What to do when a cancer subtype can’t be targeted with drugs or hormones? Researchers of e:Med Her2low alliance focused their attention on understanding the metabolic needs of cancer cells. Their study revealed that cancer cells operate with altered metabolic and nutrient-sensing pathways to sustain tumorigenesis and these alterations might be targeted as a therapy approach
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Scientists from the e:Med junior alliance LeukoSyStem have developed the method MutaSeq, that can distinguish cancer stem cells, mature cancer cells, and healthy stem cells based on their genetics. The method enables researchers to create highly detailed profiles of cancer cells, helping them understand every individual cell from a cancer. The result of this study opens up new possibilities in cancer research
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G3BP proteins inhibit the metabolic driver MTOR, a signaling protein that plays a central role in tumor diseases and developmental disorders of the brain. This is reported this week in the journal Cell by scientists of the BMBF-funded e:Med junior network GlioPATH together with a Europe-wide research network. G3BP proteins may serve as molecular markers to personalize therapies.
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Success of a kidney transplant depends on how strongly the patient’s immune system reacts to the foreign cells. Scientists from the e:Med consortium e:Kid coordinated by Dr. Nina Babel have now developed the TreaT test, which uses cells from the patient's urine after a kidney transplantation to predict how well the recipient will tolerate the donor kidney. As a result, the accompanying immunosuppressive therapy can be adapted to each individual and over-medication can be prevented.
Highlights from e:Medium Newsletter
Scientists from e:Med junior alliance GlioPATH discovered that the metabolic enzyme IL4I1 promotes the spread of tumour cells and suppresses the immune system. IL4I1 is produced to a greater extent in tumours and activates the dioxin receptor. Agents that inhibit IL4I1 could open up new opportunities for cancer therapy in the future. The scientists have now published their results in the journal Cell.
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Tumors can behave differently in patients. This has already been well investigated and is a part of personalized-therapy concepts. The differences of a tumor within a patient are, however, less well known. These differences are called intratumoral heterogeneity. Heterogeneity can also influence the effectiveness of the therapy. In this project, e:Med scientists have inspected intratumoral differences and investigated transcription (scRNA-Seq), genetics and drug response in the different cells of B-cell lymphoma.
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Resistance of cancer cells against therapeutic agents is a major cause of treatment failure, especially in recurrent diseases. An international team of researchers in the e:Med junior research alliance SUPR-G has identified a novel mechanism of chemoresistance which has now been published in ‘Nature Communications’. It is driven by the Unfolded Protein Response (UPR), a cellular stress response pathway that alters gene expression and cellular metabolism to promote cell survival under stress.
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Systems medicine can help to better understand the novel corona virus and the pandemic. Substantial contributions have already been made with systems medicine methods: from the automated search for drug candidates against COVID-19, the simulation of infections or the return to normality to the examinations of which cells are preferably infected and why. Here you find a selection of corona research activities by system medicine researcher - especially by e:Med scientists.
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At the beginning of 2020, seven new junior research alliances in e:Med Module IIIb "Junior systems medicine research alliances" were launched by the support of the BMBF. In system-oriented research approaches, young scientists work on interdisciplinary medical issues relating to different types of cancer, chronic kidney disease or intestinal inflammation as well as metabolic or connective tissue diseases.
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The nine interdisciplinary research alliances of the e:Med Module I started at the end of 2019/beginning of 2020 with the support of the BMBF. In numerous sub-projects at different locations all over Germany, a common disease-related problem is being studied using systems medicine research approaches. Clinical working groups, high-throughput teams from basic biomedical research and experts in information technologies are working closely together on this.
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Four new interdisciplinary demonstrator research networks started mid/end of 2019 in the e:Med module II "Demonstrators for individualized Medicine". The goal of the new demonstrators is the systemoriented (further) development of innovative methods and models in order to use them directly in the individualized prevention, diagnostic and therapy.
to the new demonstrator projects
On Friday, September 27, 2019, the European Researchers‘ Night, an EU-funded initiative took place in Heidelberg / Mannheim. The e:Med Systems Medicine office was particularly well received by young visitors with their offer: their own name could be converted into the DNA code to make a very personal pearl bracelet.
Scientists from the e:Med alliance SMOOSE at the Technical University of Dortmund, in cooperation with physicians from Essen and Bochum, succeeded in producing a new AKT inhibitor, which is already showing initial efficacy against pancreatic cancer. The scientists succeeded in determining the first crystal structure of the complex of AKT1 with the new covalent alllosteric AKT inhibitor Borussertib, which provided important insights into the structural basis of the inhibition.
With this newsletter we would like to inform you about the results and activities of systems medical research in e:Med. Read about news on the development of anti-cancer agents, models for optimized drug delivery, the recurrence of glioblastomas, alcohol addiction in adolescence and the separation of relevant from irrelevant information in the brain.
Glioblastomas frequently relapse despite subsequent radiation- and chemotherapy. Are there specific mutations that enable glioblastoma cells to evade therapy? To answer this question, scientists of the e:Med alliances SYS-GLIO and SYSMED-NB jointly investigated glioblastoma tissue samples of 50 affected persons.
The BMBF funded ConISyM Summer School 2019 under direction of Prof. Dr. med. Bernd Pichler focused on image processing in systems medicine. ConISyM aimed to strengthen methodological skills of young scientists and to open up new perspectives on their own projects. The young scientists were inspired to think beyond their own research field and learned new techniques that can be applied in combination to optimize their use in answering various scientific questions.
Specific targeted therapies are commonly used for blood cancer patients suffering from chronic myeloid leukemia (CML). Although these medications are very effective, most patients need to take these drugs their whole life. Reducing the dosage and adapting it to each patient individually is the goal of a mathematical model developed by systems medicine scientists from Dresden.
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The "Personalized Medicine Day" in Berlin was a great success! 400 pupils, students, scientists and interested citizens have come to the Urania and have obtained information through lectures and interactive experiments on the current research of personalized medicine.
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For some patients, suffering from a specific type of Parkinson, a diabetic medication could help to stop disease progression.
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e:Med researchers from the SysMedAlcoholism consortium and their cooperation partners at the University of Tokyo found out for the first time by means of a new computational approach that the transition into an addictive drinking behavior are preceded by predictive "early warning signals". The analytical approach to elaborate longitudinal data has the potential to predict the onset of illness and changes in various stages of the disease in the state of health.
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How does Schizophrenia work on the molecular level? In this study, dynamic network neuroscience techniques and neuroimaging methods were applied by scientists of the e:Med consortia IntegraMent to uncover the molecular and genetic contributions of glutamate and brain network dynamics.
Type 2 diabetes causes pathological changes in the beta cells. Scientists have successfully depicted the processes on the basis of the metabolome and proteome for the first time. Their work has been published in Cell Metabolism.
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Personlized medicine for small cell lung cancer:
Small cell lung cancer is an aggressive type of cancer and can progress in very different, individual ways but so far no targeted therapy has been approved. By designing a mouse model mimicking a human disease phenotype, scientists discovered a promising combination therapy.
In about half of all patients with rare hereditary disorders, it is still unclear what exact position of the genome is responsible for their condition - despite whole genome sequencing analysis. Scientists from the fields of informatics and medicine have now joined forces to find a solution: A team from Munich has developed a method that significantly increases the chances of a successful search. The new approach looks not only at DNA, but also at RNA.
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Amino acids are important signaling molecules which influence cellular and organismal metabolism, however, their molecular targets are not yet completely identified. A systems study has now shed light into the molecular interaction network and the diverse cellular functions of amino acids.
Highlight from the e:MedIUM
Decoding T cell regulation in allergies:
What works differently in the immune system of allergic persons? Which immune cells can be held responsible for immune system overreaction? Scientists from Berlin, together with the e:Med consortia e:Kid around Professor Nina Babel, have now shed light on these questions and have decoded the role of the different T cells in allergies.
Mathematical models to predict and fight cancer:
How can mathematical models be used in order to improve cancer prognosis and therapy? In the studies presented here, e:Med scientists from SYSIMIT generated models to improve prediction of breast cancer development and for a personalized treatment of bacterial infection against cancer.
What are the causes of social phobia? This question was raised by scientists of the consortium IntegraMent. For this they examined mutations found in patients with social phobia. They discovered that a SNP in the serotonin transporter gene SLC6A4 is associated with the disease. Serotonin is an important substance in the brain, which also suppresses feelings of anxiety and is a common target of psychotropic drugs. The results emphasize that serotonin transporter play an important role in developing social phobia.
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Tools for improved analysis of gene regulation:
Regulatory DNA regions are important elements for gene activity control. However, these areas are very difficult to identify since the RNA produced is rapidly degraded. e:Med scientist Julien Gagneur from the junior research alliance mitOmics and colleagues published an innovative sequencing method in Science, which makes it possible to collect and map all RNA segments transcribed within 5 minutes. In addition, they created software for improved annotation of regulatory elements, which they applied to 127 human cell types and tissues.
Glioblastoma is an aggressive type of brain cancer which remains difficult to treat in children. In a (epi)genomic study, in ten percent of the patients MET-oncogene fusions were identified which promote the development of Glioblastoma but can be targeted and inhibited with clinically approved drugs. Scientists of the e:Med consortium CancerTelSys and of the demonstrator SYS-GLIO were substantially involved in this Nature Medicine publication.
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Cross-disease analysis shows genetic reasons for the common appearance of inflammatory diseases:
Why are some patients affected by several inflammatory diseases, for instance, intestinal and liver diseases, at the same time? e:Med scientists are seeking to understand the cause why inflammatory diseases appear together.
Genetic factors are responsible for bone loss with mutliple myeloma:
Bone loss is very common with multiple myeloma. Since therapy must be selected according to bone loss occurrence, predicting the course of the disease is important. Why some patients are affected whereas others are not was subject to a systems medicine analysis.
Tools enabling combined analysis of time-dependent omics data: How can cellular dynamics be defined at multiple levels and in temporal resolution? In order to map these complex processes, both the handling of large data sets as well as elaborated software solutions are required. An application for analyzing large amounts of omics data in terms of time is shown here.
Highlight from the e:Med Newsletter
An international consortium discovered that the differences between women and men in myocardial infarction are not attributed to the X chromosome. This was the first study ever to search for triggers of complex diseases on the X chromosome. The study that included more than 100,000 people was conducted by Prof. Jeanette Erdmann and Prof. Inke R. König, University of Lübeck, within the scope of the e:AtheroSysMed consortium. More than 80 scientists from 14 different countries were involved.
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In most tumors a high concentration of the transcription factor MYC is prevalent. e:Med scientists of the SYSMED-NB consortia now have discovered that high MYC-levels activate additional genes which encourage tumor formation. In low concentrations this important factor only binds to high affinity genes which are responsible for controlled cell proliferation. But when excessive amounts of MYC are produced in a cell, genes with a low affinity also get activated which leads to tumor formation. Scientists of the University of Würzburg investigated concentration-dependent expression patterns in cells and confirmed their studies using modeling approaches. Hence, the expression pattern depends on cellular MYC concentration. Partial inhibition of MYC might serve as a new target for therapy.
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In a new study, addiction researchers of the Institute of Psychopharmacology (Scientific Director: Professor Rainer Spanagel) and of the Clinic for Addictive Behavior and Addiction Medicine (Medical Director: Professor Falk Kiefer) at the CIMH found elevated concentrations of the neurotransmitter dopamine in brain regions of alcoholics who had been abstinent for a longer period of time. The results of the study has been published in the Proceedings of the National Academy of Sciences (PNAS).
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An international collaboration of organizations has reached a milestone in creating a library of complete genetic blueprints for the thousands of different proteins in human cells. The collection – consisting of open-reading frames (ORFs), the portions of genes that code for full-length proteins – is an essential resource for scientists studying the basic mechanics of human cells and how those processes go awry in disease.
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e:Med scientists from Helmholtz Zentrum München and colleagues from Technische Universität München and the European Bioinformatics Institute (EBI) have developed a computational approach which facilitates the identification of confounding factors and hidden biological processes in the analysis of single-cell RNA sequence data, enabling a more accurate picture of the different cell types. Thus, cell types can be identified that otherwise would remain undetected.
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e:Med scientists around Prof. Reinhardt from the university hospital Cologne showed an essential difference between healthy and tumor cells, which could be used as a target in cancer therapy. They found out that the enzymes MK2 and Chk1 are essential for proliferation of tumor cells with KRAS mutations. The dependence on the two enzymes distinguishes cancer from healthy cells. By blocking these enzymes, tumor growth could be inhibited without affecting healthy tissue.
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Every time a cell divides, the ends of chromosomes – the threads of DNA residing in the nucleus – shorten a bit. Once the chromosome ends, called telomeres, become too short, cells normally stop dividing. Scientists from the German Cancer Research Center (DKFZ) have now discovered how cancer cells make use of specific DNA repair enzymes to extend the telomeres. In this way, they escape the natural stop signal and can divide without limits. The Federal Ministry of Education and Research (BMBF) supports the project as part of the e:Med research initiative.
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The Deutsche Forschungsgemeinschaft awarded the Ursula M. Händel Animal Welfare Prize of to PD Dr. Dr. Hamid Noori. The e: Med Junior Research Group Leader is a scientist at the Max Planck Institute for Biological Cybernetics in Tübingen, where he and his team have developed a database and computer models that can predict the effects of novel substances on the rat brain. As a result, new studies can be designed more purposefully, avoiding unnecessary animal experiments.
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Michael Floßdorf, Leader of the e:Med junior research group Quan-T-Cell, recieved the Special MTZ Award of the DKFZ 2017 for his outstanding research. The scientist is investiating the immunological memory development and is using nmathematical models for this approach. After his Post-Doc at the DFKZ he now started his own research group in munich.
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The m4 Award was presented by the State Secretary Franz Josef Pschierer at the Munich Residenz on 1 December 2015. Dr. Nikola Müller, Martin Preusse and Prof. Dr. Dr. Fabian Theis from the Institute of Computational Biology at the Helmholtz Zentrum München are among the winners. Their project "KNOWING - Turning Big Data into Personalized Therapies" will be funded with a sum of 500,000 Euros over the next two years.
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The Berlin-Brandenburg Academy of Sciences prize - donated by the Monika Kutzner Foundation for the Promotion of Cancer Research - was awarded to Dr. (Med.) Christiane Opitz in 2014.
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Professor Peter Lichter has been presented with the Johann-Georg-Zimmermann Medal 2014/2015 for his life’s work. His merits include groundbreaking findings in the areas of molecular cytogenetics and genome structure. Furthermore, he developed new technologies to explain basic mechanisms of carcinogenesis.
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