Berlin Institute of Health

Berlin, Germany

Berlin Institute of Health

Berlin, Germany
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IMAGE:  A microscopic image of tumor tissue under the influence of TNF (left) and IFN- γ (right). Red blood cells are pictured in a magenta color. TNF bursts the blood vessels... view more Immunotherapy with T-cells offers great hope to people suffering from cancer. Some initial successes have already been made in treating blood cancer, but treating solid tumors remains a major challenge. The signaling molecule interferon gamma, which is produced by T-cells, plays a key role in the therapy. It cuts off the blood supply to tumors, as a new study in the journal Nature reveals. The immune system is the body's most powerful weapon against diseases. So what if it were possible to use the immune system to fight cancer? For a long time now, researchers have been trying to do just that - for example, by employing a special kind of immune cell called T-cells. They are "special mobile forces" that - after undergoing training - patrol the body, and can seek out and kill cancer cells. This strategy has been successful in initial clinical trials - but mostly just in the treatment of cancers that do not form tumors, such as blood cancer. Large solid tumors, on the other hand, sometimes pose big problems for T-cells. Though adept at targeting cancer cells swimming in the bloodstream, they have difficulty attacking compact tumors. The tumor weakens the aggressors through the delivery of inhibiting signals. The scientists working with Dr. Thomas Kammertöns, Prof. Thomas Blankenstein, Prof. Hans Schreiber and Christian Friese are searching for solutions with their research team at Charité - Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute of Health (BIH) and the Einstein Foundation. In a study published in the journal Nature, they investigated how the signaling molecules of T-cells affect the immediate tumor environment, which includes the connective tissue as well as the blood vessels that supply the tumor. T-cells produce not only tumor necrosis factor (TNF) but also the molecule interferon gamma (IFN-γ). Until now, however, there has been little understanding about how IFN-γ really works. "We knew that IFN-γ attacks cancer cells via the tumor microenvironment," says Kammertöns. "We now wanted to find out exactly which cells are targeted by the signaling molecules." The researchers generated genetically modified mice and used a clinically relevant cancer model. This included animals in which only blood vessel cells were susceptible to the signaling molecule. In this mouse model IFN-γ pruned back the blood vessels in the tumors, thus shutting down the supply of oxygen and nutrients and killing the tumors. The researchers were able to observe this process microscopically in living mice in fine detail. They found that the blood vessel cells alone responded to the signaling molecule. When the researchers targeted other types of cells with IFN-γ, the tumors continued their growth. These findings provided an explanation for the molecule's powerful properties, which were already well known. "IFN-γ is one of the most important weapons in the T-cells' arsenal," says Thomas Kammertöns. Thomas Blankenstein, lead investigator of the study, says: "The two together - IFN-γ and tumor necrosis factor - are a powerful team. TNF bursts tumor blood vessels, thus opening up the tissue, while IFN-γ cuts off the blood supply and keeps the tumor at bay over the long term." The study offered the researchers clues on how to improve T-cell therapy for solid cancer tumors. Thomas Blankenstein explains: "We want to understand exactly how T-cells target tumors. Destroying a tumor's infrastructure is probably more effective than killing individual cancer cells." "Our findings are significant beyond tumor therapy," says Thomas Kammertöns. "Interestingly, the mechanism used by IFN-γ to eliminate solid tumors resembles the physiological regression of blood vessels during development. It also disrupts wound healing." "IFN-γ might also affect the formation of new blood vessels after strokes or heart attacks. That's why we want to find out more about the molecular processes behind all of this."

Piper M.D.W.,University College London | Soultoukis G.A.,Max Planck Institute for Biology of Ageing | Blanc E.,Berlin Institute of Health | Mesaros A.,Max Planck Institute for Biology of Ageing | And 10 more authors.
Cell Metabolism | Year: 2017

Balancing the quantity and quality of dietary protein relative to other nutrients is a key determinant of evolutionary fitness. A theoretical framework for defining a balanced diet would both reduce the enormous workload to optimize diets empirically and represent a breakthrough toward tailoring diets to the needs of consumers. Here, we report a simple and powerful in silico technique that uses the genome information of an organism to define its dietary amino acid requirements. We show for the fruit fly Drosophila melanogaster that such “exome-matched” diets are more satiating, enhance growth, and increase reproduction relative to non-matched diets. Thus, early life fitness traits can be enhanced at low levels of dietary amino acids that do not impose a cost to lifespan. Exome matching also enhanced mouse growth, indicating that it can be applied to other organisms whose genome sequence is known. © 2017 The Author(s)

Mishto M.,Charité - Medical University of Berlin | Mishto M.,Berlin Institute of Health | Mishto M.,King's College London | Liepe J.,Max Planck Institute for Biophysical Chemistry
Trends in Immunology | Year: 2017

CD8+ T cell specificity depends on the recognition of MHC class I-epitope complexes at the cell surface. These epitopes are mainly produced via degradation of proteins by the proteasome, generating fragments of the original sequence. However, it is now clear that proteasomes can produce a significant portion of epitopes by reshuffling the antigen sequence, thus expanding the potential antigenic repertoire. MHC class I-restricted spliced epitopes have been described in tumors and infections, suggesting an unpredicted relevance of these peculiar peptides. We review current knowledge about proteasome-catalyzed peptide splicing (PCPS), the emerging rules governing this process, and the potential implications for our understanding and therapeutic use of CD8+ T cells, as well as mechanisms generating other non-canonical antigenic epitopes targeted by the T cell response. The proteasome not only cuts proteins into fragments through canonical peptide bond hydrolysis but also ligates them through PCPS.Through PCPS, the proteasome can significantly shape antigen presentation. This process is estimated to produce about one fourth of all antigenic peptide molecules and to enlarge the antigenic landscape - in term of antigenic peptide diversity and antigens presented at the cell surface - by around 30%.PCPS is not a random process that ligates any fragment produced by proteasome. On the contrary, it seems to be finely tuned by driving forces that have been only subject to preliminary investigation.Proteasome-generated spliced epitopes derived from tumor-associated antigens activate tumor-infiltrating lymphocytes, which in turn can reduce the tumor mass in patients and animal models.MHC-I and MHC-II immunopeptidomes contain other non-canonical peptides which can play a special role in autoimmune diseases such as type 1 diabetes mellitus. © 2017 Elsevier Ltd.

Laube G.,Charité - Medical University of Berlin | Laube G.,Berlin Institute of Health | Bernstein H.-G.,Otto Von Guericke University of Magdeburg
Biochemical Journal | Year: 2017

Agmatine, the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α2-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague. The purification and biochemical characterization of natural mammalian arginine decarboxylase and agmatinase still are open issues. Nevertheless, the agmatinergic system is currently one of the most promising candidates in order to pharmacologically interfere with some major diseases of the central nervous system, which are summarized in the present review. Particularly with respect to major depression, agmatine, its derivatives, and metabolizing enzymes show great promise for the development of an improved treatment of this common disease. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

News Article | October 7, 2016

The MDC research team headed by Dr. Oliver Rocks is investigating the mechanisms that control the remodeling of the cell skeleton. During a screen of proteins involved in this process the scientists made an interesting discovery - they noticed that one of the proteins binds the catalytic subunit of the PKA. "We were surprised to find the catalytic subunit of PKA, because normally control of this pathway is through the regulatory subunit," says the researcher. In the classical model of PKA regulation, the regulatory subunits dock onto the catalytic ones and stop them sending signals. They only release the catalytic subunits when the cell receives a signal that increases the levels of the cellular chemical cAMP. cAMP clips onto the regulatory subunits and force them to set the catalytic subunits free. In the screen the catalytic subunit of PKA (PKAC) was binding to a protein called ARHGAP36. For her PhD research in Dr. Rocks's lab, Rebecca Eccles investigated how ARHGAP36 interacts with PKAC. She worked with other scientists at the MDC, the Berlin Institute of Health (BIH), as well as partners at the University of Liverpool. Eccles found that ARHGAP36 can turn off PKAC in two ways: by binding to it and blocking its action, and by sending it on the path to one of the cell's degradation centers. PKA's job in the cell is to pass on signals, which the catalytic subunit does by its kinase action - kinases attach a phosphate molecule to their target proteins (substrates). ARHGAP36 stops PKAC from binding its substrates in much the same way as a key stuck in a lock prevents you opening a door. Because PKA occurs in almost all tissues, the researchers wanted to identify where and when it is inhibited by ARHGAP36. "ARGAP36 is a strong inhibitor, so you wouldn't want it turning off PKA everywhere," Rocks explains. He and his team found that ARHGAP36 is not present in all cells all the time - in fact its expression is quite limited, for example to embryonic muscle cells. Abnormally high levels of ARHGAP3 are also found in at least one of the four subtypes of medulloblastoma, the most common childhood brain cancer, as well as in neuroblastoma, another frequent cancer of the nervous system in children. The exact biological role of ARHGAP36 is not yet understood, but it may well play a role in muscle development and in tumor progression in some cancers. For example, changes in PKA signaling could influence tumor growth in many types of cancer. Understanding how signaling pathways are controlled may also be useful in drug development since it opens up opportunities for regulating proteins indirectly and thus blocking enzymes that are otherwise hard to manipulate. Explore further: Study reveals the regulatory mechanism of key enzyme More information: Rebecca L. Eccles et al, Bimodal antagonism of PKA signalling by ARHGAP36, Nature Communications (2016). DOI: 10.1038/NCOMMS12963

Chu V.T.,Max Delbrück Center for Molecular Medicine | Weber T.,Max Delbrück Center for Molecular Medicine | Wefers B.,Helmholtz Center for Environmental Research | Wefers B.,Deutsches Zentrum fur Neurodegenerative Erkrankungen E.V. | And 8 more authors.
Nature Biotechnology | Year: 2015

The insertion of precise genetic modifications by genome editing tools such as CRISPR-Cas9 is limited by the relatively low efficiency of homology-directed repair (HDR) compared with the higher efficiency of the nonhomologous end-joining (NHEJ) pathway. To enhance HDR, enabling the insertion of precise genetic modifications, we suppressed the NHEJ key molecules KU70, KU80 or DNA ligase IV by gene silencing, the ligase IV inhibitor SCR7 or the coexpression of adenovirus 4 E1B55K and E4orf6 proteins in a 'traffic light' and other reporter systems. Suppression of KU70 and DNA ligase IV promotes the efficiency of HDR 4-5-fold. When co-expressed with the Cas9 system, E1B55K and E4orf6 improved the efficiency of HDR up to eightfold and essentially abolished NHEJ activity in both human and mouse cell lines. Our findings provide useful tools to improve the frequency of precise gene modifications in mammalian cells. © 2015 Nature America, Inc. All rights reserved.

Ebert A.D.,Stanford University | Diecke S.,Max Delbrück Center for Molecular Medicine | Diecke S.,Berlin Institute of Health | Chen I.Y.,Stanford University | Wu J.C.,Stanford University
EMBO Molecular Medicine | Year: 2015

Heart disease remains a leading cause of mortality and a major worldwide healthcare burden. Recent advances in stem cell biology have made it feasible to derive large quantities of cardiomyocytes for disease modeling, drug development, and regenerative medicine. The discoveries of reprogramming and transdifferentiation as novel biological processes have significantly contributed to this paradigm. This review surveys the means by which reprogramming and transdifferentiation can be employed to generate induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and induced cardiomyocytes (iCMs). The application of these patient-specific cardiomyocytes for both in vitro disease modeling and in vivo therapies for various cardiovascular diseases will also be discussed. We propose that, with additional refinement, human disease-specific cardiomyocytes will allow us to significantly advance the understanding of cardiovascular disease mechanisms and accelerate the development of novel therapeutic options. © 2015 The Authors.

Bielow C.,Max Delbrück Center for Molecular Medicine | Bielow C.,Berlin Institute of Health | Mastrobuoni G.,Max Delbrück Center for Molecular Medicine | Kempa S.,Max Delbrück Center for Molecular Medicine | Kempa S.,Berlin Institute of Health
Journal of Proteome Research | Year: 2016

Mass spectrometry-based proteomics coupled to liquid chromatography has matured into an automatized, high-throughput technology, producing data on the scale of multiple gigabytes per instrument per day. Consequently, an automated quality control (QC) and quality analysis (QA) capable of detecting measurement bias, verifying consistency, and avoiding propagation of error is paramount for instrument operators and scientists in charge of downstream analysis. We have developed an R-based QC pipeline called Proteomics Quality Control (PTXQC) for bottom-up LC-MS data generated by the MaxQuant1 software pipeline. PTXQC creates a QC report containing a comprehensive and powerful set of QC metrics, augmented with automated scoring functions. The automated scores are collated to create an overview heatmap at the beginning of the report, giving valuable guidance also to nonspecialists. Our software supports a wide range of experimental designs, including stable isotope labeling by amino acids in cell culture (SILAC), tandem mass tags (TMT), and label-free data. Furthermore, we introduce new metrics to score MaxQuant's Match-between-runs (MBR) functionality by which peptide identifications can be transferred across Raw files based on accurate retention time and m/z. Last but not least, PTXQC is easy to install and use and represents the first QC software capable of processing MaxQuant result tables. PTXQC is freely available at © 2015 American Chemical Society.

Kuhnen P.,Charité - Medical University of Berlin | Clement K.,University Pierre and Marie Curie | Wiegand S.,Charité - Medical University of Berlin | Blankenstein O.,Charité - Medical University of Berlin | And 7 more authors.
New England Journal of Medicine | Year: 2016

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopio-melanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2). Copyright © 2016 Massachusetts Medical Society.

Holman C.,Charité - Medical University of Berlin | Piper S.K.,Charité - Medical University of Berlin | Grittner U.,Charité - Medical University of Berlin | Diamantaras A.A.,Charité - Medical University of Berlin | And 5 more authors.
PLoS Biology | Year: 2016

Given small sample sizes, loss of animals in preclinical experiments can dramatically alter results. However, effects of attrition on distortion of results are unknown. We used a simulation study to analyze the effects of random and biased attrition. As expected, random loss of samples decreased statistical power, but biased removal, including that of outliers, dramatically increased probability of false positive results. Next, we performed a meta-analysis of animal reporting and attrition in stroke and cancer. Most papers did not adequately report attrition, and extrapolating from the results of the simulation data, we suggest that their effect sizes were likely overestimated. © 2016 Holman et al.

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