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Findings of the PREDICT study on acute decompensation and acute-on-chronic liver failure
Acute-on-chronic liver failure (ACLF) is a common cause of death in patients with cirrhosis. In ACLF the progressive loss of function of the scarred liver can no longer be compensated (acute decompensation). As a result, other organs such as the kidney or brain fail. The triggers for acute decompensation of liver cirrhosis and an ACLF are most frequently bacterial infections, liver inflammation caused by alcohol, or a combination of both factors. This was revealed by the evaluation of the PREDICT study, which was conducted by an international team of researchers led by Professor Jonel Trebicka from the University Hospital Frankfurt.
FRANKFURT. Chronic liver disease and even
cirrhosis can go unnoticed for a long time because many patients have no symptoms:
the liver suffers silently. When the body is no longer able to compensate for
the liver's declining performance, the condition deteriorates dramatically in a
very short time: tissue fluid collects in the abdomen (ascites), internal
bleeding occurs in the oesophagus and elsewhere, and the brain is at risk of
being poisoned by metabolic products. This acute decompensation of liver
cirrhosis can develop into acute-on-chronic liver failure with inflammatory
reactions throughout the body and failure of several organs.
In the PREDICT study, led by Professor
Jonel Trebicka, scientists from 15 European countries observed 1273 patients
who were hospitalized with acute decompensation of their liver cirrhosis. The
current evaluation of the study focused on the question of what can trigger
acute decompensation of liver cirrhosis. The result: in the vast majority of cases
(>90%), a bacterial infection, liver inflammation caused by alcohol
consumption, or both together could be identified as the trigger.
Bleeding in the digestive tract and brain dysfunction
induced by painkillers or sedatives (drug-induced toxic encephalopathy) were
identified as further trigger, although at a lower rate.
Lead investigator Professor Jonel
Trebicka, gastroenterologist and hepatologist at the Medical Clinic I of the
University Hospital Frankfurt, explains: "The acute decompensation of
liver cirrhosis demands rapid and targeted action. In the PREDICT study, we
therefore want to learn a lot about the triggering factors of this
life-threatening disease in order to be able to derive recommendations for
diagnostics and therapy. Knowing what the most likely triggers of acute
decompensation are will help to further develop diagnostic and treatment
strategies for patients with this life-threatening disease."
The pan-European PREDICT study has
monitored the clinical course of acute decompensations of liver cirrhosis to
find early signs of the development of acute-on-chronic liver failure (ACLF).
PREDICT is funded by the European Foundation for the Study of Chronic Liver
Failure. A total of 136 scientists from 47 centres and institutions in 15
European countries are participating in PREDICT.
Publication:
Jonel Trebicka, Javier Fernandez, et al.
for the PREDICT STUDY group of the EASL-CLIF CONSORTIUM: PREDICT identifies precipitating events associated with the clinical
course of acutely decompensated cirrhosis. Journal of Hepatology (2020), https://doi.org/10.1016/j.jhep.2020.11.019
Further
information:
University Hospital Frankfurt, Goethe
University Frankfurt
Medical Clinic I
Professor Jonel Trebicka
Section Translational Hepatology,
Medical Clinic I (Director: Professor
Stefan Zeuzem)
Goethe University/University Hospital
Frankfurt
Tel. +49 69 6301 80789 (Jennifer Biondo,
secretarial office)
Jonel.Trebicka@kgu.de
The
European Foundation for the Study of Chronic Liver Failure (EF Clif) is a private, non-profit Foundation whose mission is to promote study
and research on Acute-on-Chronic Liver Failure and thus, contribute to
improving both the quality of life and survival of patients with liver
cirrhosis.
The EF Clif was created in 2015 to support the
research work carried out by the EASL Clif Consortium, a research network of
more than 100 European University Hospitals and 200 clinical investigators. In
2013, the Consortium described a new syndrome: Acute-on-Chronic Liver Failure
(ACLF), which is the most common cause of death in cirrhosis.
Currently, the research activity of the EF Clif is
fostered through two chairs: the EASL Clif Chair, to promote observational,
pathophysiological and therapeutic studies through the EASL-Clif Consortium's
hospital network; and the Grifols Chair, which promotes the development of
translational research projects with the creation of a network of centres
across Europe:
The European Network for Translational Research in Chronic Liver Failure
(ENTR-CLIF).
To know more about the EF Clif: http://www.efclif.com Twitter: @ef_clif
Research project on East Asia led by Goethe University receives 2 million euros in funding
The economies of China and Singapore are among the
most dynamic migration regions in the world. But Japan and Korea also rely on
the immigration of skilled workers. The competition for qualified professionals
sets several million people on the move in these regions every year. The role
that skills and education play in mobility is now being investigated by scholars
on East Asia from the universities of Frankfurt and Duisburg-Essen, the Free
University of Berlin, and the Max Planck Institute for the Study of Multiethnic
and Multireligious Societies in Göttingen. The junior research group
coordinated by Goethe University will receive a total of more than 2 million
euros from the Federal Ministry of Education and Research (BMBF) for the next
four years as part of the "Small Subjects " funding initiative.
FRANKFURT. Aging societies in
industrialised nations need skilled workers - specialists in the IT sector, in
innovative start-ups, or from top universities. This applies to Germany as well
as to the East Asian countries of South Korea, Singapore, China, and especially
Japan. Because of their quality of life and lucrative renumeration, these
countries are attractive for qualified migrants. But the recipe for success in
the competition for the best brains is far from clear: What attracts
well-trained specialists to Japan, South Korea, China, or Singapore? What facilitates,
and what hinders the integration of skilled foreign workers? What social
networks do skilled migrant workers develop? What role does their own
initiative for further qualification, their ethnicity and nationality, their
gender and multilingualism play? And what causes skilled workers to return to
their home countries after years?
"If a country's immigration policy is to be
sustainable," explains project leader Dr Ruth Achenbach from Goethe
University, "then we need to know exactly what the perceptions of migrants
are." The aim of the research project, which will receive funding by the
BMBF of more than 2 million euros, is to examine the role of skills of migrant professionals.
The researchers hope their findings will contribute to sustainable immigration
policies in industrial nations.
In addition to Ruth Achenbach and Dr Joohyun Justine Park from the
Interdisciplinary Centre for East Asian Studies (Goethe University), the
academic team includes Dr Helena Hof (MPI Göttingen) as well as Dr Megha Wadhwa
(Free University Berlin) and Dr Aimi Muranaka (University Duisburg-Essen). In
addition, the researchers work with numerous external regional cooperation
partners.
The research project will collect qualitative data in different East Asian
countries over a period of three years. It will investigate the situation of
East Asian start-ups in Japan and Singapore as well as East Asian professionals
in South Korea; Chinese professionals in Japan, professionals who have returned
to China, and Vietnamese IT workers and Indian professionals in Japan will also
be interviewed. The Frankfurt sub-project also accompanies Chinese graduates of
the 20 best Japanese universities from the beginning of their job-hunting to
their first years on the labour market.
In the final year of funding, quantitative
research will be conducted in the East Asin countries to test a theory
developed from the qualitative research and previous migration research. In
doing so, the researchers also aim to improve the dominant Western concepts of
international migration research. Influenced by experiences of migration to
America and Europe, these concepts assume that the economic situation in the
country of origin and the country of immigration differ considerably. This is
not necessarily the case anymore with East Asian labour migration and the
project will differentiate between socioeconomic backgrounds of migrants.
The results of the empirical research as well as the
development of theory will not only be published scientifically, but they will
also be disseminated to the broader public. The project team’s dissemination
activities include workshops for high school teachers in the subjects of
politics and economics, and the release of a documentary film.
The researchers hope that their project will
strengthen the "small subjects" by linking the researchers' knowledge
of these regions with current research questions from sociology, political
science and economics, thus increasing the visibility of the small subjects.
Further information:
Dr Ruth Achenbach
Interdisciplinary Centre for East Asian Studies
Goethe University Frankfurt
Telefon 069/798-23284
E-Mail: izo@uni-frankfurt.de
Contributions from more than 2000 large and small donors make numerous research projects at Goethe University and Frankfurt University Hospital on overcoming the pandemic
A short ten months after Goethe University and
Frankfurt University Hospital first called for donations, the Goethe Coronavirus
Fund has passed the targeted 5 million euro mark. The idea of the Goethe Coronavirus
Fund came about in the first days of the pandemic: researchers require
immediate and unbureaucratic support in order to make their contribution to
overcoming the coronavirus crisis. More than 2000 private individuals,
foundations and companies have meanwhile supported the goal of joining forces
and providing competent help.
FRANKFURT. “Making
a donation to research helped me overcome a feeling of helplessness during the
first days of the coronavirus crisis,” says Raina Jockers, one of the more than
2000 donors for the Goethe Coronavirus Fund, explaining her motivation. The
feelings of the Goethe University graduate are undoubtedly shared by many. The
majority of donors contributed between 10 and 100 euros to the fund. The
smallest donation came from the donation of bonus points from the “payback” programme
and amounted to 2 cents; the largest was almost one million euros. Eight donors
gave sums of more than 100,000 euros.
Using the non-profit online fundraising
platform betterplace.org for the
first time, the university’s call for donations reached even beyond Frankfurt
citizens and foundations and companies from the Rhine-Main area, with donations
coming in from Hamburg, Munich and even the USA. The fundraising platform also
reported regularly on the work of the scientists, which may have motivated some
donors to stick with it: one anonymous donor contributed 20 euros to the fund
every month.
“In the pandemic, we wanted to help with
what we do best: with our research,” says Professor Manfred Schubert-Zsilavecz,
Goethe University Vice President. “So we simply jumped in at the deep end with
our fundraising campaign and set ourselves an ambitious target: 5 million euros
in donations. The fact that we have reached the 5 million euro mark in less than
a year after our first call for donations makes us deeply grateful. Many
private donors, as well as foundations and companies have been extremely
generous. They funded research that helps us all, keeping others in mind during this pandemic. This
should really encourage us for the long road ahead.”
The Goethe Coronavirus Fund provided researchers at Goethe
University and Frankfurt University Hospital with start-up support. Many of
them have in the meantime raised additional funds for research having to do
with SARS-CoV-2. The virologist Professor Sandra Ciesek and the infectologist
Professor Maria Vehreschild, for example, are today part of the EU-funded CARE
Consortium. Sandra Ciesek’s successes in drug research have made her one of the
most prominent coronavirus researchers in Germany. Maria Vehreschild was one of
the first to systematically collect clinical data and samples from COVID-19
patients and supplied her samples to vaccine and drug researchers throughout
Germany; in the meantime, her database has been merged into a Germany-wide
biobank.
But researchers from the social sciences
and humanities have also profited from the Goethe Coronavirus Fund. More than
40 projects are now being funded – including the coronavirus crisis hotline,
and studies by psychologist Professor Ulrich Stagnier on the psychological consequences
of the pandemic.
The latest project supported by the
Coronavirus Fund is dedicated to the work situation of healthcare workers and
doctors in COVID-19 care in Hessian hospitals who are under particular strain.
The cooperation project of the University Hospital Frankfurt and the Protestant
University of Applied Sciences in Darmstadt first examines the effects on the
employees. The results will be used to make recommendations for managers and healthcare
workers, as well as concrete options for workplace health promotion. The
evaluation of the first sub-study of the project is currently underway.
Further
donations possible at: https://www.goethe-corona-fonds.betterplace.org and
through
the donation account: Landesbank Hessen-Thüringen
IBAN: DE95 5005 0000
0001 0064 10
Reason
for payment: Goethe-Corona-Fonds
International research team investigates the binding kinetics of kinase inhibitors
Scientists at Goethe University Frankfurt, together
with colleagues from Darmstadt, Heidelberg, Oxford and Dundee (UK), have
investigated how the fit of potent inhibitors to their binding sites can be
optimised so that they engage longer with their target proteins. Long target
residency has been associated with more efficient pharmacological responses for
instance in cancer therapy. The result: High resolution structures revealed that
when the interaction between the inhibitors and the target proteins lasts
particularly long, the target proteins "nestle" against the inhibitors.
In future, the researchers want to use computer simulations to predict the residence
time of inhibitors during drug development.
FRANKFURT. Many
anti-cancer drugs block signals in cancer cells that help degenerated cells to
multiply uncontrollably and detach from tissue. For example, blocking the
signalling protein FAK, a so-called kinase, causes breast cancer cells to
become less mobile and thus less likely to metastasise. The problem is that
when FAK is blocked by an inhibitor, the closely related signalling protein
PYK2 becomes much more active and thus takes over some of FAK's tasks. The
ideal would therefore be an inhibitor that inhibits both FAK and PYK2 in the
same way for as long as possible.
An international team led by the pharmaceutical
chemist Prof. Stefan Knapp from Goethe University has investigated a series of
specially synthesised FAK inhibitors. All inhibitors bound to the FAK protein
at about the same rate. However, they differed in the duration of binding: The
most effective inhibitor remained bound to the FAK signalling protein the
longest.
Using structural and molecular biological
analyses as well as computer simulations, the research team discovered that binding
of inhibitors that remain in the FAK binding pocket for a long time induce a
structural change. Thus, through binding of these inhibitors, FAK changes its
shape and forms a specific, water-repellent structure at contact sites with the
inhibitor, comparable to an intimate embrace.
The closely related protein PYK2, on the
other hand, remained comparatively rigid, and although the most effective FAK
inhibitor also blocked PYK2, its effect was significantly weaker due to quickly
dissociating inhibitors from the binding site. Interestingly, computer
simulations were able to predict the kinetics of binding very well, providing a
method for accurate simulation of drug dissociation rates for future optimisation
of drug candidates.
Prof. Stefan Knapp explains: "Because
we now have a better understanding of the molecular mechanisms of the
interaction of potent inhibitors of these two kinases, we hope to be able to
use computer simulations to better predict drug residence times of inhibitors
and drugs candidates in the future. So far, little attention has been paid to
the kinetic properties of drug binding. However, this property has now emerged
as an important parameter for the development of more effective drugs that are
designed to inhibit their target proteins - as in the case of FAK and PYK2 -
not only potently but also for a long time."
Publication:
Benedict-Tilman Berger, Marta Amaral,
Daria B. Kokh, Ariane Nunes-Alves, Djordje Musil, Timo Heinrich, Martin
Schröder, Rebecca Neil, Jing Wang, Iva Navratilova, Joerg Bomke, Jonathan M.
Elkins, Susanne Müller, Matthias Frech, Rebecca C. Wade, Stefan Knapp: Structure-kinetic relationship reveals the
mechanism of selectivity of FAK inhibitors over PYK2. Cell Chemical Biology
https://doi.org/10.1016/j.chembiol.2021.01.003
This work was carried out within the
framework of the public-private partnership K4DD (Kinetics for Drug Discovery)
of the Innovative Medicinces Initiatives (IMI). https://www.k4dd.eu/home/
Images
for download:
Picture with and without text: http://www.uni-frankfurt.de/96999809
Caption:
Upper
part: Long residence time. An inhibitor
(left: stick model) binds to the signal molecule FAK (right: part oft the FAK
protein depicted as calotte model with spheres). The structural change of FAK
causes hydrophobic contacts (yellow, so-called DFG motif) and a long-lasting
engagement.
Lower
part: Short residence time. PYK2 signal protein
does not change its structure upon inhibitor binding, thus resulting in a fast
inhibitor dissociation. Graphics: Knapp Laboratory, Goethe University Frankfurt
Further
information:
Professor Stefan Knapp
Institute for Pharmaceutical Chemistry
Goethe University Frankfurt
Germany
knapp@pharmchem.uni-frankfurt.de
2021 Paul Ehrlich and Ludwig Darmstaedter Prize
Bacteria
act in groups to accomplish feats that are impossible to achieve if a single
bacterium acts alone. For example, pathogenic bacteria act collectively to synthesize
toxins to attack the host and to encase themselves in a shield that protects
them from the host immune system and allows them to resist antibiotic treatment.
To do this, bacteria communicate with each other with chemical “words", count
their numbers, and act in synchrony when they have sufficient cell numbers for
success. The award winners have discovered the dictionary and syntax underlying
bacterial communication, opening up new and unprecedented opportunities to
fight bacterial infections.
FRANKFURT am MAIN. Two American scientists,
Bonnie L. Bassler and Michael R. Silverman, receive the 2021 Paul Ehrlich
and Ludwig Darmstaedter Prize, which is endowed with 120,000 €. Bassler is
Professor at Princeton University and a Howard Hughes Medical Institute Investigator,
Michael R. Silverman is Emeritus Professor of the Agouron Institute in La
Jolla. The two researchers are honoured for their ground-breaking discoveries concerning
bacterial "quorum sensing", which refers to sophisticated systems of
cell-to-cell communication that bacteria use to coordinate group behaviours.
The award ceremony in St. Paul's Church, which is traditionally held on March
14, Paul Ehrlich's birthday, has been postponed due to the Coronavirus
pandemic. Instead, Bassler and Silverman will receive the award at the ceremony
in 2022.
"Silverman and Bassler have shown that, as
for multicellular organisms, collective behaviour is the rule among bacteria, rather
than the exception," wrote the Scientific Council in substantiating its
decision. "Bacteria talk to each other, they eavesdrop on other bacteria, and
they may even join forces. But: This ubiquitous chitchat, whose molecular
underpinnings were discovered by Bassler and Silverman, also represents a
previously unappreciated Achilles' heel in combating harmful microbes. Instead
of killing bacteria with antibiotics, substances may be developed that
interfere with bacterial communication effectively reducing their collective fitness.
The prize-winners' research thus has considerable relevance for medicine".
Bacteria are extremely communicative. They send
and receive chemical messages to find out whether they are alone or if additional
members of their or other species are present in the vicinal community. To take
a census of cell numbers, bacteria produce and release chemical signal
molecules that accumulate in step with increasing cell numbers. When a
threshold level of the chemical signal is achieved, the bacteria detect its
presence. In response to it, in unison, bacteria undertake behaviours that are
only productive when carried out in synchrony by the group, but not when
enacted by a single bacterium acting in isolation. This chemical
communication process is called quorum sensing and it controls hundreds of
collective activities across the bacterial kingdom.
In the 1980s, Silverman discovered the first quorum-sensing
circuit in the bioluminescent marine bacterium Vibrio fischeri. He identified
the genes and proteins enabling production and detection of the extracellular
signal molecule. He defined how the components functioned to promote collective
behaviour. In the case of Vibrio fischeri, group-wide behaviour
is the production of blue-green bioluminescence. Today, we know that quorum
sensing is the norm in the bacterial world. Indeed, there are thousands of
bacterial species that possess genes nearly identical to those discovered by
Silverman. In all of these cases, these components allow bacteria to engage in
group behaviours.
In the early 1990s, Bonnie
Bassler proved that bacteria were “multilingual" and that they conversed with
multiple chemical signal molecules. One communication molecule that Bassler
discovered and named autoinducer- 2 enables bacteria to communicate across species
boundaries. She went on to demonstrate that bacteria use
quorum-sensing-mediated communication to differentiate self from
other, showing that a sophisticated trait thought to be the purview of higher
organisms, in fact, evolved in bacteria billions of years ago. In recent years,
Bassler has shown that quorum sensing transcends kingdom boundaries as viruses
and host cells, including human cells, engage in this ubiquitous chit-chat. She
and other researchers also demonstrated that pathogenic bacteria rely on quorum
sensing to be virulent. Bassler developed anti-quorum-sensing strategies that,
in animal models, halt infection from bacterial pathogens of global
significance.
“The full significance of the discoveries of
the two laureates for microbiology and medicine has only recently been
recognized," says Professor Thomas Boehm, Director at the Max Planck
Institute for Immunobiology and Epigenetic and Chairman of the Scientific
Council. "Decades of meticulous and painstaking work, showed that essentially
all bacteria master the art of cell-to-cell communication," says Boehm.
"What began with work on Vibrio fischeri and Vibro harveyi led
to a fundamental change in perspective in bacteriology, and now opens up new and
unprecedented opportunities in dealing with antibiotic resistance".
Short biography Professor Dr.
Bonnie L. Bassler Ph.D. (58).
Bonnie Bassler is a microbiologist. She studied
biochemistry at the University of California at Davis and received her Ph.D.
from the Johns Hopkins University in Baltimore. She joined the laboratory of
Michael Silverman at the Agouron Institute in La Jolla as a postdoctoral fellow
in 1990. She has been at Princeton University since 1994. Bonnie Bassler is a
member of the National Academy of Sciences, the National Academy of Medicine,
and the Royal Society. She is a researcher at the Howard Hughes Medical
Institute and Squibb Professor and Chair of the Department of Molecular Biology
at Princeton University. President Obama appointed her to a six-year term on
the United States National Science Board. She has received more than twenty prestigious
national and international awards.
Short biography Professor
Michael R. Silverman, Ph.D. (77).
Michael Silverman is a microbiologist. He
studied chemistry and bacteriology at the University of Nebraska at Lincoln and
received his Ph.D. in 1972 from the University of California at San Diego.
During the period from 1972-1982, Silverman made seminal contributions to the
understanding of bacterial motility and chemotaxis. From 1982 until his
retirement, he worked at the Agouron Institute in La Jolla, of which he is a
co-founder.
The Paul Ehrlich and Ludwig
Darmstaedter Prize
The Paul Ehrlich and Ludwig Darmstaedter Prize
is traditionally awarded on Paul Ehrlich's birthday, March 14, in the
Paulskirche, Frankfurt. It honors scientists who have made significant
contributions in Paul Ehrlich's field of research, in particular immunology,
cancer research, microbiology, and chemotherapy. The Prize, which has been
awarded since 1952, is financed by the German Federal Ministry of Health, the
State of Hesse, the German association of research-based pharmaceutical company
vfa e.V. and specially earmarked donations from the following companies,
foundations and organizations: Else Kröner-Fresenius-Stiftung, Sanofi-Aventis
Deutschland GmbH, C.H. Boehringer Pharma GmbH & Co. KG, Biotest AG, Hans und Wolfgang
Schleussner-Stiftung, Fresenius SE & Co. KGaA, F. Hoffmann-LaRoche Ltd.,
Grünenthal GmbH, Janssen-Cilag GmbH, Merck KGaA, Bayer AG, Holtzbrinck
Publishing Group, AbbVie Deutschland GmbH & Co. KG, die
Baden-Württembergische Bank, B. Metzler seel. Sohn & Co. and
Goethe-Universität. The prizewinners
are selected by the Scientific Council of the Paul Ehrlich Foundation.
The
Paul Ehrlich Foundation
The
Paul Ehrlich Foundation is a legally dependent foundation which is managed in a
fiduciary capacity by the Association of Friends and Sponsors of the Goethe
University, Frankfurt. The Honorary Chairman of the Foundation, which was
established by Hedwig Ehrlich in 1929, is Professor Dr. Katja Becker, president
of the German Research Foundation, who also appoints the elected members of the
Scientific Council and the Board of Trustees. The Chairman of the Scientific
Council is Professor Thomas Boehm, Director at the Max Planck Institute of
Immunobiology and Epigenetics in Freiburg, the Chair of the Board of Trustees
is Professor Dr. Jochen Maas, Head of Research and Development and Member of
the Management Board, Sanofi-Aventis Deutschland GmbH. Professor Wilhelm
Bender, in his function as Chair of the Association of Friends and Sponsors of the
Goethe University, is Member of the Scientific Council. The President of the Goethe University is at the same time a member of
the Board of Trustees.
Further
information:
You can obtain selected
publications, the list of publications and a photograph of the laureate from
Dr. Hildegard Kaulen, phone: +49 (0)6122/52718, email: h.k@kaulen-wissenschaft.de and at www.paul-ehrlich-stiftung.de
Background on the
award of the 2021 Paul Ehrlich and Ludwig Darmstaedter Prize to Professor
Bonnie L. Bassler, Ph.D. and Professor Michael R. Silverman, Ph.D.