylations were detected on viral transcripts and viral particle RNA genomes, as previously described, but additional patterns were identified. This work used differential epitranscriptomic analysis to identify novel players involved in HIV life cycle, thereby providing innovative opportunities for HIV regulation.

Metastases and tumor recurrence have a major prognostic impact in head and neck squamous cell carcinoma (HNSCC); however, cellular models that comprehensively characterize metastatic and recurrent HNSCC are lacking. To this end, we obtained genomic, transcriptomic, and copy number profiles of the UM-SCC cell line panel, encompassing patient-matched metastatic and recurrent cells. UM-SCC cells recapitulate the most prevalent genomic alterations described in HNSCC, featuring common TP53, PI3K, NOTCH, and Hippo pathway mutations. This analysis identified a novel F977Y kinase domain PIK3CA mutation exclusively present in a recurrent cell line (UM-SCC14B), potentially conferring resistance to PI3K inhibitors. Small proline-rich protein 2A (SPRR2A), a protein involved in epithelial homeostasis and invasion, was one of the most consistently downregulated transcripts in metastatic and recurrent UM-SCC cells. Assessment of SPRR2A protein expression in a clinical cohort of patients with HNSCC confirmed common SPRR2A downregulation in primary tumors (61.9% of cases) and lymph node metastases (31.3%), but not in normal tissue. High expression of SPRR2A in lymph node metastases was, along with nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence after surgery and radiotherapy (HR 2.81; 95% CI, 1.16–6.79; P = 0.02). These results suggest that SPRR2A plays a dual role in invasion and therapeutic resistance in HNSCC, respectively through its downregulation and overexpression. Implications: The current study reveals translationally relevant mechanisms underlying metastasis and recurrence in HNSCC and represents an adjuvant tool for preclinical research in this disease setting. Underlining its discovery potential this approach identified a PIK3CA-resistant mutation as well as SPRR2A as possible theragnostic markers.

The study of RNA modifications, today known as epitranscriptomics, is of growing interest. The N6-methyladenosine (m6A) and 5-methylcytosine (m5C) RNA modifications are abundantly present on mRNA molecules, and impact RNA interactions with other proteins or molecules, thereby affecting cellular processes, such as RNA splicing, export, stability and translation. Recently m6A and m5C marks were found to be present on human immunodeficiency (HIV) transcripts as well and affect viral replication. Therefore, the discovery of RNA methylation provides a new layer of regulation of HIV expression and replication, and thus offers novel array of opportunities to inhibit replication. However, no study has been performed to date to investigate the impact of HIV replication on the transcript methylation level in the infected cell. We used a productive HIV infection model, consisting of the CD4+ SupT1 T cell line infected with a VSV-G pseudotyped HIVeGFP-based vector, to explore the temporal landscape of m6A and m5C epitranscriptomic marks upon HIV infection, and compare it to mock-treated cells. Cells were collected at 12, 24 and 36h post-infection for mRNA extraction and FACS analysis. M6A RNA modifications were investigated by methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-Seq). M5C RNA modifications were investigated using a bisulfite conversion approach followed by high-throughput sequencing (BS-Seq).Our data suggest that HIV Infection impacted the methylation landscape of HIV-infected cells, inducing mostly increased methylation of cellular transcripts upon infection. Indeed, differential methylation (DM) analysis identified 59 m6A hypermethylated and only 2 hypomethylated transcripts and 14 m5C hypermethylated transcripts and 7 hypomethylated ones. All data and analyses are also freely accessible on an interactive web resource (http://sib-pc17.unil.ch/HIVmain.html). Furthermore, both m6A and m5C methylations were detected on viral transcripts and viral particle RNA genomes, as previously described, but additional patterns were identified.This work used differential epitranscriptomic analysis to identify novel players involved in HIV life cycle, thereby providing innovative opportunities for HIV regulation.

This paper presents the current state of the global gyrokinetic code ORB5 as an update of the previous reference [Jolliet et al., Comp. Phys. Commun. 177 409 (2007)]. The ORB5 code solves the electromagnetic Vlasov-Maxwell system of equations using a PIC scheme and also includes collisions and strong flows. The code assumes multiple gyrokinetic ion species at all wavelengths for the polarization density and drift-kinetic electrons. Variants of the physical model can be selected for electrons such as assuming an adiabatic response or a ``hybrid'' model in which passing electrons are assumed adiabatic and trapped electrons are drift-kinetic. A Fourier filter as well as various control variates and noise reduction techniques enable simulations with good signal-to-noise ratios at a limited numerical cost. They are completed with different momentum and zonal flow-conserving heat sources allowing for temperature-gradient and flux-driven simulations. The code, which runs on both CPUs and GPUs, is well benchmarked against other similar codes and analytical predictions, and shows good scalability up to thousands of nodes.

Simple Summary Unfortunately, not all patients with urothelial cancer benefit from checkpoint inhibitors (ICIs). Currently, the first radiological response evaluation is not performed until after 9 to 12 weeks of ICI therapy. Early response biomarkers might enable an early switch to more effective therapies in patients that do not respond. In this study, we aimed to identify early response biomarkers in the blood of patients treated with ICIs. In whole blood of patients with clinical benefit, genes involved in DNA replication and cell cycle regulation were upregulated after 2 to 6 weeks of treatment. This appeared to be a result of T cell proliferation and was not observed in patients without clinical benefit. Our results suggest that whole blood RNA sequencing can contribute to early response prediction in patients treated with ICIs and warrants further research. Abstract Although immune checkpoint inhibitors improve median overall survival in patients with metastatic urothelial cancer (mUC), only a minority of patients benefit from it. Early blood-based response biomarkers may provide a reliable way to assess response weeks before imaging is available, enabling an early switch to other therapies. We conducted an exploratory study aimed at the identification of early markers of response to anti-PD-1 in patients with mUC. Whole blood RNA sequencing and phenotyping of peripheral blood mononuclear cells were performed on samples of 26 patients obtained before and after 2 to 6 weeks of anti-PD-1. Between baseline and on-treatment samples of patients with clinical benefit, 51 differentially expressed genes (DEGs) were identified, of which 37 were upregulated during treatment. Among the upregulated genes was PDCD1, the gene encoding PD-1. STRING network analysis revealed a cluster of five interconnected DEGs which were all involved in DNA replication or cell cycle regulation. We hypothesized that the upregulation of DNA replication/cell cycle genes is a result of T cell proliferation and we were able to detect an increase in Ki-67+ CD8+ T cells in patients with clinical benefit (median increase: 1.65%, range −0.63 to 7.06%, p = 0.012). In patients without clinical benefit, no DEGs were identified and no increase in Ki-67+ CD8+ T cells was observed. In conclusion, whole blood transcriptome profiling identified early changes in DNA replication and cell cycle regulation genes as markers of clinical benefit to anti-PD-1 in patients with urothelial cancer. Although promising, our findings require further validation before implementation in the clinic.

Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent CTNNB1 mutations, hepatoblastoma is a Wnt/β-catenin-driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma. First, we demonstrated that glucose transporter GLUT3 is a direct TCF4/β-catenin target gene. RNA sequencing enabled to identify molecular and metabolic features specific to hepatoblastoma and revealed that several glycolytic enzymes are overexpressed in embryonal-like compared to fetal-like tumor cells. This led us to implement successfully three biomarkers to distinguish embryonal from fetal components by immunohistochemistry from a large panel of human hepatoblastoma samples. Functional analyses demonstrated that embryonal-like hepatoblastoma cells are highly glycolytic and sensitive to hexokinase-1 silencing. Altogether, our findings reveal a new, metabolic classification of human hepatoblastoma, with potential future implications for patients' diagnosis and treatment.

Activation of cancer-associated fibroblasts (CAFs) promotes tumorigenesis. Kim et al. show that ATF3 and CSL converge in negative regulation of CAF activation through long-distance chromatin control. Bromodomain and extra-terminal (BET) inhibitors counteract the effects of ATF3 and CSL loss in CAF activation and cancer–stromal cell expansion., Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes. Consistent with this mode of regulation, deletion of one such site 2 Mb upstream of IL6 induces expression of the gene. Observed changes are of translational significance, as bromodomain and extra-terminal (BET) inhibitors, unlinking activated chromatin from basic transcription, counteract the effects of ATF3 or CSL loss on global gene expression and suppress CAF tumor-promoting properties in an in vivo model of squamous cancer–stromal cell expansion. Thus, ATF3 converges with CSL in negative control of CAF activation with epigenetic changes amenable to cancer- and stroma-focused intervention.

Loss of epithelial differentiation and extracellular matrix (ECM) remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. We have identified Receptor-interacting serine/threonine protein kinase 4 (RIP4) as a regulator of tumor differentiation in lung adenocarcinoma (AC). Bioinformatics analyses of human lung AC samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival. In vitro, lung tumor cells expressing reduced RIP4 levels showed enhanced activation of STAT3 signaling and had a greater ability to invade through collagen. In contrast, overexpression of RIP4 inhibited STAT3 activation, which abrogated interleukin-6-dependent induction of lysyl oxidase, a collagen cross-linking enzyme. In an autochthonous mouse model of lung AC initiated by Kras(G12D) expression with loss of p53, Rip4 knockdown tumors progressed to a poorly differentiated state marked by an increase in Hmga2, reduced Ttf1, and enrichment of genes regulating extracellular remodeling and Jak-Stat signaling. Tail vein injections of cells overexpressing Rip4 showed a reduced potential to invade and form tumors, which was restored by co-expression of Stat3. Altogether, our work has identified that loss of RIP4 enhances STAT3 signaling in lung cancer cells, promoting the expression of ECM remodeling genes and cancer dedifferentiation.

We present a model-based method, designated Inverse Metabolic Control Analysis (IMCA), which can be used in conjunction with classical Metabolic Control Analysis for the analysis and design of cellular metabolism. We demonstrate the capabilities of the method by first developing a comprehensively cu rated kinetic model of sphingolipid biosynthesis in the yeast Saccharomyces cerevisiae. Next we apply IMCA using the model and integrating lipidomics data. The combinatorial complexity of the synthesis of sphingolipid molecules, along with the operational complexity of the participating enzymes of the pathway, presents an excellent case study for testing the capabilities of the IMCA. The exceptional agreement of the predictions of the method with genome-wide data highlights the importance and value of a comprehensive and consistent engineering approach for the development of such methods and models. Based on the analysis, we identified the class of enzymes regulating the distribution of sphin-golipids among species and hydroxylation states, with the D-phospholipase SP014 being one of the most prominent. The method and the applications presented here can be used for a broader, model-based inverse metabolic engineering approach. (C) 2016 The Authors. Published by Elsevier Inc. On behalf of International Metabolic Engineering Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nci/4.0/).

The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells.

Background Colorectal Cancer (CRC) is the second leading cause of cancer mortality worldwide. An effective and convenient blood test for early detection of CRC is urgently needed to increase screening compliance and reduce mortality. The development of a new blood test for early CRC detection was initiated that leverage the transcriptome analysis of circulating immune cells (ImmunoTranscriptomics) using artificial intelligence and machine learning tools. Methods To identify new transcriptional biomarkers for CRC and adenoma detections, peripheral blood mononuclear cells (PBMC) transcriptome were analyzed by RNA-sequencing of 561 subjects (300 Caucasians and 261 Asians) enrolled in the DGNP-COL-0310 study (Ciarloni et al., 2016), a multi-centers case-control study. The cohort included 189 subjects with CRC, 115 with advanced adenoma (AA), 39 with other types of cancer (OC) as well as 218 individuals without any colorectal lesions (CON). Several univariate and multivariate methods were applied to the discovery set (n = 282) and results were integrated into a ranking system. Top ranked genes were selected for further validation and algorithm development in an independent set (n = 279). Results A large panel of differentially expressed genes were identified in non-metastatic CRC (I-II-III) and AA compared to CON and OC with significantly high power of discrimination (P-value = 10-13). The novel developed data analytics pipeline was used to analyse the transcriptomic data measurements and the diagnostic accuracy of the new gene signature for CRC, through application of Machine Learning (ML) and bootstrap, was 82% sensitivity and 88% specificity and AUC of 90%. The signature was enriched in genes associated with myeloid cells activation, inflammation and hemostasis, suggesting a key role of the innate immunity in the early response to cancer. Conclusions Mapping the reaction of the immune system to onset of cancer and disease identification through application ML methods is a new approach to ensure an unbiased, genome-wide, unsupervised gene expression analysis for a highly specific biomarker identification. Legal entity responsible for the study Novigenix SA. Funding Novigenix SA. Disclosure S. Hosseinian Ehrensberger: Shareholder / Stockholder / Stock options: Novigenix SA. L. Ciarloni: Shareholder / Stockholder / Stock options: Novigenix. All other authors have declared no conflicts of interest.

In this work, a Fourier solver [B.F. McMillan, S. Jolliet, A. Bottino, P. Angelino, T.M. Tran, L Villard, Comp. Phys. Commun. 181 (2010) 7151 is implemented in the global Eulerian gyrokinetic code GT5D [Y. Idomura, H. Urano, N. Aiba, S. Tokuda, Nucl. Fusion 49 (2009) 0650291 and in the global Particle-In-Cell code ORB5 [S. Jolliet, A. Bottino, P. Angelino, It Hatzky. T.M. Iran, B.F. McMillan, O. Sauter, K. Appert, Y. Idomura, L Villard, Comp. Phys. Commun. 177 (2007) 4091 in order to reduce the memory of the matrix associated with the field equation. This scheme is verified with linear and nonlinear simulations of turbulence. It is demonstrated that the straight-field-line angle is the coordinate that optimizes the Fourier solver, that both linear and nonlinear turbulent states are unaffected by the parallel filtering, and that the k(parallel to) spectrum is independent of plasma size at fixed normalized poloidal wave number. (C) 2011 Elsevier Inc. All rights reserved.

Critical physical issues can be specifically tackled with the global full-f gyrokinetic code GYSELA. Three main results are presented. First, the self-consistent treatment of equilibrium and fluctuations highlights the competition between two compensation mechanisms for the curvature driven vertical charge separation, namely, parallel flow and polarization. The impact of the latter on the turbulent transport is discussed. In the non-linear regime, the benchmark with the Particle-In-Cell code ORB5 looks satisfactory. Second, the transport scaling with p. is found to depend both on p. itself and on the distance to the linear threshold. Finally, a statistical steady-state turbulent regime is achieved in a reduced version of GYSELA by prescribing a constant heat source.

A global plasma turbulence simulation code, ORB5, is presented. It solves the gyrokinetic electrostatic equations including zonal flows in axisymmetric magnetic geometry. The present version of the code assumes a Boltzmann electron response on magnetic surfaces. It uses a Particle-In-Cell (PIC), delta f scheme, 3D cubic B-splines finite elements for the field solver and several numerical noise reduction techniques. A particular feature is the use of straight-field-1 line magnetic coordinates and a field-aligned Fourier filtering technique that dramatically improves the performance of the code in terms of both the numerical noise reduction and the maximum time step allowed. Another feature is the capability to treat arbitrary axisymmetric ideal MHD equilibrium configurations. The code is heavily parallelized, with scalability demonstrated up to 4096 processors and 109 marker particles. Various numerical convergence tests are performed. The code is validated against an analytical theory of zonal flow residual, geodesic acoustic oscillations and damping, and against other codes for a selection of linear and nonlinear tests. (c) 2007 Elsevier B.V. All rights reserved.

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use -- https://www.nature.com/authors/policies/license.html#terms Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMS) with distinguishing features: CMS1 (MSI Immune, 14%), hypermutated, microsatellite unstable, strong immune activation; CMS2 (Canonical, 37%), epithelial, chromosomally unstable, marked WNT and MYC signaling activation; CMS3 (Metabolic, 13%), epithelial, evident metabolic dysregulation; and CMS4 (Mesenchymal, 23%), prominent transforming growth factor β activation, stromal invasion, and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intra-tumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC - with clear biological interpretability - and the basis for future clinical stratification and subtype-based targeted interventions.

It is now widely believed that low frequency turbulence developing from smallscale instabilities is responsible for the phenomenon of anomalous transport generally observed in magnetic confinement fusion experiments. The microinstabilities are driven by gradients of equilibrium density, ion and electron temperatures and magnetic field strength. Gyrokinetic theory is based on the Vlasov-Maxwell equations and, consistent with the ordering, averages out the fast particle gyromotion, reducing the phase space from 6 to 5 dimensions. Solving the resulting equations is a non-trivial task. Difficulties are associated with the magnetic confinement geometry, the strong disparities in space and time scales perpendicular and parallel to B, the different time scales of ion and electron dynamics, and the complex nonlinear behaviour of the system. The main numerical methods are briefly presented together with some recent developments and improvements to the basic algorithms. Recent results are shown, with emphasis on the roles of zonal E x B flows, of parallel nonlinearity and of toroidal coupling on the saturation of ion temperature gradient (ITG) driven turbulence in tokamaks.

Linear, fully gyrokinetic, full radius (global), large aspect ratio studies of Alfven-ion temperature gradient mode (AITG) or kinetic ballooning modes or beta-induced Alfven eigenmodes considering only "passing" species is presented. Effects hitherto completely neglected in a full radius approach such as B-parallel to-fluctuations and the ones which have been treated partly [Phys. Plasmas 10, 1424 (2003)] such as Shafranov shifts are included. To this end, an existing code EM-GLOGYSTO has been upgraded to incorporate these effects. Among others, the most interesting results include: (i) For relatively large positive magnetic shear (s) over cap [1.25

Flux-driven global gyrokinetic codes are now mature enough to make predictions in terms of turbulence and transport in tokamak plasmas. Some of the recent breakthroughs of three such codes, namely GYSELA, ORB5 and XGC1, are reported and compared wherever appropriate. In all three codes, turbulent transport appears to be mediated by avalanche-like events, for a broad range of ρ* = ρi/a values, ratio of the gyro-radius over the minor radius. Still, the radial correlation length scales with ρi, leading to the gyro-Bohm scaling of the effective transport coefficient below ρ* ≈ 1/300. The possible explanation could be due to the fact that avalanches remain meso-scale due to the interaction with zonal flows, whose characteristic radial wavelength appears to be almost independent of the system size. As a result of the radial corrugation of the turbulence driven zonal and mean flows, the shear of the radial electric field can be significantly underestimated if poloidal rotation is assumed to be governed by the neoclassical theory, especially at low collisionality. Indeed, the turbulence contribution to the poloidal rotation increases when collisionality decreases. Finally, the numerical verification of toroidal momentum balance shows that both neoclassical and turbulent contributions to the Reynolds' stress tensor play the dominant role. The phase space analysis further reveals that barely passing supra-thermal particles mostly contribute to the toroidal flow generation, consistently with quasi-linear predictions.

Fluctuating quantities in magnetic confinement geometries often inherit a strong anisotropy along the field lines. One technique for describing these structures is the use of a certain set of Fourier components on the tori of nested flux surfaces. We describe an implementation of this approach for solving partial differential equations, like Poisson's equation, where a different set of Fourier components may be chosen on each surface according to the changing safety factor profile. Allowing the resolved components to change to follow the anisotropy significantly reduces the total number of degrees of freedom in the description. This can permit large gains in computational performance. We describe, in particular, how this approach can be applied to rapidly solve the gyrokinetic Poisson equation in a particle code, ORB5 (Jolliet et al., (2007) [5]), with a regular (non-field-aligned) mesh. (C) 2009 Published by Elsevier B.V.

The main results of the Tore Supra experimental programme in the years 2007–2008 are reported. They document significant progress achieved in the domain of steady-state tokamak research, as well as in more general issues relevant for ITER and for fusion physics research. Three areas are covered: ITER relevant technology developments and tests in a real machine environment, tokamak operational issues for high power and long pulses, and fusion plasma physics. Results presented in this paper include test and validation of a new, load-resilient concept of ion cycotron resonance heating antenna and of an inspection robot operated under ultra-high vacuum and high temperature conditions; an extensive experimental campaign (5 h of plasma) aiming at deuterium inventory and carbon migration studies; real-time control of sawteeth by electron cyclotron current drive in the presence of fast ion tails; ECRH-assisted plasma start-up studies; dimensionless scalings of transport and turbulence; transport experiments using active perturbation methods; resistive and fast-particle driven MHD studies. The potential role of Tore Supra in the worldwide fusion programme before the start of ITER operation is also discussed.

The theoretical study of plasma turbulence is of central importance to fusion research. Experimental evidence indicates that the confinement time results mainly from the turbulent transport of energy, the magnitude of which depends on the turbulent state resulting from nonlinear saturation mechanisms, in particular, the self-generation of coherent macroscopic structures and large scale flows. Plasma geometry has a strong impact on the structure and magnitude of these flows and also modifies the mode linear growth rates. Nonlinear global gyrokinetic simulations in realistic tokamak magnetohydrodynamic equilibria show how plasma shape can control the turbulent transport. Results are best described in terms of an effective temperature gradient. With increasing plasma elongation, the nonlinear critical effective gradient is not modified while the stiffness of transport is decreasing.

Collisionless delta-f gyrokinetic particle-in-cell simulations suffer from the entropy paradox, in which the entropy grows linearly in time while low-order moments are saturated. As a consequence, these simulations do not reach a steady state and are unsuited to make quantitative predictions. A solution to this issue is the introduction of artificial dissipation. The notion of steady state in gyrokinetic simulations is studied by deriving an evolution equation for the fluctuation entropy and applying it to the global collisionless particle-in-cell code ORB5 [S. Jolliet et al., Comput. Phys. Commun. 177, 409 (2007)]. It is shown that a recently implemented noise-control algorithm [B. F. McMillan et al., Phys. Plasmas 15, 052308 (2008)] based on a W-stat provides the necessary dissipation to reach a steady state. The two interesting situations of decaying and driven turbulence are considered. In addition, it is shown that a separate heating algorithm, not based on a W-stat, does not lead to a statistical steady state.

Drift wave turbulence is known to self-organize to form axisymmetric macroscopic flows. The basic mechanism for macroscopic flow generation is called inverse energy cascade. Essentially, it is an energy transfer from the short wavelengths to the long wavelengths in the turbulent spectrum due to nonlinear interactions. A class of macroscopic flows, the poloidally symmetric zonal flows, is widely recognized as a key constituent in nearly all cases and regimes of microturbulence, also because of the realization that zonal flows are a critical agent of self-regulation for turbulent transport. In tokamaks and other toroidal magnetic confinement systems, axisymmetric flows exist in two branches, a zero frequency branch and a finite frequency branch, named Geodesic Acoustic Modes (GAMs). The finite frequency is due to the geodesic curvature of the magnetic field. There is a growing body of evidence that suggests strong GAM activity in most devices. Theoretical investigation of the GAMs is still an open field of ...

In global gyrokinetic simulations it takes a long time for the turbulence to reach a quasisteady state, and quantitative predictions about the quasisteady state turbulence have been difficult to obtain computationally. In particular, global particle-in-cell gyrokinetic simulations have been inefficient for long simulations due to the accumulation of noise. It is demonstrated that a simple Krook operator can effectively control noise; it also introduces an unphysical dissipation, which damps the zonal flows and can significantly affect simulation results even when the relaxation time is very long. However, it is possible to project out the effects of the Krook operator on the zonal flows. This permits noise accumulation to be controlled while preserving the physics of interest; simulations are then run to determine the level of quasisteady state transport and the variation across the ensemble of turbulent dynamics. Convergence is demonstrated both in the number of computational particles and the unphysical relaxation time. © 2008 American Institute of Physics.

International audience; This paper presents the results obtained with a set of gyrokinetic codes based on a semi-Lagrangian scheme. Several physics issues are addressed, namely, the comparison between fluid and kinetic descriptions, the intermittent behaviour of flux driven turbulence and the role of large scale flows in toroidal ITG turbulence. The question of the initialization of full-F simulations is also discussed.

Background: Gene expression-based subtyping is widely accepted as a relevant source of disease stratification. Despite the widespread use, its translational and clinical utility is hampered by discrepant results, likely related to differences in data processing and algorithms applied to diverse patient cohorts, sample preparation methods, and gene expression platforms. In the absence of a clear methodological gold standard to perform such analyses, a more general framework that integrates and compares multiple strategies is needed to define common disease patterns in a principled, unbiased manner. Methods: We formed a consortium of 6 independent experts groups - each with a previously published CRC classifier, ranging from 3 to 6 subtypes - to understand similarities and differences of their subtyping systems. Sage Bionetworks functioned as neutral party to aggregate public and proprietary data (Synapse platform) and perform meta-analysis. Each group applied its CRC subtyping signature to the collection of data sets with gene expression (n = 4,151, predominantly stage II and III). Using the resulting subtype labels, we developed a network-based model and applied a Markov cluster algorithm to detect robust network substructures that would indicate recurring subtype patterns and therefore a consensus subtyping system. Correlative analyses using clinico-pathological, genomic and epigenomic features was performed to robustly characterize the identified subtypes. Results: This analytical framework revealed significant interconnectivity between the six independent classification systems, leading to the identification of four biologically distinct consensus molecular subtypes (CMS) enriched for key pathway traits: CMS1 (MSI Immune), hypermutated, microsatellite unstable, with strong immune activation; CMS2 (Canonical), epithelial, chromosomally unstable, with marked WNT and MYC signaling activation; CMS3 (Metabolic), epithelial, with evident metabolic dysregulation; and CMS4 (Mesenchymal), prominent TGFβ activation, angiogenesis, stromal invasion. Patients diagnosed with MSI Immune tumors had worse survival after relapse and those with mesenchymal tumors had increased risk of metastasis and worse overall survival. Discussion: We describe a novel methodological paradigm for deriving benchmarks of disease subtyping. Our work represents the first example of a community of experts identifying and advocating for a single reproducible model for cancer subtyping, effectively unifying previous classifiers. In the CRC domain, the uniformity afforded by this new classification system and its application to a large data set revealed important subtype-specific biological associations that were previously unnoticed or marginally significant, supporting a new taxonomy of the disease. Citation Format: Justin Guinney, Rodrigo Dienstmann, Xin Wang, Aurelien de Reynies, Andreas Schlicker, Charlotte Soneson, Laetitia Marisa, Paul Roepman, Gift Nyamundanda, Paolo Angelino, Brian Bot, Jeffrey S. Morris, Iris Simon, Sarah Gerster, Evelyn Fessler, Felipe de Sousa e Melo, Edoardo Missiaglia, Hena Ramay, David Barras, Krisztian Homicsko, Dipen Maru, Ganiraju Manyam, Bradley Broom, Valerie Boige, Ted Laderas, Ramon Salazar, Joe W. Gray, Josep Tabernero, Rene Bernards, Stephen Friend, Pierre Laurent-Puig, Jan P. Medema, Anguraj Sadanandam, Lodewyk Wessels, Mauro Delorenzi, Scott Kopetz, Louis Vermeulen, Sabine Tejpar. Consensus molecular subtyping through a community of experts advances unsupervised gene expression-based disease classification and facilitates clinical translation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 603. doi:10.1158/1538-7445.AM2015-603

The mutual interactions of ion temperature gradient (ITG) driven modes, zonal flows and geodesic acoustic modes (GAM) in tokamak plasmas are investigated using a global nonlinear gyrokinetic formulation with totally unconstrained evolution of temperature gradient and profile. A series of numerical simulations with the same initial temperature and density profile specifications is performed using a sequence of ideal MHD equilibria differing only in the value of the total plasma current, in particular with identical magnetic shear profiles and shapes of magnetic surfaces. On top of a bursty or quasi-steady state behaviour the zonal flows oscillate at the GAM frequency. The amplitude of these oscillations increases with the value of the safety factor q, resulting in a less effective suppression of ITG turbulence by zonal flows at a lower plasma current. The turbulence-driven volume-averaged radial heat transport is found to scale inversely with the total plasma current.

Geodesic acoustic mode (GAM) oscillations in tokamak plasmas are known to be sensitive to the value of the safety factor q. Through its linear and nonlinear interactions with ITG turbulence it has recently been shown in direct numerical global simulations that the turbulence driven heat transport is larger when GAM oscilations of large amplitude are present, resulting in an anomalous transport scaling with the inverse plasma current. GAM dispersion relations have been derived for circular, large aspect ratio configurations, and, recently, for helical configurations. Linear simulation results are presented using the global, PIC, finite element codes GYGLES and ORB5 for the GAM frequency, damping rate and Rosenbluth‐Hinton residual zonal flow for a scan in plasma elongation. It is found that CAM frequency slightly decreases, while GAM damping rate and residual zonal flows increase with elongation. Nonlinear ITG simulations using the ORB5 code show that elongation reduces heat transport and that this is related to the plasma current and not q alone.

Nonlinear electrostatic global gyrokinetic simulations of collisionless ion temperature gradient (ITG) turbulence and ExB zonal flows in axisymmetric toroidal plasmas are examined for different choices of the initial distribution function. Using a local Maxwellian leads to the generation of axisymmetric ExB flows that can be so strong as to prevent ITG mode growth. A method using a canonical Maxwellian is shown to avoid this spurious generation of ExB flows. In addition, a revised delta f scheme is introduced and compared to the standard delta f method. (c) 2006 American Institute of Physics.

ITG and ETG turbulence is investigated with the nonlinear global PIC code ORB5. The large variety of numerical schemes and simulations domains used has sometimes lead to important discrepancies in the transport predictions. In order to discuss these disagreements, emphasis must be put on ways to check the numerical accuracy, such as energy conservation and numerical noise measurement. This paper therefore presents benchmarks, new algorithms and a noise diagnostic. After having demonstrated the numerical quality of our simulations, 2 topics are visited: the unclear role of the parallel nonlinearity and the transport level in ETG turbulence, for which predictions differing by one order of magnitude had been made elsewhere.

The aim of this study was to prospectively evaluate the incidence of cardiac rupture during myocardial infarction (MI) as well as the predictive value of the main cardiac rupture risk factors.The study was carried out in 17 coronary care units (CCU) between January and December 1999 in the Piedmont region (Italy).The incidence of cardiac rupture was 1.4% of the total number of MI (n = 3041). Data from 13 out of 17 CCU showed the following causes of death during MI: 66% heart failure, 16% cardiac rupture, 7% arrhythmias, 11% others. Twenty-seven percent out of 44 cardiac ruptures had prior angina, 9% prior MI; 24% of patients were diabetic; 38% had anterior wall MI; 62% infero-postero-lateral MI; 86% showed ST-segment elevation, and 79.5% developed Q waves. Thrombolysis was administered in 39% of cases. Forty-three percent cardiac ruptures occurred within 24 hours. Electromechanical dissociation was present in 73% of cases, syncope and hypotension in 43%, bradycardia in 30%. An echocardiogram was performed in 89% of cases in the suspicion of cardiac rupture but only 45% showed severe pericardial effusion. One patient was referred to surgery but he died in the postoperative period. Autoptical diagnosis was made in 32% of cases. All patients died. The analysis of some qualitative variables (gender, thrombolysis, MI localization, ST-segment/non-ST-segment elevation) in 8 out of 17 CCU, between the cardiac rupture group (n = 22) and the MI group (n = 1330) showed a significant result only for the female gender.Cardiac rupture is the second cause of death during MI after heart failure; there is a higher incidence of cardiac rupture in infero-postero-lateral MI, after the first 24 hours particularly in the female gender; there is a low global incidence (1.4%).

Global gyrokinetic simulations of ion temperature gradient (ITG) driven turbulence in an ideal MHD ITER equilibrium plasma are performed with the ORB5 code. The noise control and field-aligned Fourier filtering procedures implemented in ORB5 are essential in obtaining numerically healthy results with a reasonable amount of computational effort: typical simulations require 109 grid points, 109 particles and, despite a particle per cell ratio of unity, achieve a signal to noise ratio larger than 50. As compared with a circular concentric configuration with otherwise similar parameters (same ρ* = 1/720), the effective heat diffusivity is considerably reduced for the ITER MHD equilibrium. A self-organized radial structure appears, with long-lived zonal flows (ZF), modulating turbulence heat transport and resulting in a corrugated temperature gradient profile. The ratio of long-lived ZF to the fluctuating ZF is markedly higher for the ITER MHD equilibrium as compared with circular configurations, thereby producing a more effective ITG turbulence suppression, in spite of a higher linear growth rate. As a result, the nonlinear critical temperature gradient, R/LTcrit,NL, is about twice the linear critical temperature gradient, R/LTcrit,lin. Moreover, the heat transport stiffness above the nonlinear threshold is considerably reduced as compared with circular cases. Plasma elongation is probably one of the essential causes of this behaviour: indeed, undamped ZF residual levels and geodesic acoustic mode damping are both increasing with elongation. Other possible causes of the difference, such as magnetic shear profile effects, are also investigated.

The convergence properties of global electrostatic particle-in-cell gyrokinetic simulations have been studied by means of a set of new 3D diagnostics recently implemented in the code ORB5, allowing for measurements of electromagnetic potentials and relevant fluid quantities (density, temperature, vorticity) as well as turbulence spectral analysis. For all the quantities considered, non converged simulations show flatter spectra. However, not all the physically relevant quantities converge with the same rate: density fluctuation spectra can still show an unphysical flattening of the spectrum at high kθ ρs, even when electrostatic potential and heat fluxes appear to be converged. A remarkable results is that resolution in terms of number of markers, required to correctly describe the turbulence density fluctuations, is found to be size-dependent: larger systems (ITER like) require less numerical particles per active mode than smaller systems.

Electrons whether adiabatic or non-adiabatic play important role in determining the stability properties of a global electrostatic mode. In the present analysis, the effect of non-adiabaticity of electrons with all its kinetic effects is investigated for ion temperature gradient driven mode in the presence of fast ions using a linear gyro-kinetic code EM-GLOGYSTO-F.

The effect of trapped electrons on the ion temperature gradient ITG mode in a regime where its wavelength is shorter than the conventional ITG mode k Li 1 has been studied. Such a mode propagates in the ion diamagnetic direction with a typical scale length k Li 1 and is termed as the short wavelength ITG SWITG mode. The effect of the trapped electrons on this SWITG mode is investigated, for the first time, using a global and local linear gyrokinetic model. The trapped electrons are observed to destabilize the mode strongly. Comparison of the various parameter scans for the SWITG mode with and without the trapped electrons is presented. One important result obtained is that, while in the absence of the trapped electrons the mode was found to subside with increasing value of n=Ln /R exhibiting the character of a slablike mode, the presence of the trapped electrons has been observed to enhance the n=Ln /R window of the existence of the SWITG mode making the mode more toroidal like. © 2009 American Institute of Physics.

It is believed that low frequency microinstabilities such as ion temperature gradient (ITG) driven modes and trapped electron modes (TEMs) are largely responsible for the experimentally observed anomalous transport via the ion and electron channels in a tokamak. In the present work, a comprehensive global linear gyrokinetic model incorporating fully kinetic (trapped and passing) electrons and ions, actual ion to electron mass ratio, radial coupling, and profile variation is used to investigate the ITG driven modes and pure TEMs. These modes are found to exhibit multiscale structures in the presence of nonadiabatic passing electrons. The multiscale structure is related to the large nonadiabaticity of electrons in the vicinity of mode rational magnetic surfaces and leads to reduced mixing length estimates of transport compared to those obtained from adiabatic electron models.

Highly variable flux surface averaged heat fluxes are resolved in gyrokinetic simulations of ion temperature gradient (ITG) turbulence, even in large systems. Radially propagating fronts or avalanches are also seen. Their propagation lengths in gyroradii and relative amplitude remain constant as simulation size is increased, so the avalanches appear to result from local dynamics, rather than global relaxation events. For the Cyclone [Dimits et al., Phys. Plasmas 7, 969 (2000)] case, the avalanche propagation direction is found to depend on the sign of the shearing rate. A mechanism for avalanche propagation based on the advection of turbulence tilted by the shear flows is proposed: The Cyclone linear ITG dispersion relation explains the propagation direction of tilted vortices. It also explains why there is no such preferred direction in a simulation with reduced magnetic shear. The paper explores several models for these bursts. First, certain types of models based on nonlinear heat diffusion equations a...

A cross-comparison and verification of state-of-the-art European codes describing gradient-driven plasma turbulence in the core and edge regions of tokamaks, carried out within the EFDA Task Force on Integrated Tokamak Modelling, is presented. In the case of core ion temperature gradient (ITG) driven turbulence with adiabatic electrons (neglecting trapped particles), good/reasonable agreement is found between various gyrokinetic/gyrofluid codes. The main physical reasons for some deviations observed in nonlocal simulations are discussed. The edge simulations agree very well on collisionality scaling and acceptably well on beta scaling (below the MHD boundary) for cold-ion cases, also in terms of the non-linear mode structure.

In this work, role of nonadiabatic untrapped electrons in the context of a global ion temperature gradient driven mode has been investigated. In past studies, untrapped electrons have been assumed to be able to respond "instantaneously" to a disturbance. It is proposed that such adiabatic electron models should be reexamined for two important reasons: (i) It is known that global modes with n in the range of 3

International audience; The influence of the initial state on the turbulence and transport is addressed in collisionless, global, and full-f gyrokinetic simulations solving both the equilibrium and the fluctuations. For two strongly differing initial states, it is found that the steady turbulent regime exhibits nearly identical statistical properties. This result is in marked contrast with the claim of different final states. In fact, a long transient with very different properties finally evolves towards the same turbulent regime for long simulation times. When the initial state is a local Maxwellian, i.e., constant on flux surfaces, a large-scale sheared electric potential develops on short time scales to compensate for the vertical curvature and grad-B drifts. We predict analytically i the temporal dynamics at short times of this electric potential, ii its poloidal structure, and iii its saturation time. All agree well with numerical simulations using the GYSELA code. The impact on the transport is twofold, as compared to the canonical initial state, where f only depends on the motion invariants: i the turbulence is delayed due to a weaker effective growth rate, ii the same transport level is obtained at long times and the turbulence exhibits nearly identical statistical characteristics. In agreement, the electric potential of these two cases has the same magnitude despite very different transients.

In this paper, the influence of the parallel nonlinearity on zonal flows and heat transport in global particle-in-cell ion-temperature-gradient simulations is studied. Although this term is in theory orders of magnitude smaller than the others, several authors [L. Villard, P. Angelino, A. Bottino , Plasma Phys. Contr. Fusion 46, B51 (2004); L. Villard, S. J. Allfrey, A. Bottino , Nucl. Fusion 44, 172 (2004); J. C. Kniep, J. N. G. Leboeuf, and V. C. Decyck, Comput. Phys. Commun. 164, 98 (2004); J. Candy, R. E. Waltz, S. E. Parker , Phys. Plasmas 13, 074501 (2006)] found different results on its role. The study is performed using the global gyrokinetic particle-in-cell codes TORB (theta-pinch) [R. Hatzky, T. M. Tran, A. Koumlnies , Phys. Plasmas 9, 898 (2002)] and ORB5 (tokamak geometry) [S. Jolliet, A. Bottino, P. Angelino , Comput. Phys. Commun. 177, 409 (2007)]. In particular, it is demonstrated that the parallel nonlinearity, while important for energy conservation, affects the zonal electric field only if the simulation is noise dominated. When a proper convergence is reached, the influence of parallel nonlinearity on the zonal electric field, if any, is shown to be small for both the cases of decaying and driven turbulence.

Background Colorectal Cancer (CRC) is the second leading cause of cancer mortality worldwide. Effective and non-invasive biomarkers are needed to improve early diagnosis and disease management. Immune cells play a key role in tumor progression. Circulating immune cell count is a potential cancer biomarker, as indicated by the association of high blood neutrophil-to-lymphocyte ratio with poor prognosis in patients with cancer. The study goal was to determine the correlation between circulating immune cell counts and immune cell-specific RNA signatures and to evaluate the signature potential for CRC detection. Methods The transcriptome profiles of peripheral blood mononuclear cells from 561 Asian and Caucasian subjects (189 CRC, 115 advanced adenomas, 39 other cancers, 218 controls without colorectal lesions (CON)) were generated by RNA-seq on the Illumina platform. Neutrophils, lymphocytes and monocytes counts were obtained by standard hematology testing. Specific RNA signatures for neutrophils, monocyte/macrophages, T cells, CD4, CD8, B cells, NK cells were compiled from literature. The mean expression level of all genes in each Immune cell signature was calculated and used for statistical analyses. Results The main immune cell type RNA signatures showed correlation with the relative cell counts (r: 0.4-0.6), indicating the validity of the RNA signatures. Myeloid cell (monocyte/macrophage and neutrophil) RNA signatures were the most significantly upregulated in CRC compared to CON (p Conclusion This study shows that measuring specific immune cell type by RNA signatures correlate with traditional cell counting methods, enabling the extraction of valuable clinical information from blood transcriptomic data. This data suggests that both blood myeloid and T cells RNA signatures are promising biomarkers for CRC detection. Further biomarker development would require the optimization of the RNA signatures to validate and increase their diagnostic power. Legal entity responsible for the study Novigenix. Funding Novigenix. Disclosure S. Morgenthaler: Advisory / Consultancy: Novigenix. L. Ciarloni: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novigenix. G. Dorta: Advisory / Consultancy: Novigenix. S. Hosseinian Ehrensberger: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novigenix. All other authors have declared no conflicts of interest.