We are interested in the safety of critical systems whose development is based on models. Implementing failure analyses for this kind of system requires modeling the failures and conditions of their ...appearances. The failure analysis approaches are mainly based on the structures of systems where boolean equations depict the propagation of faults. The objective of the analysis is to calculate Minimal Cut Sets (MCS), i.e., the smallest sets of basic faults that may cause a feared event and their probabilities. The most efficient MCS resolution method is based on Binary Decision Diagrams (BDD). In this paper, we present a model-based toolset to construct from SysML structural models of systems, the fault trees, and their BDD-representation enabling us to compute MCS. Faults in our approach are not limited to boolean variables; they can be expressed by constraints coming from an arbitrary decidable theory. We validate the toolset capabilities with an oil burner system use case.
Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the ...cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more than 500 granulocyte and monocyte terminal differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these noncytotoxic treatments extended survival by more than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant NPM1 represses monocyte and granulocyte terminal differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically directed dosing of clinical small molecules.
Recent developments in data-driven science have led researchers to integrate data from several sources, over diverse experimental procedures, or databases. This alone poses a major challenge in ...truthfully visualizing data, especially when the number of data points varies between classes. To aid the representation of datasets with differing sample size, we have developed a new type of plot overcoming limitations of current standard visualization charts. SinaPlot is inspired by the strip chart and the violin plot and operates by letting the normalized density of points restrict the jitter along the x-axis. The plot displays the same contour as a violin plot but resembles a simple strip chart for a small number of data points. By normalizing jitter over all classes, the plot provides a fair representation for comparison between classes with a varying number of samples. In this way, the plot conveys information of both the number of data points, the density distribution, outliers and data spread in a very simple, comprehensible, and condensed format. The package for producing the plots is available for R through the CRAN network using base graphics package and as geom for ggplot through ggforce. We also provide access to a web-server accepting excel sheets to produce the plots (
http://servers.binf.ku.dk:8890/sinaplot/
).
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BFBNIB, GIS, IJS, INZLJ, KISLJ, NMLJ, NUK, PNG, UL, UM, UPUK, ZRSKP
MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. ...These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL-induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion-driven transformation and find that it sharply demarcates tumor initiation and maintenance.
Abstract
Mutations in cancer cells may lead to the formation of neo-epitopes potentially presented by both major histocompatibility complex (MHC) class I or II. These neo-epitopes may be recognized ...by CD8+ or CD4+ T-cells, and trigger an immune response. Only a small fraction of the neoepitopes will be displayed by the MHC class I or II. One of the challenges of cancer immunotherapy is therefore to predict which neoepitopes are susceptible to elicit a T-cell response. Software tools such as netMHC, MHC Flury and many others are over-predictive as the bulk part of the data used to train these methods are based on affinity assays. Several publications have indicated that stability assays may provide data that better correlate with epitope presentation by MHC. Prediction tools trained on stability assays may therefore be better at selecting neoepitopes resulting in more effective cancer vaccine design. We performed stability assay measurements for 10 MHC class I and 10 MHC class II alleles using a peptide scan library approach. In brief, random 9-mers where one position is known were used to measure stability of the peptide MHC complex. Next, the data were used to train a prediction tool, PrDx, that relies on a combination of different machine learning methods (random forest, feed forward neural networks and recurrent neural networks), of which the outputs are gathered in an assemble model. The model was then further trained with peptides predicted to bind with high stability, to the MHC alleles, until satisfactory performances were attained. To our surprise, PrDx showed new binding patterns for the alleles we trained. Although mostly similar to the binding patterns seen with affinity data trained method, the stability trained method is able to show new important positions in the binding patterns of the peptide-MHC complexes. Through retrospective analysis, our method seems able to select more accurately peptides susceptible to elicit a T-cell response, compared to state-of-the-art epitope prediction methods. Our results suggest that PrDx may be an attractive prediction tool for neo-epitopes discovery.
Citation Format: Stephan Thorgrimsen, Sune Justesen, Nicolas Rapin. Development of prediction software PrDx, trained on peptide-MHC stability assays, shows new important positions in the binding patterns of the peptides-MHC I and II complexes abstract. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B093.
Abstract
BloodSpot is a specialised database integrating gene expression data from acute myeloid leukaemia (AML) patients related to blood cell development and maturation. The database and interface ...has helped numerous researchers and clinicians to quickly get an overview of gene expression patterns in healthy and malignant haematopoiesis. Here, we present an update to our framework that includes protein expression data of sorted single cells. With this update we also introduce datasets broadly spanning age groups, which many users have requested, with particular interest for researchers studying paediatric leukaemias. The backend of the database has been rewritten and migrated to a cloud-based environment to accommodate the growth, and provide a better user-experience for our many international users. Users can now enjoy faster transfer speeds and a more responsive interface. In conclusion, the continuing popularity of the database and emergence of new data modalities has prompted us to rewrite and futureproof the back-end, including paediatric centric views, as well as single cell protein data, allowing us to keep the database updated and relevant for the years to come. The database is freely available at www.bloodspot.eu.
Graphical Abstract
Graphical Abstract
Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in ...drug–drug interaction (DDI) investigations.
Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered.
Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.
We apply a ...novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14
CD16
monocytes, CD66b
CD16
neutrophils, and CD4
CD45RA
naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers.
Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability .
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