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International team from Goethe University and the University of Kent identifies nitroxoline as a potential drug
Mpox – previously known as "monkeypox" – is currently spreading worldwide. An international research team from Goethe University and the University of Kent has now identified a compound that could help fight the disease. Their study has been published in the “Journal of Medical Virology".
Nitroxoline is the name of the new drug candidate that could potentially be used to treat mpox. It was identified by scientists at Goethe University and the University of Kent as part of a multi-site study. The results of their research will now allow clinical trials to begin soon.
The current mpox outbreak is the first of this size to occur outside of Africa and also the first mpox outbreak caused by human-to-human transmission. People with immunodeficiencies are particularly at risk from the disease. Although antiviral agents have already been shown to inhibit the replication of the mpox virus in experimental models, the efficacy of these substances has not yet been confirmed in humans and some may have significant side effects. In addition, there are insufficient stocks to treat all mpox patients. Moreover, resistance formation against tecovirimat, the most promising mpox drug candidate to date, has already been reported.
In the present study, the international team led by Professor Jindrich Cinatl (of Goethe University Frankfurt and the Dr. Petra Joh-Research Institute) and Professor Martin Michaelis (School of Biosciences, University of Kent) has identified nitroxoline, a well-tolerated antibiotic, as a potential treatment alternative for the mpox virus based on experiments using cell culture and skin explant models.
Nitroxoline is also effective against a tecovirimat-resistant strain of the mpox virus, as well as other bacterial and viral pathogens that are frequently co-transmitted with mpox viruses, meaning it simultaneously suppresses multiple pathogens that are often involved in severe courses of mpox. Since nitroxoline is a well-tolerated antibiotic that has long been used to treat humans, it can be tested directly against mpox in clinical trials.
"The emergence of resistant virus strains is a cause of great concern," says Professor Jindrich Cinatl of Goethe University and the Dr. Petra Joh-Research Institute. "It is very reassuring that nitroxoline is effective against a tecovirimat-resistant virus."
Professor Martin Michaelis of the University of Kent adds: "The more different drugs become available to treat viral diseases, the better. We hope that nitroxoline will turn out to be an effective treatment for mpox patients."
Publication: Denisa Bojkova, Nadja Zöller, Manuela Tietgen, Katja Steinhorst, Marco Bechtel, Tamara Rothenburger, Joshua Kandler, Sandra Ciesek, Holger Rabenau, Jindrich Cinatl (Goethe University Frankfurt); Mark Wass, Martin Michaelis (University of Kent); Julia Schneider, Victor Corman (Charité Berlin), Repurposing of the antibiotic nitroxoline for the treatment of mpox. In: Journal of Medical Virology
Prof. Jindrich Cinatl
Working Group Head
Institute for Medical Virology
Tel.: +49 (0)69 6301-6409
Award ceremony in Frankfurt’s Paulskirche – Acknowledgement of Frederick W. Alt and David G. Schatz, winners of the main prize, and of Leif S. Ludwig, winner of the Early Career Award
The 2023 Paul Ehrlich and Ludwig Darmstaedter Prize, worth €120,000, will today be awarded to immunologists Frederick W. Alt and David G. Schatz in Frankfurt's Paulskirche for their discovery of molecules and mechanisms that enable our immune system to perform the astonishing feat of recognizing billions of different bacterial, viral and other antigens on first contact. The Early Career Award goes to Leif S. Ludwig, biochemist and physician, for a method he has devised to analyze the origin and development of human blood cells, which also include the cells of the immune system.
Unlike more primitive organisms, jawed vertebrates like we humans not only have an innate immune system but also an adaptive one that is capable of preparing itself for all kinds of invaders. This is because – at some point in the course of evolution – one of our ancestors apparently succeeded in taming a DNA parasite that had implanted itself in his genome. This is how the parasite became the gene for an enzyme that advanced to become the command center of immunological diversity. This enzyme, RAG1/2, excises fragments from the DNA of certain chromosomes in maturing immune cells (lymphocytes) and recombines them to form functional genes in a random process. This somatic recombination multiplies the variability of antibodies and T cell receptors. It is a prerequisite for our body's ability to build around ten billion different antibodies, although it only has about 20,000 protein blueprints in the form of genes. David G. Schatz discovered the RAG1/2 enzyme, Frederick W. Alt the enzymes that repair the DNA excised by it. “In decades of research, Alt and Schatz have shed light on the previously hidden evolution of our adaptive immunity, and in so doing they have raised our knowledge of the development of the immune system to a new level," says Professor Thomas Boehm, Chairman of the Scientific Council of the Paul Ehrlich Foundation, commending the achievements of the two winners of the main prize.
The RAG1/2 enzyme is the motor for somatic recombination. Without it, neither functional B and T cells nor effective adaptive immunity can develop. Many cases of severe immunodeficiency are caused by mutations of the RAG genes, and some lymphomas and leukemias are associated with malfunctions of the enzymes encoded by these genes. This makes understanding not only the molecular mechanism but also their evolutionary origin and how they behave in the living cell nucleus even more important. According to Schatz's findings, RAG1/2 originates from a gene that began jumping at will through the genome of our very early ancestors millions of years ago, like a kind of selfish parasite. In structural biology studies, Schatz has traced these jumps (transposons) over several stages of evolution. He has shown which biochemical tricks we vertebrates used to fix the jumping RAG1/2 gene at a certain position and harness it for the immune system.
As they migrate through the cell nucleus of immature lymphocytes, RAG enzymes draw together chromatin clusters, in which the DNA is coiled up in a space-saving way, temporarily and again and again to form recombination centers. There, they perform chromatin scanning, which Alt has described for the first time. They draw a chromatin thread, which can be over a million DNA letters long, through the recombination center like a loop. The result is that gene segments previously far apart are suddenly opposite each other and can be joined firmly together.
The B and T lymphocytes, on which acquired immunity rests, are components of our blood, in which at least 500 billion old cells per day are replaced by new ones in a healthy person. They originate from hematopoietic stem cells in the bone marrow and then mature on divergent developmental trajectories over several stages, like all other blood cells. Determining the resulting lineages and relationships is highly interesting for medicine, for example for identifying at which branch point a leukemia cell forms. Leif S. Ludwig, the winner of this year's Early Career Award, has devised a method that opens up the possibility for the first time for medicine to do this relatively inexpensively, quickly and reliably. Ludwig's method, which has already been tested on individual patients, combines the analysis of mutations in mitochondria with the latest technologies for the gene sequencing of individual cells.
2023 Paul Ehrlich and Ludwig Darmstaedter Prize
Dr. Frederick W. Alt is Charles A. Janeway Professor of Pediatrics and Director of the Program in Cellular and Molecular Medicine at Boston Children's Hospital, a Howard Hughes Medical Institute Investigator, and Professor of Genetics at Harvard Medical School.
Dr. David G. Schatz is Professor of Molecular Biophysics and Biochemistry at Yale University and Chairperson of the Department of Immunobiology at Yale School of Medicine.
2023 Paul Ehrlich and Ludwig Darmstaedter Early Career Award
Dr. Leif S. Ludwig is the leader of the Emmy Noether Junior Research Group “Stem Cell Dynamics and Mitochondrial Genomics" at the Berlin Institute of Health at Charité and the Max Delbrück Center. https://www.mdc-berlin.de/de/ludwig
Editors: Joachim Pietzsch / Dr Markus Bernards, Science Editor, PR & Communication Department, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, email@example.com.
Defect in gene regulation is responsible for high leukaemia risk in children with Down syndrome – biochemical analysis creates basis for therapy development
People with a third copy of chromosome 21, known as trisomy 21, are at high risk of developing Acute Myeloid Leukaemia (AML), an aggressive form of blood cancer. Scientists led by the Department of Paediatrics at University Hospital Frankfurt have now identified the cause: although the additional chromosome 21 leads to increased gene dosage of many genes, it is above all the perturbation of the RUNX1 gene – a gene that regulates many other genes – that seems to be responsible for AML pathogenesis. Targeting the perturbed regulator could pave the way for new therapies.
Leukaemia (blood cancer) is a group of malignant and aggressive diseases of the blood-forming cells in the bone marrow. Very intensive chemotherapy and in some cases a bone marrow transplant are the only cure. Like all cancers, leukaemia is caused by changes in the DNA, the heredity material present in human cells in the form of 46 chromosomes. In many forms of leukaemia, large parts of these chromosomes are altered. People with Down syndrome, who have three copies of chromosome 21 (trisomy 21), are highly vulnerable: the risk of developing aggressive Acute Myeloid Leukaemia (AML) in the first four years of their life is more than 100 times greater for children with Down syndrome. Down syndrome is the most common congenital genetic disorder, affecting about one in 700 newborn babies.
RUNX1 transcription factor is responsible
The research group led by Professor Jan-Henning Klusmann, Director of the Department of Paediatric and Adolescent Medicine at University Hospital Frankfurt, has now discovered how the additional chromosome 21 can promote AML. With the help of genetic scissors (CRISPR-Cas9), they examined each of the 218 genes on chromosome 21 for its carcinogenic effect. It emerged that the RUNX1 gene is responsible for the chromosome's specific carcinogenic properties. In further analyses, the researchers were able to corroborate that only one particular variant – or isoform – of the gene promotes the development of leukaemia. Klusmann explains: “Other RUNX1 isoforms were even able to prevent the cells from degenerating. This explains why RUNX1 has so far not stood out – in several decades of extensive cancer research."
The RUNX1 gene encodes a “transcription factor" – a protein responsible for regulating the activity of other genes. RUNX1 regulates many processes, including embryonic development and early and late haematopoiesis, or blood formation. Disruption of this important regulator is therefore a key event in the development of AML. “Thanks to our research results, we now have a better understanding of what happens in leukemogenesis," explains Klusmann, an expert in paediatric cancer. “The study underlines how important it is to examine all gene variants in carcinogenesis. In many cases, certain mutations in cancer cells alter how these variants form," he says.
Development of more sophisticated therapeutic approaches
These insights are important for a better understanding of the complex mechanisms of carcinogenesis, as Klusmann explains: “In this way, we have laid the groundwork for developing more sophisticated therapeutic approaches. Through our biochemical analyses, we now know exactly how the gene variant alters the blood cells. From there, we were able to use specific substances that block the disease mechanism." The intention now is to further explore the effect of these substances for use in medical care. Klusmann: “On the basis of our expertise, we now want to develop therapies to correct this malfunction. Applying them in clinical practice will certainly take a few more years, but hopefully they will lead in the future to sparing our young patients from intensive chemotherapy."
Publication: Gialesaki S, Bräuer-Hartmann D, Issa H, Bhayadia R, Alejo-Valle O, Verboon L, Schmell AL, Laszig S, Regenyi EM, Schuschel K, Labuhn M, Ng M, Winkler R, Ihling C, Sinz A, Glaß M, Hüttelmaier S, Matzk S, Schmid L, Strüwe FJ, Kadel SK, Reinhardt D, Yaspo ML, Heckl D, Klusmann JH. RUNX1 isoform disequilibrium promotes the development of trisomy 21 associated myeloid leukemia. Blood (2023)
Caption 1: Professor Jan Klusmann, MD, University Hospital Frankfurt. Photo credit: Klaus Waeldele, University Hospital Frankfurt
Caption 2: Bone marrow smear from a child with Down syndrome who suffers from leukemia. The purple-coloured leukemic blasts displace normal blood formation. Photo credit: Jan Klusmann, University Hospital Frankfurt
Professor Jan-Henning Klusmann
Department of Paediatric and Adolescent Medicine
University Hospital Frankfurt
Tel.: +49 69 6301-5094
Twitter: @UK_Frankfurt @goetheuni
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: +49 (0) 69 798-12498, firstname.lastname@example.org
Goethe University’s Archaeology Department participates in a new German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)-funded project: Cooperation with the State Service for Heritage Protection and Management Hesse and the Universities of Mainz and Kiel.
The Landgraben, the body of water between the German cities of Groß-Gerau and Trebur, flows into the Rhine northwest of Astheim. Its name goes back to Count Georg I (1547-1596) of Hesse-Darmstadt, to whom the origin of this artificial watercourse has been attributed until now. Archaeologists, however, suspect the waterway had a different genesis. A team from the State Service for Heritage Protection and Management Hesse and the universities of Frankfurt, Mainz and Kiel can now use the DFG's funding to research the Roman past.
Following archaeological investigations in the Hessian Ried, initial indications show the canal may have been dug much earlier than previously estimated: It is thought the Roman military created the artificial body of water during the conquest and development of the Ried, located on the right bank of the Rhine, in the 1st century AD. The land ditch, which merged into today's Schwarzbach stream near Trebur, probably served to supply materials and goods to the Roman fort and its nearby civilian settlement in Groß-Gerau. With the new funds in hand, further research is now getting underway.
The German Research Foundation has made 370,000 euros available to continue the explorations. The money will go towards geophysical investigations, drillings and smaller archaeological excavations aimed at finding the canal's original course and taking a closer look at the Roman settlement sites in Berkach, Groß-Gerau, Wallerstädten, Trebur and Astheim, located along its course, as well as their relationship to the body of water. The resulting findings will form the basis for two dissertations in the subjects of archaeology and geography at the universities of Frankfurt and Mainz.
The search for the course of the Roman land ditch currently is being conducted in the area of Groß-Gerau – Wallerstädten. As part of the practical field course at the University of Mainz, a group of students is surveying the area, taking measurements of the electrical resistance in the subsoil and drilling at selected points to clarify the soil structure and obtain dating evidence for the site's original appearance. At the same time, Kiel University is carrying out large-scale geophysical measurements to clarify the relationship between the Roman settlement site and the artificial watercourse in this area.
Both written records and corresponding findings such as the so-called canal of Corbulo in the Netherlands constitute proof of the fact that the Romans already had the technical skills to steer and manipulate water bodies or even to create artificial canals. If the upcoming investigations confirm the hypothesis of the Landgraben's Roman origins, this would be the first evidence of such a structure from the Roman period in Germany. The fact that the artificial watercourse exists as a body of water to this day would illustrate just how massive and lasting an impact the Romans' intervention in the landscape has had.
The Roman fort "Biebelslache", near Wallerstädten, was of decisive importance for the initial dating of the Landgraben, explains Prof. Markus Scholz, archaeologist at Goethe University. The fort bordered directly on the canal or – this is something the current research has set out to verify – was actually intersected by it. In the first case, Scholz says, the canal would be at least as old as the camp. In the second case, the camp, which existed from about 40 to 70 AD, would likely have served as a terminus post quem for the canal's construction. "Our Institute held several teaching excavations at fort 'Biebelslache' between 2008 and 2012," Scholz explains, adding that there now is a new opportunity to evaluate the excavations with the latest hypothesis in mind. As such, doctoral student Henrik Leif Schäfer will date and analyze other Roman sites along the trench in his dissertation. At the same time, doctoral student Elena Appel will study the geo-archaeological aspects of the project, which also gives students the opportunity to conduct fieldwork.
Images for download: https://www.uni-frankfurt.de/132990291
Image 1: At a site visit in the Hessian Ried (from left): Prof. Andreas Vött, University of Mainz, Prof. Markus Scholz, Goethe University, Dr. Thomas Becker and Prof. Udo Recker, both State Service for Heritage Protection and Management Hesse. (Photo: Lars Görze, State Service for Heritage Protection and Management Hesse)
Image 2: The investigation of the Landgraben's history will include the use of geophysical surveys, drillings and smaller archaeological excavations. (Photo: Lars Görze, State Service for Heritage Protection and Management Hesse)
Image 3: The explorations at the Landgraben will take several years. From left: Dr. Thomas Becker, State Service for Heritage Protection and Management Hesse, Prof. Markus Scholz, Goethe University. (Photo: Lars Görze, Hessian State Office for the Preservation of Historical Monuments).
Prof. Markus Scholz
Archaeology and History of the Roman Provinces
Institute for Archaeological Sciences, Department II
Tel. +49 (0)69 798 32265
Fax +49 (0)69 798 32268