Heart failure is the leading cause of death worldwide. Scientists at the International Clinical Research Centre (ICRC) in Brno have identified a potential target for the treatment of heart disease that is related to the location and function of a protein called hnRNPC. They have now published their findings in the prestigious journal Science Translational Medicine, opening up the possibility of finding new treatments.

Cardiac diseases are accompanied by intense modifications of the architecture of the heart muscle tissue, a process which is defined as negative remodeling. During this process, a scar is formed within the muscle which impairs its contractile function and eventually leads to the failure of the organ in the long run.

Despite the advances in therapies and prevention, heart failure remains the leading cause of mortality worldwide. This pandemic accounts for over 1.8 million deaths every year, which means more than one in three deaths in the world are caused by heart failure.

For many years, scientists have known that the progression of heart failure is associated with the modification of the internal functioning of the cardiac cells, including those processes controlling the maturation of RNA molecules. These processes are important for the production of the structural proteins, which account for the ability of cardiac cells to produce force, contract and make the heart beat. Altered RNA metabolism in the diseased heart is considered largely responsible for the disease.

The research group led by Dr. Giancarlo Forte at the International Clinical Research Center (ICRC) of St. Anne’s University Hospital Brno and Faculty of Medicine, Masaryk University, finally identified how the formation of the scar in the heart leads to altered RNA metabolism by affecting the localization and function of a protein named hnRNPC. These results might pave the way to the design of new treatments based on the interference with the displacement of the protein.

The research, which is the subject of a publication on the leading international journal Science Translational Medicine, started in 2015 and was conducted mostly on human patient samples thanks to the decisive collaboration of the Center of Cardiovascular and Transplant Surgery (Centrum kardiovaskulární a transplantační chirurgie, CKTCH) Brno. Other collaborators of the study include researchers from Central European Institute of Technology (CEITEC) in Brno, as well as from the University of Melbourne (Australia), King’s College, Imperial College London and the University of Surrey (UK).

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Microscopic images of tissue from a healthy (left) and diseased (right) human heart. The muscle tissue is shown in red and the appearance of the scar in the diseased heart is shown in blue.

The research was generously supported by the European Regional Development Fund – Projects ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868) and MAGNET (No. CZ.02.1.01/0.0/0.0/15_003/0000492), European Union Horizon 2020 Research and Innovation Program NANOSUPREMI (No. 690901) and the Czech Science Foundation.

A scientist’s dream! An event that happens once every 384 years! And the immense joy of all involved, the humility and respect for the work done. All of this is embodied in the success of the scientists from the Loschmidt Laboratories of the Faculty of Science of Masaryk University and the International Clinical Research Center (ICRC) in Brno. Manuscripts of four of them were all accepted in one day for publication in prestigious journals Nature Catalysis, ACS Catalysis, Analytical Chemistry and Computational and Structural Biotechnology Journal.

Mountaineers climb peaks, athletes break records, artists create masterpieces. For scientists, publishing articles in peer-reviewed journals is a core part of their work. In doing so, they spread awareness of their research, get feedback, develop collaborations with like-minded colleagues, and move the research forward. The most prestigious journals are those that are peer-reviewed and have a high impact factor, i.e. a value reflecting the average citation rate of all articles published in a journal over a certain period. Impact journals are ranked within their fields according to various metrics and are divided into four quartiles. The best ones are in the first quartile.

This elite group includes all the journals in which Martin Marek, Zbynek Prokop, Jan Velecký and Jan Mičan from Loschmidt Laboratories have managed to publish. Jan Velecký, for whom the acceptance of his first-authored article was a condition for the completion of his doctoral studies, wittily compared it to the milestones of a person’s first smile, first word, first day at school or first A or F grade at school. His colleague Michal Vašina, who has also recently enjoyed publication in the internationally recognised journal Chem Catalysis, likened the process of publishing a paper to the aging of wine. It happens that scientists have to rewrite and refine an article for several years before their “gran reserva” is accepted for publication.

Specifically, the accepted manuscripts describe the catalytic mechanism of the enzyme luciferase, the improvement of plastic-degrading enzymes by protein engineering, a microfluidic platform for monitoring enzymatic reactions, and the development of a new database for predicting the effect of mutations on protein solubility.

In his congratulatory message on social media, Prof. Petr Slavíček from the University of Chemistry and Technology in Prague calculated that with the current scientific performance of the team, the probability of 4 papers being accepted in prestigious journals at the same time is 0.09%, and we can therefore expect a similar phenomenon again in 384 years. We congratulate all the authors and wish them to break the statistics and celebrate more similar achievements soon.

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Celebrating the success of the research teams, 11/11/2022 – from left Michal Vašina, Jan Velecký, Jan Mičan, Zbyněk Prokop, Martin Marek

Nature cannot do without enzymes – proteins that speed up chemical reactions in all living organisms. For example, we owe our beer and wine to enzymes; we wouldn’t enjoy hard cheeses and, in principle, wouldn’t do laundry without them. But people also use enzymes in biomedicine, industry, and environmental protection. Unfortunately, relatively few enzymes perform optimally, so scientists have been working for decades on searching for more efficient enzymes. In doing so, they keep running into a fundamental question: Is it better to modify existing enzymes through protein engineering or to search for new ones in nature’s vast diversity?

Researchers from the Loschmidt Laboratories at RECETOX, Faculty of Science, Masaryk University and the International Clinical Research Center (ICRC), in collaboration with colleagues from ETH Zurich and the University of Greifswald, decided to go down the route of searching for new enzymes. They published the results of their six-year research project in the international prestigious journal Chem Catalysis. Their aim was to find more efficient variants of an enzyme family that can degrade halogenated hydrocarbons polluting the environment. The search began in genomic databases, which currently contain hundreds of millions of gene sequences that encode previously unknown proteins. Using the in-house web tool EnzymeMiner, they were able to select the most promising candidates from this plethora of sequences. “You could compare it to finding needles in a haystack. With EnzymeMiner we can distinguish the needle from the straw very well. However, in the next step we need to find out if the selected needles are sharp enough – this means to experimentally verify that the selected enzymes are fast enough,” said Michal Vašina, the first author of the study.

Therefore, the researchers then prepared these selected candidates in the laboratory and studied their properties using two microfluidic platforms – modern technologies that can handle miniature sample volumes and save time. The first platform, MicroPEX, was used by the researchers to systematically characterize enzymatic reaction rates, while the second platform, KinMAP, gave them insight into the actual mechanism of enzymatic reactions. “The savings in time and money are tremendous. Thanks to this method, we can measure the same amount of data in a single week that would take months to obtain with conventional technologies,” said the microfluidic expert Zbyněk Prokop.

Coming back to the question from the beginning of the article, whether it is better to discover or engineer new enzymes, this scientific study gives a clear answer. Historically, the first enzymes degrading halogenated hydrocarbons were identified more than 30 years ago, while protein engineering has been used for their modification for 25 years. During this time, the properties of twenty-five discovered and more than one hundred modified enzyme variants have been described. When comparing the data obtained, the researchers found that the newly obtained enzymes had better properties than any previously discovered or modified enzyme from the same family.

So how to get more efficient enzymes? Based on their experience, the scientists in the Loschmidt Laboratories answer: “Let’s not underestimate nature. Thanks to its diversity, it has an arsenal of effective enzymes just waiting to be discovered!”

Publication:

https://doi.org/10.1016/j.checat.2022.09.011

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The synergy of advanced bioinformatics and microfluidics helps to find efficient enzymes for recy-cling chemical synthesis intermediates, degrading environmental pollutants, or preparing active pharmaceutical ingredients.

Representatives of the ICRC received a certificate from the Swedish Ambassador H.E. Frederik Jörgensen on the successful completion of the gender pay equity analysis by Logib.

The International Clinical Research Centre (ICRC) in Brno is among 18 institutions and companies awarded for the Gender Equity Assessment. The presentation of the certificates took place on 12 September 2022 at the Embassy of Sweden in the Czech Republic, aptly underlining the importance of the Nordic countries in equality and diversity issues.

The ICRC is among the first employers to undergo this assessment. At the same time, we are the very first hospital representative in the country. We thus subscribe to the principles of transparency and fairness in gender pay. The analysis is part of the implementation of the FNUSA-ICRC Gender Equality Plan for the period 2022-2024.

The Logib tool is an analytical tool that allows employers to assess the status of equal pay for their employees. It is a summary of the gender pay gap by gender and educational attainment, length of experience with a given employer, and the demands and responsibilities of the job.

The first step is to assess the situation, analysing the trend from 2021 and 2022. Based on the results, we will develop a plan for the next steps towards a fairer remuneration system. We want to weigh everyone equally, as the scale our representatives received as a gift with their certificate suggests.

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ICRC representatives, Zuzana Hochelová and Milan Košdy, at the certificate ceremony

Preventing diabetes or understanding the causes of Alzheimer’s disease – these are also topics supported by the Molecular, Cellular and Clinical Approach to Healthy Ageing (ENOCH) project, whose investigators met in Brno at the end of September. More than a hundred representatives from five top Moravian research centres evaluated the achievements of ENOCH so far. The project has succeeded in creating a unique space for mutual cooperation of experts in the field and the application of the qualities of each of the participating workplaces. The knowledge gained is a further step on the road to active and healthy ageing.

The Continental Hotel in Brno hosted the ENOCH (MolEcular, cellular and cliNical apprOaCH to healthy aging) project meeting on 29-30 September 2022. Led by the International Clinical Research Centre (ICRC) in Brno, the platform includes partners from Palacký University in Olomouc, Masaryk Cancer Institute, University of Ostrava and Olomouc University Hospital. The project was born in 2018 with the idea of coordinating research centres dedicated to topics related to population ageing.

As Professor Irena Rektorová, Head of the ICRC, reminded us in her introduction, “The goal is not immortal life, but a healthy old age, i.e. to age actively and healthily.” The development of new preventive, diagnostic and therapeutic solutions for age-related disorders should contribute to this. “ENOCH purposefully unifies current research on healthy ageing and makes full use of its potential to share know-how, experts and resources across the region. It is the networking of different institutions that is crucial to ENOCH’s contribution, as each of the researchers has unique practices and expertise to offer the field”, adds project coordinator, Dr. Gorazd B. Stokin of the ICRC.

Specifically, the research teams are studying, for example, dementia, cancer, chronic inflammation and heart disease. These disorders affect a large part of the population in advanced age and therefore affect not only the elderly but also their families. The consequences are also reflected in the healthcare system and the budget for health and social services.

The results are coming out both in the field of basic research, i.e. in laboratories, and in medical practice. For example, the Kardiovize team at the ICRC, with the support of the ENOCH project, has designed a diabetes prevention programme. Based on measurements of the health status of the local population, the researchers have put together a set of effective measures in the form of a preventive lifestyle programme, which takes place regularly at the St. Anne’s University Hospital in Brno and offers participants training in a lifestyle that suits them while supporting their long-term health.

After two years of metal restrictions, the annual meeting of the ENOCH project was once again held in full attendance. It offered a discussion on the progress of the project implementation, both in terms of the fulfilment of the binding indicators and benchmarks, and in particular on the research activities carried out by the different teams. The Steering Committee also met and positively evaluated the performance and results of the project so far and also focused on the commitments and plans for its subsequent sustainability. The programme also offered presentations by three guests. Dr. Robert Zorec from the University of Ljubljana addressed the topic “Noradrenergic hypotheses of cognitive decline and astroglia”. Dr. GIampiero Leanza from the University of Catania followed with an online presentation on “Noradrenaline and the regulation of spatial memory”. The trio was rounded off by Dr Kenneth Moya from the Department of Biology, École Normale Supérieure, Paris with “Neuroprotective action of the homeoprotein Engrailed 1 and motoneuron physiology”.

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The ENOCH project (Molecular, Cellular and Clinical Approach to Healthy Ageing, CZ.02.1.01/0.0/0.0/16_019/0000868) is funded by the European Regional Development Fund. The implementation phase of the project ends in June 2023, when a five-year sustainability period will follow.

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Scientists from several research teams at the International Clinical Research Centre (ICRC), a joint facility of the Masaryk University Faculty of Medicine and St. Anne’s University Hospital in Brno, focused on microbial infections and Alzheimer’s disease. The link between the two has been demonstrated in many studies, and the research focused on the frequency of the most common viral and bacterial pathogens in the brains of Alzheimer’s patients.

The paper, entitled “Increased occurrence of Treponema spp. and double-species infections in patients with Alzheimer’s disease,” was published in the scientific journal Science of The Total Environment (IF – 10.75).

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative pathology. It accounts for 60-80% of cases of dementia. Dementia is a general term encompassing memory loss and the gradual decline of other cognitive abilities, often severe enough to interfere with an individual’s daily life and independence. The origin of Alzheimer’s disease is not yet fully understood. The disease is characterised by a pathological cascade of protein clotting. One of these is amyloid, whose function is to protect the brain from infectious agents, i.e. viruses or bacteria. There are theories that the action of a particular virus or pathogen may cause this protein to clot more than is permissible and thus trigger the pathological cascade.

For the detection of five bacterial and five viral pathogens, a multiplex PCR assay kit has been developed in collaboration with BioVendor, where all of the aforementioned pathogens can be detected simultaneously. “Although the link between microbial infections and Alzheimer’s disease has been demonstrated in many studies, the contribution of pathogens to the onset of Alzheimer’s disease remains unclear,” said the first author of the paper, Dr Michal Nemergut from the Loschmidt Laboratories of the MU Faculty of Science and the ICRC. “Therefore, we investigated the frequency of the ten most frequently reported viral (HSV-1, EBV, HHV-6, HHV-7, CMV) and bacterial (Chlamydia pneumoniae, Helicobacter pylori, Borrelia burgdorferi, Porphyromonas gingivalis, Treponema spp.) pathogens in serum, cerebrospinal fluid and brain tissue of Alzheimer’s disease patients.”

Serum and liquor samples from 50 patients with Alzheimer’s disease and 53 control subjects without cognitive deficits were used. The samples and data were provided by the Czech Brain Aging study – a national aging study led by Kateřina Sheardová, MD, and Prof. Jakub Hort, MD. A significantly higher frequency of patients with Alzheimer’s disease who were positive for Treponema spp. was observed compared to controls (62.2% vs 30.3%). Furthermore, a significantly higher incidence of cases with two or more concurrent infections was confirmed in patients with Alzheimer’s disease compared to controls (24% vs 7.5%). The studied pathogens were detected with comparable frequency in serum and cerebrospinal fluid. In contrast, Borrelia burgdorferi, human herpesvirus 7 and human cytomegalovirus were not detected in any of the studied samples.

This study provides further evidence of an association between microbial infections and Alzheimer’s disease. “The results show that parallel analysis of multiple pathogens and detection of their occurrence from multiple different biological samples provides interesting additional information, and this methodology should be considered for future studies working with this hypothesis in the context of Alzheimer’s disease.” said Katerina Sheardová, MD.

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Scientists from the Noninvasive cardiac imaging – CMR team at the International Clinical Research Centre of St. Anne’s University Hospital in Brno have published a study entitled “Stress pulmonary circulation parameters assessed by a cardiovascular magnetic resonance in patients after a heart transplant”. It was published in Scientific Reports (IF 4,996) and deals with the use of cardiovascular magnetic resonance in the assessment of selected parameters of pulmonary function.

“The aim of this study was to investigate novel pulmonary circulation stress parameters in patients after heart transplantation.  These patients were hypothesized to have mild diastolic dysfunction, which is more pronounced under stress conditions. The results of comparison of the obtained parameters with the control group of patients confirm this assumption. We were also the first to use “ratio” parameters, which work with the ratio of stress and rest parameters” said the first author of the paper, Lukáš Opatřil, MD.

The pulmonary circulation parameters obtained by non-invasive methods are not completely new. Resting forms in different forms and obtained by different methods have been studied for years. However, the most recent method is cardiac magnetic resonance, which offers significant advantages over other methods and is the only one that can determine stress parameters. From the analysis of data obtained in this way, parameters such as pulmonary transit time (PTT), pulmonary transit beats (PTB) and pulmonary blood volume index (PBVI) can be obtained. Similarly, their variations during exercise can be obtained.

These parameters could be used in the future to determine diastolic dysfunction. Thus, a study conducted on a group of 48 heart transplant patients provided further evidence of pulmonary circulation parameters obtained by cardiac MRI. It investigated stress parameters in this group as a potential marker of diastolic dysfunction and introduced ratio parameters as potential new biomarkers.

Dr Opatril

More than 1,700 primary school pupils from the Czech Republic, Slovakia, Poland and Hungary have received special training on stroke and heart attack through e-learning. A total of 152 classes from 29 primary schools and 56 teachers from the Visegrad Four countries participated in the project “V4 HOBIT: Saving Lives in the V4 through Health Education in Schools”.

The V4 HOBIT project was launched in March 2021 and its main coordinator is the Public Health Group of the Cerebrovascular Team of the International Clinical Research Centre of St. Anne’s University Hospital in Brno. The project partners are Semmelweis University (HU), Jagiellonian University in Krakow (PL) and University Hospital of L. Pasteur (SK).

The HOBIT programme has been running in Czech schools since 2014. However, it is new for teachers and pupils from the other three countries. In Slovakia, pupils from 68 classes in 10 schools learned how to recognise the symptoms of a stroke or heart attack and what to do in that moment. Most of them were from Košice, but there were also schools from Bratislava, Považská Bystrica and Trstená. In Poland, most of the schools from one city, Krakow, participated. In total, there were 24 classes from 5 schools. In Hungary, schoolchildren from different schools and towns participated in the project. The 28 classes from 9 schools came from cities such as Szeged, Nyírbátor, Zalaegerszeg or Szigetszentmiklós. The Czech Republic was represented by 32 classes from 5 schools coming from Ostrava, Brno, Ústí nad Orlicí, Domažlice and Štětí.

HOBIT educates through simulation scenes

The e-learning of the HOBIT educational programme consists of three parts. First, pupils go through a short section of several test questions to find out how much they already know about stroke and heart attack. Then they watch a video and finally go through the test again.

In each of the participating countries, pupils’ knowledge of the selected diseases increased by at least 10% after completing the full test. The biggest jump was in Slovakia, where the numbers jumped from an average of 44.8% (pupils’ success rate on the first questions) to 59.5% (pupils’ success rate on the final test). The smallest difference between the first and second tests was in Hungary. While Hungarian pupils passed the first test with an average pass rate of 53.5%, they achieved a pass rate of 57% in the second test.

One test is not the end of the project

Around 1,700 pupils from the V4 countries took the e-learning and tests in two rounds. The results allowed the research team to compare what the pupils remembered from the previous testing and thus evaluate the effectiveness of the international HOBIT learning platform.

“The result of the overall testing of the pupils’ success rate in the second round is very similar to that of the first round, ranging from 55% to 60%. For us and for the teachers, this means that the HOBIT education programme makes sense. These diseases (note: stroke and heart attack) are part of our everyday lives. Pupils are enthusiastic about the programme and learn something they can really use in their lives. They are not so helpless in crisis situations,” says Renata Hejnová, the coordinator of the HOBIT programme in the Czech Republic.

The e-learning of the HOBIT training programme is still active on the website https://projecthobit.eu/ in all four languages. If you are interested in taking part in the training programme, you can contact the coordinators and get the necessary information by e-mail: projekthobit@fnusa.cz.

The implementation of the training programme in schools was carried out by GrapePR in Slovakia, Agencja Pretty Good in Poland and Diamond Agency in Hungary. In the Czech Republic, schools that had already been involved in the HOBIT programme in previous years were contacted.

The International Clinical Research Centre of St. Anne’s University Hospital in Brno was visited by Mgr. Helena Langšádlová, Minister of Science, Research and Innovation. During her visit, she learned not only about the history and current activities of the Centre, but also about future plans and visited the workplaces of several research teams.

At the FNUSA-ICRC she was welcomed by the director of the hospital Ing. Vlastimil Vajdák and the director of the centre, prof. MUDr. Irena Rektorová, Ph.D. In a short presentation, the Minister was presented, among other things, the NPO EXCELES project focused on research on neurodegenerative brain diseases, which also aims to create a national authority, the National Institute for Neurological Research (NINR). Eleven institutions from all over the country are cooperating in the project and the main beneficiary of the grant and coordinator is the St. Anne’s University Hospital in Brno.

The presentation was followed by a tour of the selected departments. Minister Langšádlová visited the laboratory of the Centre for Cell and Tissue Engineering, where she learned about the production of cell-based medicines, as well as the workplace and operating rooms of the Interventional Cardiac Electrophysiology team. “I was very pleased with the Minister’s visit and her keen interest in our research and the NPO’s neurology project,” said Director Rektorová.

Minister Langšádlová visited the researchers of the Centre for Translational Medicine in Biological Park Brno. The head of the CTM, researcher Giancarlo Forte, introduced her to the work of the teams dedicated to basic research using, for example, organoids, both theoretically and practically directly in the laboratories. “For me, visiting the Centre of Excellence is a confirmation that we are really competitive in science and research. My ambition is to support excellent research, cooperation between the individual science centres, but also their internationalisation,” added Minister Langšádlová.

Minister visit Minister visit

Neuroblastoma is one of the most common malignant tumors in children. It typically affects very young children and sometimes occurs before birth. Neuroblastoma arises from immature cells that commonly form peripheral nerve tissue, including the adrenal medulla, where this tumour is most commonly diagnosed. The causes of the tumour are not fully understood, although it is known that tumour growth is associated with mutations that prevent proper cell development and maturation.

In the Czech Republic, neuroblastoma is diagnosed in approximately 20-30 children per year. The biggest challenge in the treatment of this tumour is its variability. While in some patients the tumour disappears spontaneously, neuroblastomas of so-called high risk often do not respond to treatment at all or the disease returns. Only about half of these patients are successfully cured.

The causes of tumour formation, treatment failure and the reasons for recurrence are therefore the focus of attention of scientists from all over the world. At the International Clinical Research Centre of St. Anne’s University Hospital in Brno, Jan Škoda, Ph.D., head of the Laboratory Oncology Translational Research team, is researching neuroblastoma. “During my internship at Children’s Hospital of Philadelphia, I worked in the lab with Dr. Michael Hogarty, a leading expert in neuroblastoma research and treatment. We established a long-term collaboration, the results of which we are gradually publishing,” described Dr. Škoda.

One of the results of their collaboration is the paper “Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistanceR”, which was published this year in the prestigious scientific journal EMBO Journal (IF 11.6) and which Dr. Škoda co-authored.

In the publication, the researchers focused on mitochondria in cancer cells and their role in therapy. Mitochondria are cellular organelles, i.e. microscopic formations in cells that perform specific functions, similar to organs in the human body, for example. They are fascinating components of our cells, which probably originated from bacteria sometime over two billion years ago. Mitochondria provide unique functions for the cell. They act as a kind of cellular powerhouse and are involved in, among other things, cell differentiation or cell death.

It is programmed cell death, so-called apoptosis, that is an important process in the human body. It is often more beneficial to the organism than spontaneous cell death, because during apoptosis the cell breaks down into smaller vesicles in a controlled manner and there is no risk of it bursting and spilling its harmful contents into the environment. It is also the activation of apoptosis that is the target of most anticancer drugs. The research team, which included Dr. Skoda, described a new mechanism by which neuroblastoma cells can escape available treatments. “Essentially, we found that therapy-resistant cancer cells lose the tight contacts between mitochondria and the endoplasmic reticulum, another very important cellular organelle. This leads to a change in the composition of the mitochondria and they become less sensitive to cell death signals. This leads to a general resistance of the tumour cells, which are therefore very difficult to destroy even with otherwise perfectly effective drugs. Simply put, the changes that anticancer drugs induce in the cell are not perceived by these mitochondria and apoptosis is not triggered,” explained Dr Škoda.

Describing this new mechanism opens a new avenue for developing strategies to treat these resistant tumours.

Jan Skoda