Strong reversal of the lung fibrosis disease signature by autotaxin inhibitor GLPG1690 in a mouse model for IPF
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Strong reversal of the lung fibrosis disease signature by autotaxin inhibitor GLPG1690 in a mouse model for IPF Maté Ongenaert (Mechelen, Belgium), Maté Ongenaert, Sonia Dupont, Roland Blanqué, Reginald Brys, Ellen van der Aar, Bertrand Heckmann ERS - European Respiratory Society International Congress 2016. Session: Therapeutic horizons: novel targets and pharmacological models Background and objectives GLPG1690 is a novel potent autotaxin (ATX) inhibitor shown to be efficacious in the mouse bleomycin (BLM) lung fibrosis model. Here, we analyze the impact of GLPG1690 on the gene expression signature in mouse fibrotic lung tissue. Methods Lung fibrosis was induced by intranasal administration of BLM. Animals were treated with GLPG1690 or vehicle.Whole superior right lung was used for RNA extraction. Full transcriptome analysis was performed using the Agilent SurePrint G3 mouse chip. Analysis was performed using empirical Bayes methods and linear models. Public human IPF expression data were re-analyzed. Results GLPG1690 strongly reduced lung fibrosis as shown by reduction of Ashcroft scores and collagen content. Microarray analysis of the lungs revealed that GLPG1690 strongly reversed the impact of gene expression caused by BLM (367 out of the 2375 probes). As GLPG1690 treatment affects 395 probes, this treatment effect is highly relevant in the model. Gene clusters affected by BLM treatment and reverted by GLPG1690 are related to extracellular matrix (such as Tnc and Spp1), collagen (Col3a1) and cytokines/chemokines (Cxcl12). Several of the affected genes are known to be involved in the development or progression of lung fibrosis in IPF patients. Conclusions These data provide further mechanistic understanding of the efficacy of ATX inhibition in a pre-clinical lung fibrosis model, highlighting a role for extracellular matrix and inflammation biology. These data strongly suggest that GLPG1690 may be beneficial in treating IPF patients and support its evaluation in a clinical study
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The document provides information about EasyGenomics, a cloud-based bioinformatics platform developed by BGI. It discusses:
- BGI's background as the world's largest genome sequencing center with significant sequencing, computing, and storage capabilities.
- The team building EasyGenomics, which is run like a software company and supported by BGI algorithm teams.
- The key features of EasyGenomics, including bioinformatics workflows, data management, high-speed data transfer, and a simple user interface.
- Future directions for the product, including questions around market positioning and sustainable business models.
ENCODE project: brief summary of main findings
A brief summary of the ENCODE project and ist main finding. Most important publications for cancer researchers and how to make use of the ENCODe data.
Best pratices at BGI for the Challenges in the Era of Big Genomics Data
BGI is the world's largest genome sequencing center, with over 150 sequencers and a sequencing throughput of 6 TB per day. It also has the largest computing and storage center for genomics in China, with over 20,000 CPU cores, 19 GPUs, 220+ teraflops of peak performance, and 17 petabytes of data storage. BGI faces challenges from the exponential growth of genomic data, complex data analysis processes, and widely distributed data. It addresses these challenges through solutions like high-speed data transfer, cloud computing platforms like EasyGenomics, and distributed algorithms and infrastructure using Hadoop and GPU acceleration.
Workshop NGS data analysis - 2
Workshop NGS data analysis - 2
Mapping of reads to a reference genome, QC and first downstream analysis
Open human genome data
Open human genome data - presentation at the annual TKT/CLIDP doctoral programme symposium 2016 "Open up! – Open Data and Open Access" of the University of Turku.
A Platform for Integrated Genome Data Analysis
"A Platform for Integrated Genome Data Analysis" presented on the "All About Data Congress 2014" at at the UMC Groningen.
New Progress in Pyrosequencing for DNA Methylation
Pyrosequencing is a highly flexible technology that lets you rapidly analyze short- to medium-length sequences fast and quantitatively with high accuracy. The real-time, high-resolution sequence output makes the technology highly suitable for applications including complex mutation analysis, microbial identification and DNA methylation quantification.
The main bottleneck in Pyrosequencing has been limited sequence length, which is critical for some applications. Our new technology, software, and chemistry overcome this bottleneck and give sequence reads that are typically twice as long as those from previous PyroMark systems. The new PyroMark Q24 Advanced system also reduces background noise, improving quantification even at sites distant from the sequencing start. The new system is ideal for applications requiring analysis of longer sequences, such as DNA methylation analysis in epigenetic research, frequency determination in mutation analysis, and various de novo sequencing applications.
In this presentation, we will discuss the following applications and technology improvements:
• DNA methylation analysis at single base resolution at CpG and CpN sites
• Improved quantification of sequence variations at any sequence position
• Easy and improved base calling functionality
PCR - From Setup to Cleanup: A Beginner`s Guide with Useful Tips and Tricks -...
This End-Point PCR Beginner´s Guide will not only give you a comprehensive overview of tools and techniques to help you to get the most out of your samples, but also give you information on dedicated solutions and complete workflows on multiplex PCR and PCR fragment analysis.
Microbiome Profiling with the Microbial Genomics Pro Suite
In this slide deck, we introduce the scientist-friendly Microbial Genomics Pro Suite offering workflows optimized for microbiome profiling, microbial typing and outbreak analysis. The workflows and tools for microbial genomics introduced with this software package are further extending the comprehensive set of genomics, transcriptomics and epigenomics analysis solutions that researchers know from CLC Genomics Workbench.
Clinical Metagenomics for Rapid Detection of Enteric Pathogens and Characteri...
High-throughput sequencing, combined with high-resolution metagenomic analysis, provides a powerful diagnostic tool for clinical management of enteric disease. Forty-five patient samples of known and unknown disease etiology and 20 samples from health individuals were subjected to next-generation sequencing. Subsequent metagenomic analysis identified all microorganisms (bacteria, viruses, fungi and parasites) in the samples, including the expected pathogens in the samples of known etiology. Multiple pathogens were detected in the individual samples, providing evidence for polymicrobial infection. Patients were clearly differentiated from healthy individuals based on microorganism abundance and diversity. The speed, accuracy and actionable features of CosmosID bioinformatics and curated GenBook® databases, implemented in the QIAGEN Microbial Genomics Pro Suite, and the functional analysis, leveraging the QIAGEN functional metagenomics workflow, provide a powerful tool contributing to the revolution in clinical diagnostics, prophylactics and therapeutics that is now in progress globally.
Workshop NGS data analysis - 1
Workshop 1 - NGS data analysis
- Introduction
- Sequence flow and analysis
- Data formats throughout sequencing data analysis
Advanced NGS Data Analysis & Interpretation- BGW + IVA: NGS Tech Overview Web...
This slidedeck details two comprehensive informatics solutions — the Biomedical Genomics Workbench and Ingenuity Knowledge Base Variant Analysis platforms. We show the intuitive user interface of CLC Cancer Research Workbench and demonstrate how the rich biological content from Ingenuity Knowledge Base helps you rapidly identify critical variants in your samples.
NGS Targeted Enrichment Technology in Cancer Research: NGS Tech Overview Webi...
This slidedeck discusses the most biologically efficient, cost-effective method for successful NGS. The GeneRead DNA QuantiMIZE Kits enable determination of the optimum conditions for targeted enrichment of DNA isolated from biological samples, while the GeneRead DNAseq Panels V2 allow you to quickly and reliably deep sequence your genes of interest. Applications in translational and clinical research are highlighted.
Next-Generation Sequencing an Intro to Tech and Applications: NGS Tech Overvi...
This slidedeck provides a technical overview of DNA/RNA preprocessing, template preparation, sequencing and data analysis. It covers the applications for NGS technologies, including guidelines for how to select the technology that will best address your biological question.
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Best pratices at BGI for the Challenges in the Era of Big Genomics Data
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New Progress in Pyrosequencing for DNA Methylation
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Microbiome Profiling with the Microbial Genomics Pro Suite
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Clinical Metagenomics for Rapid Detection of Enteric Pathogens and Characteri...
Clinical Metagenomics for Rapid Detection of Enteric Pathogens and Characteri...
Advanced NGS Data Analysis & Interpretation- BGW + IVA: NGS Tech Overview Web...
Advanced NGS Data Analysis & Interpretation- BGW + IVA: NGS Tech Overview Web...
NGS Targeted Enrichment Technology in Cancer Research: NGS Tech Overview Webi...
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Similar to Strong reversal of the lung fibrosis disease signature by autotaxin inhibitor GLPG1690 in a mouse model for IPF
Primary Human Cell Systems Analysis of Drug Mechanisms
The document summarizes a presentation about using BioMAP human cell systems to analyze the mechanisms of drug compounds, including PPAR agonists. It describes how BioMAP uses primary human cells in disease-like conditions to generate quantitative readouts that can discriminate between clinical compounds. Profiling of PPAR agonists using BioMAP revealed both shared and unique anti-inflammatory, tissue remodeling, and prostaglandin pathway effects. Differential activities suggested priorities for therapeutic areas and potential side effects.
A cd36 synthetic peptide inhibits bleomycin induced pulmonary inflammation an...
This study investigated the effects of administering a synthetic peptide of CD36 (a receptor for thrombospondin-1) along with bleomycin to induce lung injury in rats. The results showed that administering the CD36 peptide inhibited the activation of latent TGF-β1 by alveolar macrophages, reduced inflammation and connective tissue synthesis in the lung compared to bleomycin alone. This suggests that the thrombospondin-1 and CD36 interaction plays a key role in the in vivo activation of latent TGF-β1 during lung injury, and that activated TGF-β1 from alveolar macrophages drives pulmonary inflammation and fibrosis.
Fingolimod the path from a fungal metabolite to fda approved drug-biom255-sp...
Fingolimod the path from a fungal metabolite to fda approved drug-biom255-sp...People with Multiple Sclerosis (Vic) Inc.
This document discusses sphingosine 1-phosphate (S1P) receptor signaling in multiple sclerosis (MS). It describes how S1P receptors signal in both the immune system and central nervous system (CNS), with effects on astrocytes in the CNS. Fingolimod, an FDA-approved drug for MS, acts as an S1P receptor modulator and has immune and CNS effects. The document provides contact information for Dr. Jerold Chun who studies lysophospholipid receptors including S1P receptors and their roles in diseases like MS.Y. Sun et al. ASM Microbe 2018
1) A transposon sequencing screen identified the citrate synthase gene gltA as having decreased abundance in wild-type mice lungs but not in Lcn2-/- mice during Klebsiella pneumoniae infection, suggesting an interaction between gltA and murine Lcn2.
2) Validation experiments showed a gltA mutant strain had a significant fitness defect compared to the wild type in wild-type mice but not in Lcn2-/- mice. The gltA mutant grew similarly to wild type in rich media but not in minimal media, and growth was restored by glutamate or human serum supplementation.
3) Further experiments showed the gltA mutant had a defect in the spleen
PHd defense presentation Final RIVES
The document discusses the functional interaction between mGlu1a and GABAB receptors. It first provides background on G protein-coupled receptors and their importance as drug targets. It then reviews evidence that mGlu1a and GABAB receptors physically interact in cortical neurons and Purkinje cells based on co-localization and co-immunoprecipitation studies. The study aims to further investigate the physical interaction between the receptors and the mechanism underlying their functional cross-talk using biophysical techniques like BRET, TR-FRET, and cell-surface co-immunoprecipitation. Preliminary data suggests mGlu1a and GABAB do not form complexes at the cell surface but may oligomerize intracellularly.
An Expert Analysis of New Data for Uncontrolled Persistent Asthma Treatments:...
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Mario Castro, MD, prepared useful practice aids pertaining to asthma management for this CME activity titled "An Expert Analysis of New Data for Uncontrolled Persistent Asthma Treatments: Clinical Updates From Paris." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2yphUo5. CME credit will be available until October 28, 2019.PPAR alpha final research paper
The document discusses using the Burmese python as a model to study lipid homeostasis. After eating, pythons show a doubling in size of major organs and a 52-fold increase in triglycerides without signs of lipotoxicity. This suggests a more efficient mechanism of lipid homeostasis than humans. The nuclear receptor PPARα is identified as a master regulator of lipid homeostasis and is the gene of interest. Methods are described to isolate RNA from python liver, synthesize cDNA, validate and test primers for PPARα and other genes, and perform quantitative real-time PCR to analyze gene expression levels at different time points after feeding.
Poster
TGF-β1 increases expression of the inhibitor of apoptosis proteins XIAP, cIAP-1, and cIAP-2 in lung fibroblasts. Researchers treated lung fibroblasts with TGF-β1 for four hours and found increased mRNA and protein levels of XIAP and increased mRNA levels of cIAP-1, but no significant change in cIAP-2. This suggests that TGF-β1 regulation of XIAP and possibly cIAP-1 may contribute to fibroblast survival and the abnormal lung scarring associated with idiopathic pulmonary fibrosis.
Discovery PBPK: Efficiently using machine learning & PBPK modeling to drive l...
1) The document discusses using machine learning and physiologically-based pharmacokinetic (PBPK) modeling to efficiently guide lead selection and optimization in drug discovery.
2) Case studies are presented showing that local machine learning models built on small numbers (15-70) of rat data points can accurately predict clearance and bioavailability of compounds within congeneric series.
3) A high throughput PBPK simulation module is described that takes predictive ADMET input and rapidly generates pharmacokinetic profiles and metrics to enable early screening of large compound libraries.
48x36_horizontal7_23_14
This study aimed to investigate mechanisms regulating expression of the tumor suppressor DAPK1 in chronic lymphocytic leukemia (CLL) cells. The researchers found that ZIPK, an interacting partner of the transcription factor ATF6, plays a critical role in IFN-γ-induced autophagy by promoting DAPK1 expression. Knockdown of ZIPK in cells prevented autophagy stimulation by IFN-γ. Additionally, primary CLL cells showed low levels of transcripts for proteins involved in autophagy induction like C/EBP-β, ATF6, and DAPK1, suggesting dysregulation of the pathway. Understanding how DAPK1 expression is controlled could help develop therapies
dkNET Webinar "Uncovering Novel Mediators and Mechanisms of Leptin Action" 02...
dkNET New Investigator Pilot Program in Bioinformatics Awardee Seminar Series
Presenter: Alan Rupp, Ph.D. Research Investigator in Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School.
Abstract
Rates of obesity and diabetes continue to rise, impacting the health and wellbeing of millions. Treatment options are limited, in part because of our incomplete understanding of the biology of hunger and energy expenditure. The hormone leptin is produced by adipose tissue and signals the repletion of adipose energy stores to leptin receptor (Lepr)-expressing neurons in the hypothalamus. Leptin- and Lepr-deficient humans and rodents display marked hyperphagia, reduced energy expenditure, and extreme obesity. The crucial cellular targets (i.e., Lepr neurons) and transcriptional mechanisms that mediate these responses remain largely unknown, however. To reveal the cellular architecture of Lepr cells, we performed single nucleus RNA-seq of the hypothalamus in lean and obese rodents and macaques and in enriched mouse Lepr neurons. We identified over a dozen distinct Lepr neuron populations distributed across multiple hypothalamic nuclei, including a novel conserved population of Lepr neurons that is marked by Glp1r expression and which displays strong transcriptional responses to diet-induced obesity. Deleting Lepr from these Lepr/Glp1r cells resulted in excessive food intake and weight gain, revealing the importance of these for the control of energy balance by leptin. In contrast, we found that ventromedial hypothalamic (VMH) Lepr neurons represent a distinct class of VMH neurons that promote energy expenditure. Finally, we showed that leptin signaling during obesity remains intact in a subset of hypothalamic Lepr populations, while other Lepr neurons that play key roles in energy balance exhibited blunted responses. Overall, these studies reveal the neuronal structure of leptin action and highlight cell populations and molecular pathways that represent potential targets for obesity therapy.
Upcoming webinars schedule: https://dknet.org/about/webinar
Perspective on QSAR modeling of transport
The document discusses quantitative structure-activity relationship (QSAR) modeling of drug transporters. It summarizes the evolution of QSAR models for various transporters like P-glycoprotein (P-gp) and describes approaches like pharmacophore modeling that have been used to predict transporter substrates and inhibitors. Key challenges addressed are small datasets and evaluating model predictivity. The development and validation of Bayesian classification and quantitative pharmacophore models for transporters like the apical sodium-dependent bile acid transporter (ASBT) and organic cation transporter 2 (OCTN2) are also summarized.
Nc3R\'s Meeting
This document discusses translational models of drug-induced liver injury. It begins by outlining the integrated mechanistic drug safety approach, which investigates chemicals, patients, and the interaction between the two. A key part of this approach is understanding the mechanisms of drug bioactivation and the consequences for cellular toxicity. Paracetamol is used as a case study, as it is a common cause of drug-induced liver injury. The document explores the mechanisms of paracetamol toxicity, including how its reactive metabolite NAPQI causes oxidative stress and depletion of glutathione, leading to liver cell damage through both necrosis and inflammation. It also discusses the role of the Nrf2 transcription factor in regulating the antioxidant response and adapting cells to
Pharmacogenomics
Pharmacogenomics is the study of how an individual's genetic inheritance affects their response to drugs. It aims to develop personalized medicine by determining the "right dose of the right drug to the right person". Genetic variations can influence drug pharmacokinetics, pharmacodynamics, and disease mechanisms. Examples include CYP2C19 polymorphisms affecting clopidogrel metabolism and VKORC1/CYP2C9 variants influencing warfarin dosing. While pharmacogenomics holds promise for optimizing drug therapy, barriers include complexity in identifying clinically-relevant genetic factors and challenges in educating healthcare providers and patients.
Dann lab presentation
The document summarizes experiments conducted to analyze the effect of manipulating SOHLH1 and OCT4 expression levels on stemness and differentiation. Key points:
1) A SOHLH1-GFP reporter cell line was created by ligating the SOHLH1 insert into the pLLU2G vector and transfecting it into cells. Analysis by FACS showed increased SOHLH1 decreased GFP levels, indicating increased differentiation.
2) GFP analysis of cell lines expressing SOHLH1-GFP, TEX17-myc, and various OCT4 constructs showed their expression levels and subcellular localization by FACS and immunostaining.
3) OCT4 cell lines with higher OCT4 mRNA levels by qPCR
Anti Tumor Necrosis Factor Alpha And Asthma
Anti Tumor Necrosis Factor Alpha And AsthmaChulalongkorn Allergy and Clinical Immunology Research Group
1) Treatment with the TNF-α antagonist etanercept was associated with improvements in asthma-related quality of life scores, lung function, and exacerbations in patients with severe corticosteroid-refractory asthma in an open-label clinical trial.
2) A double-blind placebo-controlled trial found that 10 weeks of etanercept treatment was associated with increased bronchial hyperresponsiveness and improved asthma control in patients with refractory asthma but not mild-moderate asthma.
3) Intravenous infusion of the TNF-α antagonist infliximab was associated with decreased exacerbations and improved lung function in a double-blind placebo-controlled trial of patients with moderate asthma uncontrolled by inhaledA novel PPAR pan-agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-met...
A novel PPAR pan-agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-met...Synthetic Medicinal Chemistry Lab, College of Pharmacy , Pusan National University
MHY2013 is a novel PPAR pan-agonist that was shown to have beneficial effects on metabolic disorders in mouse models of obesity and diabetes. It activated all PPAR subtypes and increased fatty acid oxidation and energy expenditure in liver, adipose tissue, and skeletal muscle by upregulating genes involved in these pathways. MHY2013 improved insulin sensitivity, lowered blood triglycerides and fatty acids, and reduced hepatic steatosis in obese mice without affecting food intake or body weight. The compound's metabolic effects were mediated through increased levels of the hormones FGF21 and adiponectin.Epidermal growth factor and its receptor tyrosine kinase
The document discusses epidermal growth factor (EGF) signaling and the EGF receptor. It notes that EGF is involved in normal cell processes like development, differentiation, and wound healing. The EGF receptor belongs to the ErbB family of receptor tyrosine kinases and plays a key role in signaling pathways regulating cell proliferation, survival, and apoptosis. Overexpression or abnormal activation of the EGF receptor and other ErbB family members is implicated in many epithelial cancers.
Activation of rat alveolar macrophage derived latent transforming growth fact...
This document summarizes a study that investigated the activation of latent transforming growth factor beta-1 (TGF-β1) by plasmin in rat alveolar macrophages. The study found that thrombospondin-1 (TSP-1) and its cell surface receptor CD36 are also important for the activation of latent TGF-β1. TSP-1/latent TGF-β1 complexes were present on alveolar macrophages, and plasmin decreased these complexes, indicating TSP-1-associated latent TGF-β1 is released by plasmin. Colocalization of TGF-β1 with CD36 suggested latent TGF-β1 complexes with TSP-1 localize to
YALE POSTER presentation (3)
- STEP levels are elevated in Fragile X mice and inhibit long-term potentiation.
- Researchers tested the STEP inhibitor TC-2153 in wild type and Fragile X mice.
- TC-2153 treatment led to increased phosphorylation of STEP substrates like NR2B, Pyk2 and ERK1/2 in both wild type and Fragile X mice by inhibiting STEP.
- This suggests that TC-2153 may be an effective treatment for cognitive deficits in Fragile X Syndrome by blocking the elevated STEP activity.
Similar to Strong reversal of the lung fibrosis disease signature by autotaxin inhibitor GLPG1690 in a mouse model for IPF (20)
Primary Human Cell Systems Analysis of Drug Mechanisms
Primary Human Cell Systems Analysis of Drug Mechanisms
A cd36 synthetic peptide inhibits bleomycin induced pulmonary inflammation an...
A cd36 synthetic peptide inhibits bleomycin induced pulmonary inflammation an...
Fingolimod the path from a fungal metabolite to fda approved drug-biom255-sp...
Fingolimod the path from a fungal metabolite to fda approved drug-biom255-sp...
An Expert Analysis of New Data for Uncontrolled Persistent Asthma Treatments:...
An Expert Analysis of New Data for Uncontrolled Persistent Asthma Treatments:...
Discovery PBPK: Efficiently using machine learning & PBPK modeling to drive l...
Discovery PBPK: Efficiently using machine learning & PBPK modeling to drive l...
dkNET Webinar "Uncovering Novel Mediators and Mechanisms of Leptin Action" 02...
dkNET Webinar "Uncovering Novel Mediators and Mechanisms of Leptin Action" 02...
A novel PPAR pan-agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-met...
A novel PPAR pan-agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-met...
Epidermal growth factor and its receptor tyrosine kinase
Epidermal growth factor and its receptor tyrosine kinase
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Activation of rat alveolar macrophage derived latent transforming growth fact...
More from Maté Ongenaert
Unleash transcriptomics to gain insights in disease mechanisms: integration i...
Unleash transcriptomics to gain insights in disease mechanisms: integration in the Galapagos knowledge platform “Hydra”
Bots & spiders
This document discusses bots and spiders and their uses in bioinformatics. It begins with background on bots, spiders and how they work. Bots perform simple, repetitive tasks quickly, while spiders systematically crawl and index web pages. The Googlebot crawler is commonly used to index pages for Google search. APIs allow automated querying of databases and integration with other programming languages. Examples discussed include using bots to query PubMed and Ensembl via their APIs to gather gene and sequence data for further analysis. Real-life case studies demonstrate text mining of PubMed results and automated analysis of gene expression data from NCBI GEO.
Exploring the neuroblastoma epigenome: perspectives for improved prognosis
EXPLORING THE NEUROBLASTOMA EPIGENOME: PERSPECTIVES FOR THE DISCOVERY OF PROGNOSISTIC BIOMARKERS
M. Ongenaert, A. Decock, J. Vandesompele, F. Speleman
Center for Medical Genetics, Ghent University, Ghent, Belgium (mate.ongenaert@ugent.be)
Neuroblastoma (NB) is a childhood tumor originating from sympathetic nervous system cells. Although recently new insights into genes involved in NB have emerged, the molecular basis of neuroblastoma development and progression still remains poorly understood. The best-characterized genetic alterations include amplification of the proto-oncogene MYCN, ALK activating mutations or amplification, gain of chromosome arm 17q and losses of 1p, 3p, and 11q. Epigenetic alterations have been described as well: caspase-8 (CASP8) and RAS-association domain family 1 isoform A (RASSF1A) DNA-methylation are important events for the development and progression of neuroblastoma. In total, there are about 75 genes described as epigenetically affected in NB cell lines and/or NB primary samples.
Most of these methylation markers are found using ‘candidate gene’ approaches and the methylation frequencies are usually very low. In order to find novel methylation markers that can be used for improved prognosis, we applied a whole-genome methylation screen. This technique relies on capturing with the MBD2 protein, containing a methyl-binding domain (MBD), with a very high affinity towards methylated genomic regions. In an initial phase, MBD2-seq was performed on 8 NB cell lines (where we also had micro-array data of, before and after treatment with DAC). As these results are promising, we will explore the complete methylomes of 45 primary NB tumors.
Based on an integrative analysis (re-expression results, expression micro-arrays, MBD2-sequencing on cell lines), 48 MSP (Methylation Specific PCR) assays were tested on 89 primary neuroblastoma patients of different risk categories. The results of this validation study demonstrate the power of epigenetic biomarkers as several assays are informative for prognosis and survival.
High-throughput proteomics: from understanding data to predicting them
High-throughput proteomics: from understanding data to predicting themprof. dr. Lennart Martens
UGent - Department of Biochemistry, Faculty of Medicine and Health Sciences, VIB - Group Leader Computational Omics and Systems Biology Group (CompOmics), Department of Medical Protein Research
In proteomics, as in any high-throughput omics field, the rate of data generation has increased dramatically, yielding very large datasets that require substantial processing to render them useful and interpretable. Key concepts here are data management, data-bound analysis algorithms, and user interface design. But we do not need to limit ourselves to only the interpretation of experimental results. By combining data from across many (unrelated) experiments, we can gain substantial knowledge about the strengths and limitations of our technological approaches. High-throughput methods however, rarely serve as the endpoint for research. As exquisite parallel hypothesis testers, these approaches can quickly highlight promising follow-up targets for more detailed study. Yet moving from discovery to targeted analysis requires much more in-depth understanding of sample and methodology, which is where the insights gained from large-scale data analysis come into play. Armed with this knowledge, we can begin to predict experimental outcomes based on specific hypotheses, thus effectively creating tests or assays that can be used in focused validation experiments
Microarray data and pathway analysis: example from the bench
Microarray data and pathway analysis: example from the bench
by drs. Jolien Vermeire - HIVlab, Department of Clinical Chemistry, Microbiology and Immunology – UGent
The increased availability and lower cost of gene expression microarrays has stimulated the use of transcriptome studies in a high variety of fields. Generating expression data at whole-genome level can indeed be a powerful method to characterize cellular pathways involved in a certain biological process. However, the challenge of extracting relevant biological information from such large datasets still prevents researchers from exploiting this tool. In this presentation I will share my personal experience, as a 'researcher non-bioinformatician', with performing microarray data and pathway analyses. I will give a general overview of the different steps that where followed in order to transform raw gene expression data, obtained in context of HIV research, into useful biological information and highlight different methods and software tools that helped me in this process.
Large scale machine learning challenges for systems biology
Large scale machine learning challenges for systems biology
by dr. Yvan Saeys - Machine Learning and Data Mining group, Bioinformatics and Systems Biology Division, VIB-UGent Department of Plant Systems Biology
Due to technological advances, the amount of biological data, and the pace at which it is generated has increased dramatically during the past decade. To extract new knowledge from these ever increasing data sets, automated techniques such as data mining and machine learning techniques have become standard practice.
In this talk, I will give an overview of large scale machine learning challenges in bioinformatics and systems biology, highlighting the importance of using scalable and robust techniques such as ensemble learning methods implemented on large computing grids.
I will present some of our state-of-the-art tools to solve problems such as biomarker discovery, large scale network inference, and biomedical text mining at PubMed scale.
Integrative transcriptomics to study non-coding RNA functions
Integrative transcriptomics to study non-coding RNA functions
by dr. ir. Pieter Mestdagh - Center for Medical Genetics, Ghent University
Over the last years, non-coding RNAs (e.g. microRNAs and long non-coding RNAs) have emerged as an important layer of the transcriptome. In order to elucidate their function in disease biology, multiple tools have been developed, ranging from miRNA target prediction algorithms to the more advanced integrative genomics approaches. Through the combination of multiple layers of information, integrative genomics allows a more accurate and comprehensive assessment of non-coding RNA functions in human disease. In this presentation, I will discuss different approaches on how to combine multi-level transcriptome data in order to functionally characterize non-coding RNA networks.
Race against the sequencing machine: processing of raw DNA sequence data at t...
Race against the sequencing machine: processing of raw DNA sequence data at the Genomics Core
by dr. Luc Dehaspe - Genomics Core, UZ Leuven
To grow and function, living organisms unconsciously and continuously read instructions from the DNA sequence in each cell. Thanks to the advances in DNA sequencing technology, scientists are increasingly able to consciously read along. In 2001, sequencing efforts resulted in a first draft of human genome. Since then, the capacity of the DNA reading machines has doubled every six months on average. While the first human genome sequencing project took years of worldwide collaboration, multiple genomes can now be sequenced in 10 days on a single machine at a service facility such as the Genomics Core.
Each sequencing run gives rise to a few terabytes of raw data that, using bioinformatics techniques, must be processed in time, before the next bunch of data arrives.
I will discuss bioinformatics techniques that are commonly used in the Genomics Core and that have a chance to survive another generation of sequencing machines. <\br>A crucial feature of these techniques is that they keep up with the sequencing machines by creating sub-tasks that are distributed over an extensible network of computers.
Bringing the data back to the researchers
Bringing the data back to the researchers
by ir. Geert Trooskens - BIOBIX, UGent
Genome wide analysis is getting bigger, better and faster.
Researchers are looking for answers in the vast amounts of different data sets that come out these analyses, conceivably leaving important information on a storage disk.
We present the Hitchhikers Guide to the Genome (H2G2): a platform that allows (epi-)genetic, genomic, and proteomic data fusion and visualization.
The post-genomic era: epigenetic sequencing applications and data integration
The post-genomic era: epigenetic sequencing applications and data integration
by dr. ir. Maté Ongenaert - Center for Medical Genetics, Ghent University
The past decade is known as the post-genomic era. Ever since the first published human genomes, the pace to determine new genomes ever increased. In addition, a number of new sequencing applications gave access to previously unexplored areas at a genome-wide scale such as whole epigenomes.
In this talk, the data generated from a number of sequencing techniques to determine whole DNA-methylomes and whole genome histone marks will be discussed.
Main goal: to convince scientists that the analysis tools have matured to a level that, using a good manual and insight in the mechanisms behind the analysis, they can do their own basic analyses.
Starting from a raw sequence file, over quality control to mapping to the reference genome, peak calling, visualization and identification of differentially methylated sites: within the time-frame of this talk, the entire process will be demonstrated.
As epigenetics regulates genomic processes and literally is a layer above genetics, able to fine-tune regulatory processes, several layers of information should be look at to understand the underlying mechanisms.
Important aspect in the analysis of epigenetic datasets thus is the integration of several data sources (expression results, re-expression results, DNA-methylation information and histone-modifications).
Introduction
The document outlines the schedule for a seminar featuring several speakers on topics related to genomics, epigenetics, proteomics, and systems biology. The seminar includes talks on investigating the human gut flora using metagenomics, epigenetic sequencing applications and data integration, visualization of large datasets, processing raw DNA sequence data, integrative transcriptomics to study non-coding RNA functions, large scale machine learning challenges for systems biology, and pathway analysis and proteomics/cross-omics integration. The audience consists of a mixed background including those from various universities and research institutions in Belgium, the Netherlands, and France working in fields such as pediatric immunology, microbiology, medical genetics, computer science, physiology, and plant
Literature managment training
Maté Ongenaert presented on literature management and text mining tools. Effective literature management is important for both academic and industrial research. Tools like Mendeley and Zotero allow researchers to store metadata and full texts, perform searches, and collaborate. Text mining tools automate literature searches and extract information from results to provide summaries and highlights. Demonstrations showed how a web application could translate queries, search PubMed, analyze results, and present summaries to researchers.
Scientific literature managment - exercises
This document outlines 6 exercises for researching biomedical literature: Exercise 1 describes how to search the PubMed database; Exercise 2 discusses RSS feeds; Exercise 3 covers searching Google Scholar; Exercise 4 presents information on patents; Exercise 5 is about the reference manager Mendeley; and Exercise 6 provides advanced techniques for the NCBI E-Utilities API.
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Exploring the neuroblastoma epigenome: perspectives for improved prognosis
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High-throughput proteomics: from understanding data to predicting them
High-throughput proteomics: from understanding data to predicting them
Microarray data and pathway analysis: example from the bench
Microarray data and pathway analysis: example from the bench
Large scale machine learning challenges for systems biology
Large scale machine learning challenges for systems biology
Integrative transcriptomics to study non-coding RNA functions
Integrative transcriptomics to study non-coding RNA functions
Race against the sequencing machine: processing of raw DNA sequence data at t...
Race against the sequencing machine: processing of raw DNA sequence data at t...
The post-genomic era: epigenetic sequencing applications and data integration
The post-genomic era: epigenetic sequencing applications and data integration
Recently uploaded
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...
The pygmy halfbeak Dermogenys colletei, is known for its viviparous nature, this presents an intriguing case of relatively low fecundity, raising questions about potential compensatory reproductive strategies employed by this species. Our study delves into the examination of fecundity and the Gonadosomatic Index (GSI) in the Pygmy Halfbeak, D. colletei (Meisner, 2001), an intriguing viviparous fish indigenous to Sarawak, Borneo. We hypothesize that the Pygmy halfbeak, D. colletei, may exhibit unique reproductive adaptations to offset its low fecundity, thus enhancing its survival and fitness. To address this, we conducted a comprehensive study utilizing 28 mature female specimens of D. colletei, carefully measuring fecundity and GSI to shed light on the reproductive adaptations of this species. Our findings reveal that D. colletei indeed exhibits low fecundity, with a mean of 16.76 ± 2.01, and a mean GSI of 12.83 ± 1.27, providing crucial insights into the reproductive mechanisms at play in this species. These results underscore the existence of unique reproductive strategies in D. colletei, enabling its adaptation and persistence in Borneo's diverse aquatic ecosystems, and call for further ecological research to elucidate these mechanisms. This study lends to a better understanding of viviparous fish in Borneo and contributes to the broader field of aquatic ecology, enhancing our knowledge of species adaptations to unique ecological challenges.
如何办理(uvic毕业证书)维多利亚大学毕业证本科学位证书原版一模一样
原版纸张【微信：741003700 】【(uvic毕业证书)维多利亚大学毕业证】【微信：741003700 】学位证，留信认证（真实可查，永久存档）offer、雅思、外壳等材料/诚信可靠,可直接看成品样本，帮您解决无法毕业带来的各种难题！外壳，原版制作，诚信可靠，可直接看成品样本。行业标杆！精益求精，诚心合作，真诚制作！多年品质 ,按需精细制作，24小时接单,全套进口原装设备。十五年致力于帮助留学生解决难题，包您满意。
本公司拥有海外各大学样板无数，能完美还原海外各大学 Bachelor Diploma degree, Master Degree Diploma
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留信网认证的作用:
1:该专业认证可证明留学生真实身份
2:同时对留学生所学专业登记给予评定
3:国家专业人才认证中心颁发入库证书
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3D Hybrid PIC simulation of the plasma expansion (ISSS-14)
3D Particle-In-Cell (PIC) algorithm,
Plasma expansion in the dipole magnetic field.
在线办理(salfor毕业证书)索尔福德大学毕业证毕业完成信一模一样
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本公司拥有海外各大学样板无数，能完美还原。
1:1完美还原海外各大学毕业材料上的工艺：水印，阴影底纹，钢印LOGO烫金烫银，LOGO烫金烫银复合重叠。文字图案浮雕、激光镭射、紫外荧光、温感、复印防伪等防伪工艺。材料咨询办理、认证咨询办理请加学历顾问Q/微741003700
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留信网认证的作用:
1:该专业认证可证明留学生真实身份
2:同时对留学生所学专业登记给予评定
3:国家专业人才认证中心颁发入库证书
4:这个认证书并且可以归档倒地方
5:凡事获得留信网入网的信息将会逐步更新到个人身份内，将在公安局网内查询个人身份证信息后，同步读取人才网入库信息
6:个人职称评审加20分
7:个人信誉贷款加10分
8:在国家人才网主办的国家网络招聘大会中纳入资料，供国家高端企业选择人才
Bob Reedy - Nitrate in Texas Groundwater.pdf
Presented at June 6-7 Texas Alliance of Groundwater Districts Business Meeting
Equivariant neural networks and representation theory
Or: Beyond linear.
Abstract: Equivariant neural networks are neural networks that incorporate symmetries. The nonlinear activation functions in these networks result in interesting nonlinear equivariant maps between simple representations, and motivate the key player of this talk: piecewise linear representation theory.
Disclaimer: No one is perfect, so please mind that there might be mistakes and typos.
dtubbenhauer@gmail.com
Corrected slides: dtubbenhauer.com/talks.html
Thornton ESPP slides UK WW Network 4_6_24.pdf
ESPP presentation to EU Waste Water Network, 4th June 2024 “EU policies driving nutrient removal and recycling
and the revised UWWTD (Urban Waste Water Treatment Directive)”
Sharlene Leurig - Enabling Onsite Water Use with Net Zero Water
Sharlene Leurig - Enabling Onsite Water Use with Net Zero WaterTexas Alliance of Groundwater Districts
Presented at June 6-7 Texas Alliance of Groundwater Districts Business MeetingSAR of Medicinal Chemistry 1st by dk.pdf
In this presentation include the prototype drug SAR on thus or with their examples .
Syllabus of Second Year B. Pharmacy
2019 PATTERN.
Phenomics assisted breeding in crop improvement
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Weste...
Context. With a mass exceeding several 104 M⊙ and a rich and dense population of massive stars, supermassive young star clusters
represent the most massive star-forming environment that is dominated by the feedback from massive stars and gravitational interactions
among stars.
Aims. In this paper we present the Extended Westerlund 1 and 2 Open Clusters Survey (EWOCS) project, which aims to investigate
the influence of the starburst environment on the formation of stars and planets, and on the evolution of both low and high mass stars.
The primary targets of this project are Westerlund 1 and 2, the closest supermassive star clusters to the Sun.
Methods. The project is based primarily on recent observations conducted with the Chandra and JWST observatories. Specifically,
the Chandra survey of Westerlund 1 consists of 36 new ACIS-I observations, nearly co-pointed, for a total exposure time of 1 Msec.
Additionally, we included 8 archival Chandra/ACIS-S observations. This paper presents the resulting catalog of X-ray sources within
and around Westerlund 1. Sources were detected by combining various existing methods, and photon extraction and source validation
were carried out using the ACIS-Extract software.
Results. The EWOCS X-ray catalog comprises 5963 validated sources out of the 9420 initially provided to ACIS-Extract, reaching a
photon flux threshold of approximately 2 × 10−8 photons cm−2
s
−1
. The X-ray sources exhibit a highly concentrated spatial distribution,
with 1075 sources located within the central 1 arcmin. We have successfully detected X-ray emissions from 126 out of the 166 known
massive stars of the cluster, and we have collected over 71 000 photons from the magnetar CXO J164710.20-455217.
Micronuclei test.M.sc.zoology.fisheries.
Current Ms word generated power point presentation covers major details about the micronuclei test. It's significance and assays to conduct it. It is used to detect the micronuclei formation inside the cells of nearly every multicellular organism. It's formation takes place during chromosomal sepration at metaphase.
Randomised Optimisation Algorithms in DAPHNE
Slides from talk:
Aleš Zamuda: Randomised Optimisation Algorithms in DAPHNE .
Austrian-Slovenian HPC Meeting 2024 – ASHPC24, Seeblickhotel Grundlsee in Austria, 10–13 June 2024
https://ashpc.eu/
The debris of the ‘last major merger’ is dynamically young
The Milky Way’s (MW) inner stellar halo contains an [Fe/H]-rich component with highly eccentric orbits, often referred to as the
‘last major merger.’ Hypotheses for the origin of this component include Gaia-Sausage/Enceladus (GSE), where the progenitor
collided with the MW proto-disc 8–11 Gyr ago, and the Virgo Radial Merger (VRM), where the progenitor collided with the
MW disc within the last 3 Gyr. These two scenarios make different predictions about observable structure in local phase space,
because the morphology of debris depends on how long it has had to phase mix. The recently identified phase-space folds in Gaia
DR3 have positive caustic velocities, making them fundamentally different than the phase-mixed chevrons found in simulations
at late times. Roughly 20 per cent of the stars in the prograde local stellar halo are associated with the observed caustics. Based
on a simple phase-mixing model, the observed number of caustics are consistent with a merger that occurred 1–2 Gyr ago.
We also compare the observed phase-space distribution to FIRE-2 Latte simulations of GSE-like mergers, using a quantitative
measurement of phase mixing (2D causticality). The observed local phase-space distribution best matches the simulated data
1–2 Gyr after collision, and certainly not later than 3 Gyr. This is further evidence that the progenitor of the ‘last major merger’
did not collide with the MW proto-disc at early times, as is thought for the GSE, but instead collided with the MW disc within
the last few Gyr, consistent with the body of work surrounding the VRM.
Deep Software Variability and Frictionless Reproducibility
Deep Software Variability and Frictionless ReproducibilityUniversity of Rennes, INSA Rennes, Inria/IRISA, CNRS
The ability to recreate computational results with minimal effort and actionable metrics provides a solid foundation for scientific research and software development. When people can replicate an analysis at the touch of a button using open-source software, open data, and methods to assess and compare proposals, it significantly eases verification of results, engagement with a diverse range of contributors, and progress. However, we have yet to fully achieve this; there are still many sociotechnical frictions.
Inspired by David Donoho's vision, this talk aims to revisit the three crucial pillars of frictionless reproducibility (data sharing, code sharing, and competitive challenges) with the perspective of deep software variability.
Our observation is that multiple layers — hardware, operating systems, third-party libraries, software versions, input data, compile-time options, and parameters — are subject to variability that exacerbates frictions but is also essential for achieving robust, generalizable results and fostering innovation. I will first review the literature, providing evidence of how the complex variability interactions across these layers affect qualitative and quantitative software properties, thereby complicating the reproduction and replication of scientific studies in various fields.
I will then present some software engineering and AI techniques that can support the strategic exploration of variability spaces. These include the use of abstractions and models (e.g., feature models), sampling strategies (e.g., uniform, random), cost-effective measurements (e.g., incremental build of software configurations), and dimensionality reduction methods (e.g., transfer learning, feature selection, software debloating).
I will finally argue that deep variability is both the problem and solution of frictionless reproducibility, calling the software science community to develop new methods and tools to manage variability and foster reproducibility in software systems.
Exposé invité Journées Nationales du GDR GPL 2024
THEMATIC APPERCEPTION TEST(TAT) cognitive abilities, creativity, and critic...
THEMATIC APPERCEPTION TEST(TAT) cognitive abilities, creativity, and critic...Abdul Wali Khan University Mardan,kP,Pakistan
hematic appreciation test is a psychological assessment tool used to measure an individual's appreciation and understanding of specific themes or topics. This test helps to evaluate an individual's ability to connect different ideas and concepts within a given theme, as well as their overall comprehension and interpretation skills. The results of the test can provide valuable insights into an individual's cognitive abilities, creativity, and critical thinking skillsRecently uploaded (20)
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...
aziz sancar nobel prize winner: from mardin to nobel
aziz sancar nobel prize winner: from mardin to nobel
3D Hybrid PIC simulation of the plasma expansion (ISSS-14)
3D Hybrid PIC simulation of the plasma expansion (ISSS-14)
Equivariant neural networks and representation theory
Equivariant neural networks and representation theory
Sharlene Leurig - Enabling Onsite Water Use with Net Zero Water
Sharlene Leurig - Enabling Onsite Water Use with Net Zero Water
EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Weste...
EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Weste...
The debris of the ‘last major merger’ is dynamically young
The debris of the ‘last major merger’ is dynamically young
Deep Software Variability and Frictionless Reproducibility
Deep Software Variability and Frictionless Reproducibility
THEMATIC APPERCEPTION TEST(TAT) cognitive abilities, creativity, and critic...
THEMATIC APPERCEPTION TEST(TAT) cognitive abilities, creativity, and critic...
Strong reversal of the lung fibrosis disease signature by autotaxin inhibitor GLPG1690 in a mouse model for IPF
- 1. ©Copyright 2016 Galapagos NV Strong reversal of the lung fibrosis disease signature by autotaxin inhibitor GLPG1690 in a mouse model for IPF Maté Ongenaert, PhD Senior Scientist Bioinformatics Sonia Dupont, Roland Blanqué, Reginald Brys, Ellen van der Aar, Bertrand Heckmann ERS London, UK September 6th 2016
- 2. 2 Disclosure • I and other authors have the following real or percieved conflicts of interest that relate to this presentation: All employees of Galapagos NV (Mechelen, Belgium) or Galapagos SASU (Romainville, France)
- 3. 3 Outline Autotaxin/LPA pathway background Transcriptomics studies in BLM model Mouse bleomycin (BLM) model - GLPG1690 performance and target engagement Summary and outlook
- 4. 4 GT2645 ATX Lysophosphatidylcholine (LPC) Lysophosphatidic acid (LPA) Autotaxin (ATX) Target background • Also known as ENPP2, secreted enzyme • Widely expressed (highest in brain, lymph nodes, kidney and testis) • Converts LPC to the bioactive lipid mediator LPA • “LPA” covers a family of related molecules (i.e. LPA18:2, LPA20:4) • ATX is main source of LPA in blood
- 5. 5 LPA signalling • LPA acts through at least six distinct G-protein-coupled receptors (LPA1–6) • LPA controls activities like migration, contraction & survival • Studies with KO of LPA receptors indicate a role in bone development fertility/reproduction neurogenesis formation of blood- and lymphatic vessels Stoddard and Chun, 2015
- 6. 6 ATX/LPA pathway and IPF Preclinical and translational validation • In modeled disease: bleomycin-exposed mice increased LPA in BALF (Tager et al, 2008) ATX levels increased in lungs (Oikonomou, 2012) inhibition of ATX attenuated lung fibrosis in mice (Oikonomou, 2012) genetic or pharmacological inhibition of LPAR1 attenuates development of pulmonary fibrosis (Tager et al, 2008; Swaney et al, 2010) • In patients with idiopathic pulmonary fibrosis (IPF) LPA levels increased in BALF (Tager et al, 2008) ATX levels elevated in lung (Oikonomou et al, 2012) LPA increased in exhaled breath condensate (Montesi et al, 2014)
- 7. 7 GLPG1690 reduces fibrosis in BLM models, reduces LPA levels in BALF Mouse bleomycin model for lung fibrosis (prophylactic) Relative levels of LPA species in BALF of mice subjected to BLM treatment GLPG1690 in vivo activity LPApeakarea/ LPA17:0peakarea vehicle BLM + vehicle BLM + pirfenidone 50 mg/kg bid BLM + ‘1690 30 mg/kg bid Group Ashcroftscore
- 8. 8 GLPG1690 - bleomycin model Global transcriptomics (PCA) vehicle bleomycin GLPG1690 Lung microarray profiling: GLPG1690 protects for BLM induced effects on a global transcriptome level
- 9. 9 GLPG1690 - bleomycin model Most affected genes vehicle BLM ‘1690 • Top-40 most differentially expressed genes perfect separation of the BLM cluster from sham GLPG1690 partially reverses the BLM effect
- 10. 10 GLPG1690 - bleomycin model Relevance in model ‘1690 (log2 Fold Change) BLM(log2Foldchange) Strong negative correlation (Spearman R=-0.74) between BLM effect and GLPG1690 effects ‘1690 (DOWN) BLM (UP) 1088 probes 259 18 ^ Probes with both: - |log2(FC)|>1 - FDR< 1%
- 11. 11 GLPG1690 - bleomycin model Functions Color: log2 FC Area: log2 FC * -log10(p-value) Tnc Tnc Cxcl12 Smad6 Smad6 Col5a1 Serpine2 Col1a2 Serpine2 Ednrb Ccl2 immune response cytokines, Jak-Stat, TGFb Extracellular matrix – focal adhesion Col1a2 • Affected functions and pathways by BLM and counteracted by GLPG1690 relevant in BLM model and IPF biology: extracellular matrix (Tnc, Spp1) several collagens (Col3a1, Col5a1) cytokines / chemokines (Cxcl12, Ccl2)
- 12. 12 GLPG1690 - bleomycin model BLM/GLPG1690 – IPF relevance • Many of the genes identified are relevant in IPF and/or altered in expression in IPF patients (assessed in 4 public transcriptomics studies) • 52 genes upregulated in BLM and at least in ¾ IPF vs. normal studies and strongly counteracted by ‘1690 • BLM: log2(FC)>1 • counteracted by ‘1690: log2(FC)< -1 • IPF studies: log2(FC)>0.5 in at least ¾ studies Gene Symbols BLM mouse models GLPG1690 Human IPF (public data) Mouse Human BLM this study BLM GSE40151 GLPG1690 this study GSE32537 GSE10667 GSE53845 Yang et al. Cxcl12 CXCL12 3.09 1.11 -1.4 1.17 2.21 1.96 1.5 Col3a1 COL3A1 2.51 1.15 -0.71 1.4 2.82 1.71 2.19 Spp1 SPP1 4.19 1.59 -1.56 1.61 3.67 3.49 1.77 Tnc TNC 4.6 2.54 -2.22 1.13 0.86 1.89 1.49
- 13. 13 GLPG1690: potent and selective inhibitor of autotaxin Pharmacological and literature data support positioning in IPF Strong anti-fibrotic effects in the mouse bleomycin model IPF-related gene expression signature clearly affected after GLPG1690 administration Exploratory phase IIa study in IPF patients ongoing (FLORA)
- 14. 14 Many thanks to all involved Galapagos colleagues
Editor's Notes
- N