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Nationwide longitudinal study in Germany investigated 250 million hospital admissions
In Germany, liver cirrhosis has the highest mortality rate of any chronic disease requiring hospital admission. When diagnosed as a comorbidity of other chronic diseases, liver cirrhosis at least doubles the mortality rate. Overall, the number of patients hospitalised with liver cirrhosis has increased throughout Germany despite the introduction of very effective drugs for treating hepatitis C, and alcohol abuse remains by far the most common cause. These are the results of a study headed by Prof. Jonel Trebicka at the University Hospital Frankfurt, which observed patients over a period of 14 years.
FRANKFURT. Cirrhosis, a disease of the liver in which tissue becomes dysfunctional and scarred, is the final stage of most chronic liver diseases and the fourth most frequent cause of death in central Europe. However, until now hardly any current findings have been available on its epidemiological profile in Germany. For this reason, Prof. Jonel Trebicka and his team of researchers investigated the data sets from the German Federal Statistical Office on the approx. 250 million hospital admissions taking place from 2005 to 2018 in Germany for any reason, and categorised them according to the Tenth Revision of the International Classification of Diseases (ICD-10). They found that 0.94 per cent of these hospitalised patients had been diagnosed with cirrhosis of the liver, which in the majority of cases occurred as a comorbidity and not the primary disease. In absolute figures, admissions of patients with liver cirrhosis rose from 151,108 to 181,688 during the observation period.
The primary end point of the study was the mortality rate from liver cirrhosis in hospital. This did indeed exhibit a welcome fall from 11.57% to 9.49% during the investigation period, but it is still much higher than the respective rates for other chronic diseases such as cardiac insufficiency (8.4%), renal failure (6.4%) and chronic obstructive pulmonary disease (5.2%). In cases where liver cirrhosis was comorbid with another chronic disease, it increased that disease's mortality rate two to three fold; the greatest effect was observed with infectious respiratory diseases.
Thanks to the introduction of direct-acting antivirals to combat Hepatitis C, the proportion of HCV-related cirrhosis fell during the observation period to around one third. On the other hand, the frequency of cirrhosis caused by non-alcoholic fatty liver disease quadrupled during the same period, in parallel with a rise in the number of obese patients. However, despite these etiological trends, cirrhosis caused by alcohol abuse continues to dominate. It accounts for 52 per cent of all cirrhoses in the study, and the absolute number is still rising.
Gastrointestinal bleeding is becoming increasingly rare as a complication of liver cirrhosis in hospital patients, presumably due to the treatment guidelines that continue to be applied in German hospitals, including endoscopic procedures or the administration of non-selective beta blockers. By 2018, bleeding from oesophageal varices had shrunk to one tenth of its original level in 2005. On the other hand, deterioration of symptoms owing to ascites or hepatic encephalopathy caused by insufficient detoxification by the liver has increased. The number of portal vein thromboses doubled in parallel with the intensified use of imaging diagnostics.
The patients admitted with cirrhosis were much younger than those with other chronic diseases: half of them were under the age of 64. Higher hospitalisation rates and in-hospital mortality rates were recorded in the eastern German states than in western Germany. Across the country, around two thirds of patients hospitalised with liver cirrhosis were men. Many of them died while in their fifties or younger, which explains the large number of disability-adjusted life years and the enormous socio-economic burden caused by liver cirrhosis, as men in this age group still account for the majority of the labour force.
“The results of our study show that the
decision-makers and financing bodies in the health system should invest much
more in the prevention of alcohol-related liver cirrhosis," Prof. Jonel
Trebicka concludes. “They also point up how important it is to recognise and treat liver cirrhosis as a comorbidity of other chronic
Publication: Wenyi Gu, Hannah Hortlik, Hans-Peter Erasmus, Louisa Schaaf, Yasmin Zeleke, Frank E. Uschner, Philip Ferstl, Martin Schulz, Kai-Henrik Peiffer, Alexander Queck, Tilman Sauerbruch, Maximilian Joseph Brol, Gernot Rohde, Cristina Sanchez, Richard Moreau, Vicente Arroyo, Stefan Zeuzem, Christoph Welsch, Jonel Trebicka: Trends and the course of liver cirrhosis and its complications in Germany: Nationwide population-based study (2005 to 2018) The Lancet Regional Health - Europe 2022;12: 100240 https://doi.org/10.1016/j.lanepe.2021.100240Further information
International research team examines photoelectric effect with the aid of a COLTRIMS reaction microscope
When light hits a material, electrons can be released from this material – the photoelectric effect. Although this effect played a major role in the development of the quantum theory, it still holds a number of secrets: To date it has not been clear how quickly the electron is released after the photon is absorbed. Jonas Rist, a Ph.D. student working within an international team of researchers at the Institute for Nuclear Physics at Goethe University Frankfurt, has now been able to find an answer to this mystery with the aid of a COLTRIMS reaction microscope which had been developed in Frankfurt: The emission takes place lightning fast, namely within just a few attoseconds – within a billionths of billionths of a second.
FRANKFURT. It is now exactly one hundred years ago that Albert Einstein was awarded the Nobel Prize in Physics for his work on the photoelectric effect. The jury had not yet really understood his revolutionary theory of relativity – but Einstein had also conducted ground-breaking work on the photoelectric effect. With his analysis he was able to demonstrate that light comprises individual packets of energy – so-called photons. This was the decisive confirmation of Max Planck's hypothesis that light is made up of quanta, and paved the way for the modern quantum theory.
Although the photoelectric effect in molecules has been studied extensively in the meantime, it has not yet been possible to determine its evolution over time in an experimental measurement. How long does it take after a light quantum has hit a molecule for an electron to be dislodged in a specific direction? “The length of time between photon absorption and electron emission is very difficult to measure because it is only a matter of attoseconds," explains Till Jahnke, the PhD-supervisor of Jonas Rist. This corresponds to just a few light oscillations. “It has so far been impossible to measure this duration directly, which is why we have now determined it indirectly." To this end the scientists used a COLTRIMS reaction microscope – a measuring device with which individual atoms and molecules can be studied in incredible detail.
The researchers fired extremely intense X-ray light – generated by the synchrotron radiation source BESSY II of Helmholtz-Zentrum Berlin – at a sample of carbon monoxide in the centre of the reaction microscope. The carbon monoxide molecule consists of one oxygen atom and one carbon atom. The X-ray beam now had exactly the right amount of energy to dislodge one of the electrons from the innermost electron shell of the carbon atom. As a result, the molecule fragments. The oxygen and carbon atoms as well as the released electron were then measured.
“And this is where quantum physics comes into play," explains Rist. “The emission of the electrons does not take place symmetrically in all directions." As carbon monoxide molecules have an outstanding axis, the emitted electrons, as long as they are still in the immediate vicinity of the molecule, are still affected by its electrostatic fields. This delays the release slightly – and to differing extents depending upon the direction in which the electrons are ejected.
As, in accordance with the laws of quantum physics, electrons not only have a particle character but also a wave character, which in the end manifests in form of an interference pattern on the detector. “On the basis of these interference effects, which we were able to measure with the reaction microscope, the duration of the delay could be determined indirectly with very high accuracy, even if the time interval is incredibly short," says Rist. “To do this, however, we had to avail of several of the possible tricks offered by quantum physics."
On the one hand the measurements showed that it does indeed only take a few dozen attoseconds to emit the electron. On the other hand, they revealed that this time interval is very heavily dependent on the direction in which the electron leaves the molecule, and that this emission time is likewise greatly dependent on the velocity of the electron.
These measurements are not only
interesting for fundamental research in the field of physics. The models which
are used to describe this type of electron dynamics are also relevant for many chemical
processes in which electrons are not released entirely, but are transferred to
neighbouring molecules, for instance, and trigger further reactions there. “In
the future such experiments could also help to better understand chemical
reaction dynamics therefore," says Jahnke.
Publication: Jonas Rist, Kim Klyssek, Nikolay M. Novikovskiy, Max Kircher, Isabel Vela-Pérez, Daniel Trabert, Sven Grundmann, Dimitrios Tsitsonis, Juliane Siebert, Angelina Geyer, Niklas Melzer, Christian Schwarz, Nils Anders, Leon Kaiser, Kilian Fehre, Alexander Hartung, Sebastian Eckart, Lothar Ph. H. Schmidt,1 Markus S. Schöffler, Vernon T. Davis, Joshua B. Williams, Florian Trinter, Reinhard Dörner,1 Philipp V. Demekhin, Till Jahnke: Measuring the photoelectron emission delay in the molecular frame. Nat Commun 12, 6657 (2021). https://doi.org/10.1038/s41467-021-26994-2
High-tech: COLTRIMS reaction microscope at electron storage ring BESSY II, Helmholtz-Zentrum Berlin für Materialien und Energie (HZB). Photo: Miriam Weller, Goethe University Frankfurt
Ph.D. student Jonas Rist, Goethe University Frankfurt. Photo: Alexander Hartung, Goethe University Frankfurt
Prof. Dr. Till Jahnke
European XFEL and
Institute for Nuclear Physics, Goethe University Frankfurt, Germany
Tel.: + 49 (0)69-798 47023 (Office)
Shedding new light on the role of tumour suppressor protein pVHL
Transforming Growth Factor beta (TGF-β) is a signalling protein whose dysregulation can cause developmental disorders and cancer. Dr Xinlai Cheng and his colleagues at the Goethe University Frankfurt have discovered how a tumour suppressor known as pVHL influences signal transmission involving TGF-β. Their findings suggest possible starting points for developing new drugs.
FRANKFURT/HEIDELBERG. Signal transmission inside cells is a complex process. TGF-β, for example, regulates many cell functions during the early development of both humans and animals, but also in adult organisms. The mechanisms involved are not yet fully understood. It is, however, clear that activated TGF-β initially binds to receptors located on the cell surface. Inside the cell, the TGF-β receptors in their turn activate a protein called SMAD3, which then forms complexes with SMAD4 that translocate to the cell nucleus. There the SMAD proteins mediate the extent to which genes are activated and translated into proteins and other gene products.
Researchers at the Goethe University Frankfurt, Heidelberg University, the German Cancer Research Center (DKFZ), Heidelberg University Hospital and the University Hospital in Jena have now discovered how the von Hippel-Lindau tumour suppressor protein (pVHL) intervenes in this signalling pathway. Tumour suppressors are proteins whose defects or reduced presence in multicellular organisms are associated with a high risk that cells will degenerate into tumour cells. In the Journal of Cell Biology the scientists report the first evidence that pVHL degrades the SMAD3 protein. This occurs before SMAD3 and SMAD4 associate. pVHL thus inhibits the signalling chain that starts with activated TGF-β. “We obtained evidence of this both in cultures of human cells and in Drosophila," says the last author, Dr Xinlai Cheng. “This suggests that at a very early stage in evolution pVHL assumed the regulatory function that we have now brought to light."
Xinlai Cheng has been leading a junior research group at the Buchmann Institute for Molecular Life Sciences at the Goethe University Frankfurt since 2019. He began the investigations at the Institute of Pharmacy and Molecular Biotechnology at Heidelberg University. His mentor, Professor Stefan Wölfl, explained an important finding that emerged from the new-found connection between pVHL and the TGF-β signalling pathway: “pVHL is known to be involved in how cells 'feel' oxygen and react to varying oxygen availability. As a result, a cell's oxygen supply also mediates TGF-β signal transmission."
The researchers' discovery opens up new opportunities for
developing drugs to combat cancer. “If we could, for example, use a substance
to specifically regulate pVHL activity, we would also influence the TGF-β
signalling pathway, which in turn plays a major role in the formation of
tumours, and metastases in particular," says Xinlai Cheng. Tumour cells are
good at adapting to their environment inside the organism and to variations in oxygen
availability. Their very flexible cellular activity helps them to do so. This
activity is regulated by factors including the TGF-β signalling pathway.
Publication: Jun Zhou, Yasamin Dabiri, Rodrigo A. Gama-Brambila, Shahrouz Ghafoory, Mukaddes Altinbay, Arianeb Mehrabi, Mohammad Golriz, Biljana Blagojevic, Stefanie Reuter, Kang Han, Anna Seidel, Ivan Đikić, Stefan Wölfl, Xinlai Cheng: pVHL-mediated SMAD3 degradation suppresses TGF-β signaling. Journal of Cell Biology (2022) 221 (1): e202012097 https://doi.org/10.1083/jcb.202012097
Caption: Stained liver tissue shows the complementary occurrence of pVHL and SMAD proteins: Where pVHL (green) is abundant, SMAD2/3 (red) is scarce, and vice versa. Cell nuclei are stained blue. The lower right picture shows all three colours combined. Photos: Xinglai Cheng/Goethe University
Dr. rer. nat. habil. Xinlai Cheng
Buchmann Institute for Molecular Life Sciences Chemical Biology
Goethe University Frankfurt
Phone +49 69 798-42718
Institut of Pharmacy and Molecular Biotechnology –
Pharmaceutical Biology, Pharmaceutical Bioanalytics and Molecular Cell Biology
Phone +49 6221-544880
Doctor at Hannover Medical School explores leukaemia and colorectal cancer
The 24-year-old physician Dr. Laura Hinze from Hannover Medical School receives the Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers 2022, as announced today by the Scientific Council of the Paul Ehrlich Foundation. Laura Hinze is being honoured for her significant contribution to the understanding of signal transduction in cancer cells. She has discovered how leukaemia cells develop resistance to the chemotherapeutic agent asparaginase, thereby presenting a novel target for the treatment of acute lymphoblastic leukaemia (ALL), the most common cancer in children. Her discovery also derives a new approach for the treatment of colorectal cancer and other solid tumours.
FRANKFURT. Unlike normal body cells, leukaemia cells are not able to produce sufficient amounts of the amino acid asparagine. They have to import asparagine. Because the enzyme asparaginase catalyses the degradation of asparagine, its injection drastically reduces the extracellular supply of this amino acid. Consequently, leukaemia cells die from this depletion, while normal body cells are not harmed. However, leukaemia cells can learn to evade the effect of asparaginase.
To find out how this happens, Dr. Laura Hinze and her group used CRISPR/Cas9 gene scissors to systematically switch off around 19,000 genes in a culture of resistant ALL cells – only one in each cell – and observed what happened when they treated the cells with asparaginase. A culture to which only a buffer solution was added served as a control. In the culture treated with asparaginase, those cells in which one of the two genes NKD2 or LGR6 had been switched off, died particularly frequently. They had apparently lost their resistance. Conversely, this indicated that cells in which these genes function become resistant particularly frequently. Hinze and her team demonstrated that both genes code for inhibitors of the Wnt signalling pathway.
In the healthy organism, this signalling pathway is responsible for embryonic development and later for tissue repair and maintenance. Its untimely activation favours the development of cancer. This is mainly due to an excessive amount of the protein ß-catenin, which carries growth impulses into the cell nucleus. When the Wnt signalling pathway is inactive, the excess ß-catenin is marked for degradation with ubiquitin molecules. Central to this labelling work is the enzyme glycogen synthase kinase 3 (GSK3). It ensures that ß-catenin is fed to the proteasome, where it is broken down into small fragments and amino acids like all proteins that could harm the cell or that it does not need. It is from this source that the leukaemia cell fetches the asparagine of which it has been deprived of by treatment with asparaginase. Through a partial activation of the Wnt signalling pathway, which blocks the degradation of ß-catenin without spurring its potentially oncogenic signals, Hinze and colleagues succeeded in largely drying up this source of resistance. The same effect they achieved by selective GSK inhibition. Leukaemia mice that received both asparaginase and GSK3 inhibitors survived much longer than those treated with asparaginase alone.
Mutations in the Wnt signalling pathway that led to its overactivation are characteristic for many colorectal cancers. Hinze therefore examined to what extent her research results could be transferred to this second most common of all cancers. Her initial hypothesis: 15 percent of all Wnt signalling pathway mutations in colorectal cancer lie upstream of the enzyme GSK3. In patients with this genetic signature, the enzyme is thus endogenously inhibited. The proteasome no longer supplies asparagine. If one depletes asparagine additionally by administering asparaginase, one could starve the colon cancer cells. Laura Hinze and her group have now preclinically proven this hypothesis. It could also apply to other solid tumours that are characterised by a Wnt-induced endogenous inhibition of GSK3.
The prize will be awarded - together with
the main prize 2022 and the prizes of the year 2021 - on 14 March 2022 at 5
p.m. by the Chairman of the Scientific Council of the Paul Ehrlich Foundation
in Frankfurt's Paulskirche. Due to the pandemic, the number of available seats
is limited. The event will be broadcast via livestream. Please do not hesitate
to contact us if you have any questions.
Please find pictures of the award winner and a more comprehensive background information for download under: www.paul-ehrlich-stiftung.de
Moreover, COVID-19 drugs remain active against Omicron in cell culture study
A new study by researchers from the University of Kent and the Goethe-University Frankfurt shows that the SARS-CoV-2 Omicron variant is less effective than Delta at blocking a cellular defence mechanism against viruses, the so-called “interferon response". Moreover, cell culture findings indicate that eight important COVID-19 drugs and drug candidates remain effective against Omicron.
FRANKFURT/CANTERBURY. The SARS-CoV-2 Omicron variant causes less severe disease than Delta although it is better at escaping immune protection by vaccinations and previous infections. The reasons for this have so far remained elusive.
A new study by a research team with scientists from the University of Kent and the Goethe-University Frankfurt has now shown that Omicron variant viruses are particularly sensitive to inhibition by the so-called interferon response, an unspecific immune response that is present in all body cells. This provides the first explanation of why COVID-19 patients infected with the Omicron variant are less likely to experience severe disease.
The cell culture study also showed that Omicron viruses remain sensitive to eight of the most important antiviral drugs and drug candidates for the treatment of COVID-19. This included EIDD-1931 (active metabolite of molnupiravir), ribavirin, remdesivir, favipravir, PF-07321332 (nirmatrelvir, active ingredient of paxlovid), nafamostat, camostat, and aprotinin.
Prof Martin Michaelis, School of Bioscience, University of Kent, said: “Our study provides for the first time an explanation, why Omicron infections are less likely to cause severe disease. Obviously, Omicron can in contrast to Delta not effectively inhibit the host cell interferon immune response.“
Prof. Jindrich Cinatl, Institute of
Medical Virology at the Goethe-University, added: “Although cell culture
experiments do not exactly recapitulate the more complex situation in a
patient, our data provide encouraging evidence that the available antiviral
COVID-19 drugs are also effective against Omicron.“
Publication: Denisa Bojkova, Marek Widera, Sandra Ciesek, Mark N. Wass, Martin Michaelis, Jindrich Cinatl jr. Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates. In: Cell. Res. (2022) https://doi.org/10.1038/s41422-022-00619-9
information: The drug aprotinin inhibits entry of
SARS-CoV-2 in host cells (23rd Nov 2020)
Professor Jindrich Cinatl
Institute of MedicalVirology
Phone: +49 (0) 69 6301-6409