News

New DFG research group FOR 5628 with our participation
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The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) is establishing eight new research groups. One of these groups is FOR 5628: "Multiscale magnetic resonance elastography in cancer: The mechanical niche of tumor formation and metastatic spread – towards an improved diagnosis of cancer through mechanical imaging". The speaker and initiator is Prof. Ingolf Sack.

During the development of a tumour, the tissue changes its shape, e.g., alternating between hard and fluidic states. For this, cells exert forces and are simultaneously influenced by forces. This research group is investigating which mechanical-physical processes are behind this. How do tumours and metastases develop? What makes them resistant to therapy? The team is investigating these questions using magnetic resonance elastography (MRE) – a new clinical procedure that can be used to record the mechanical properties of body tissue. The goal is to be able to better diagnose tumours.
Dr. Karl Hillebrandt and Prof. Dr. Igor Sauer are part of the research group as PI in three projects:
  • A03 Cancer cell unjamming and jamming as prerequisites for the formation of primary and metastatic tumors
  • B03 Scaffold composition and fluid pressure in recellularized hepatic and pancreatic tumors
  • C01 Multiscale mechanical properties of tumors and tumor environment – from tissue specimens to patients

Was are happy to be part of this exzellent team!
science x media Tandem Program: "From Slices to Spaces"
Prof. Dr. Moritz Queisner and Frédéric Eyl (Designer and Managing Director of TheGreenEyl) successfully applied to the Stiftung Charité for funding as a "science x media tandem".
The science x media tandems are the first programme in the new funding priority "Open Life Science". With this funding priority, the Charité Foundation is working to make the life sciences in Berlin more comprehensible and accessible to a broader public and to strengthen the trustworthiness of medical professionals.

Under the title "From Slices to Spaces", the tandem of Moritz Queisner and Frédéric Eyl is implementing a science parcours in which spatially complex research data from surgery and biomedicine will be made multisensually accessible to a broad audience through new visualization techniques. Building on research work on new imaging techniques by Moritz Queisner, they employ Extended Reality techniques. Due to their unique ability to link digital objects with the real environment of the viewers, the 4D images they generate are particularly suited for representing and conveying spatial information.

This is where the tandem's project comes in: 4D images are not only interesting for researchers to understand complex research data but can also provide laypeople with a less presupposing insight into research data and processes. Frédéric Eyl's media expertise will be used to make the specific visual knowledge from research comprehensible and experiential for non-experts. The science parcours is intended to integrate as a digital extension into the architecture of the new research building, "Der Simulierte Mensch", located on the premises of Charité. The parcours will include the facade, the inter-floor airspace, and the central glass surfaces within the building as its stations. By enabling users to explore 4D research data within the architecture and investigate it using their own smartphones in an AR application, concrete practices and deployment locations of new image-based technologies become experiential and comprehensible. This project not only enhances the perception of Charité and the scientific location of Berlin but also opens up places of knowledge creation to the public, making practices and techniques of life sciences more visible.


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DFG | Grant for Machine Perfusion RCT
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The German Research Foundation (Deutsche Forschungsgemeinschaft – DFG) s sponsoring a multicenter randomized controlled clinical trial by Prof. Dr. Georg Lurje entitled "End-ischemic hypothermic oxygenated (HOPE) or normothermic machine perfusion (NMP) compared to conventional cold storage (CCS) in donation after brain death (DBD) liver transplantation; a prospective multicenter randomized controlled trial (HOPE-NMP)".

The purpose of this study is to test the effects of end-ischemic NMP versus end-ischemic HOPE technique in a multicentre prospective randomized controlled clinical trial (RCT) on ECD liver grafts in DBD liver-transplantation (HOPE-NMP). Two-hundred-thirteen (n = 213) human whole organ liver grafts will be submitted to either NMP (n = 85) or HOPE (n = 85) directly before implantation and going to be compared to a control-group of patients (n = 43) transplanted with static cold storage preserved ECD-allografts. Primary (surgical complications as assessed by the comprehensive complication index [CCI]) and secondary (graft- and patient survival, hospital costs, hospital stay) endpoints are going to be analysed.


Congratulations !
New DFG project "4D Imaging"
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The DFG Schwerpunktprogramm „Das Digitale Bild“ (SPP 2172) funds the new project “4D Imaging: From Image Theory to Imaging Practice” (2023-2026). Principal investigators are Prof. Dr. Kathrin Friedrich (Universität Bonn) and Prof. Dr. Moritz Queisner.

The term 4D imaging refers to a new form of digital visuality in which image, action and space are inextricably interwoven. 4D technologies capture, process and transmit information about physical space and make it computable in real time. Changes due to movements and actions become calculable in real time, making 4D images particularly important in aesthetic and operational contexts where they reconceptualize various forms of human-computer interaction. The 4D Imaging project responds to the growing need in medicine to understand, use, and design these complex imaging techniques. It transfers critical reflexive knowledge from research into clinical practices to enable surgeons to use and apply 4D Imaging techniques. Especially in surgical planning, 4D Imaging techniques may improve the understanding and accessibility of spatially complex anatomical structures. To this end, the project is developing approaches to how 4D imaging can complement and transform established topographic ("2D") imaging practices.

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EKFS grant for functional role and clinical relevance of ecDNA in pancreatic adenocarcinoma
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Dr. Matthäus Felsenstein successfully applied for funding from the Else Kröner Fresenius Stiftung (EKFS) for his project “The functional role and clinical relevance of extrachromosomal DNA (ecDNA) in pancreatic adenocarcinoma”. In close collaboration with the excellence group around Professor Anton Henssen, he is aiming at improved understanding of unique genomic patterns as a results of complex chromosomal rearrangements in pancreatic adenocarcinoma that could drive its aggressive behavior. He will use state-of-the art three-dimensional tissue culture to enrich for neoplastic cells from primary PDAC specimen and subsequently perform genome analyses to identify samples that harbor extrachromosomal DNA. The clinical impact of these chromosomal structures will be explored by clinical correlation analyses and therapy response in vitro.

Congratulations!
BMBF funds KIARA
With the programme "AI-based assistance systems for process-accompanying health applications", the Federal Ministry of Education and Research (BMBF) is funding innovative research and development work on interactive assistance systems that support processes in clinical health care using artificial intelligence methods.

Together with the partners Gebrüder Martin GmbH & Co. KG, Tuttlingen, HFC Human-Factors-Consult GmbH, Berlin and the Fraunhofer Institute for Telecommunications Heinrich-Hertz-Institut (HHI), Berlin, we successfully applied with the project "AI-based recording of work processes in the operating theatre for the automated compilation of the operating theatre report" (KIARA).


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Operating theatre reports document all relevant information during surgical interventions. They serve to ensure therapeutic safety and accountability and as proof of performance. The preparation of the OR report is time-consuming and ties up valuable working time – time that is then not available for the treatment of patients.

In the KIARA project, we are working on a system that automatically drafts operating theatre reports. The KIARA system is intended to relieve medical staff: it documents operating theatre activities and creates a draft of the report, which then only needs to be checked, completed and approved. The system works via cameras integrated into operating theatre lamps. Their image data is then analysed with the help of artificial intelligence to recognise and record objects, people and all operating theatre activities. The ambitious system is to be developed and tested in a user-centred manner for procedures in the abdominal cavity and in oral and maxillofacial surgery.

KIARA is intended to continuously learn through human feedback and to simplify clinical processes for the benefit of medical staff by automating the creation of operating theatre reports. The system can also be applied to other operating theatre areas in the future.

The project has a financial volume of € 2.16 million.
The kick-off meeting took place on 16.09.2022 at the Charité.
DFG Walter-Benjamin grant for the investigation of sex as a biological variable in alloimmunity
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With a DFG Walter-Benjamin grant Dr. med. Friederike Martin will join the laboratory of Transplant Surgery Research at Harvard under the direction of Professor Stefan G. Tullius in Boston to investigate the role of biological sex for transplantation outcome.

Influences of donor and recipient sex on transplantation outcome have been described manifold, as well as an influence of sex hormones on the innate and adaptive immune response. So far, research, investigating the impact of sex hormones and different sex- and age-dependent sex-hormone levels on alloimmune response after solid organ transplantation is lacking. The aim of the project “Sex as a biological Variable in Alloimmunity” is, to delineate the impact of sex hormones and especially estrogens and age-dependent changes in estrogen-levels on alloimmune response after allogenic transplantation.  The project is based on the publication “Recipient sex and estradiol levels affect transplant outcomes in an age-specific fashion” published in the AJT in 2021 by the workgroup of Prof. Tullius.

Friederike, who already received the Sanofi Women in Transplantation fellowship grant for research in gender and sex in transplantation in 2021, will work as a Postdoc on this project in the Tullius Lab for an expected 2 years period, starting in January 2023.


Congratulations!
Detection of nicotinamide adenine dinucleotide (NAD) in cells and blood plasma
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Priv,-Doz. Dr. med. Felix Krenzien and Dr. Jennifer Kirwan (Technologieplattform Metabolomik, Max-Delbrück-Centrum für Molekulare Medizin, Berlin) successfully applied for a grant within the Else Kröner Fresenius Stiftung funding line: Translational Research.

Recently, the molecule nicotinamide adenine dinucleotide (NAD) has attracted attention as it is involved in various important regulatory mechanisms, immune signaling, aging and regenerative processes. In this regard, it occupies key positions in many redox reactions of the body due to its role as a redox couple (NAD as an oxidized species and NADH as a reduced species). Consequently, NAD homeostasis (the maintenance of NAD in cells) is considered essential. The scientific consensus for many years was that the oxidized species resides exclusively in the intracellular milieu (iNAD). However, recent findings indicate that NAD also exists extracellularly (eNAD) and it is present in virtually all body fluids (from lymph to saliva to blood plasma). Based on these findings, precursors of NAD have recently been approved by the FDA and are commercially available. Measurement of eNAD in blood plasma is problematic due to its low concentration in the nanomolar range. However, quantifying eNAD plasma levels but also eNAD concentrations in cells is necessary to monitor the intake of NAD or its precursors and to adjust their dosage precisely.
The primary objective of this project is to validate, bioanalyze,and to document the assay for eNAD according to the ICH-M10 guidance document endorsed by the U. S. Food and Drug Administration (FDA). Adherence to the principles presented in this guideline should improve the quality and consistency of bioanalytical data, thereby supporting assay development and market approval. In addition, the assay will also be established for the measurement of intracellular NAD (iNAD), and validation of iNAD quantification will also be performed according to the guideline.

In the second part of the project, a clinical study will be conducted to determine whether the intake of nicotinamide riboside (precursor of NAD) leads to a change in eNAD and iNAD. Thus, the basis for an indication-dependent bioanalysis of the measurement of NAD will be developed to monitor the intake of NAD and its precursor or to adjust the dosage specifically on the basis of the quantification.
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DFG Funds Extension of the Digital Clinician Scientist Program
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Following the successful application for approval of the continuation of the BIH Charité Digital Clinician Scientist Program (DCSP) by the DFG, additional funding of around 1.3 million euros is now available over a period of two years: The DFG funding benefits physicians at Charité who have embarked on a scientific medical career path and, with their innovative research projects, are already playing a key role in shaping the digital transformation of healthcare during their residency training.

The Digital Clinician Scientist Program (DCSP) was jointly initiated by the German Research Foundation (DFG), the BIH, and the faculty of Charité - Universitätsmedizin Berlin in early 2019. The DCSP is an extension of the successful BIH Charité Clinician Scientist Program, which has set standards in the medical research landscape throughout Germany. The structured career path enables researching physicians to build the foundation for a successful career as a clinician scientist by providing protected time for research activities and non-clinical training during their residency. The DCSP is intended for clinically active physicians who are already actively shaping the digital transformation process of healthcare with their innovative research projects during their residency training. The main applicant of the continuation application is Prof. Dr. Igor M. Sauer, Director of the BIH Charité Digital Clinician Scientist Program, Deputy Clinic Director of the Department of Surgery, and Head of the Experimental Surgery at Charité. Since the start of the program in 2019, 24 physicians have benefited from funding, thus a broad spectrum of digital topics is already being addressed in various clinics at the Charité. The DFG originally funded the program for three years with more than three million euros. With the approved extension, the funding program now has a further 1.3 million euros available over a period of two years.
Development of human-based hydrogels as a substitute for mouse-derived Matrigel for cancer research
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With a new funding line, Charité 3R wants to support the development of animal-free cell cultures at Charité.

For in vitro cancer research, mini-tumours are grown in a gel-like cultivation structure that serves the three-dimensional growth of the mini-tumours. This gel-like cultivation substance is obtained from mouse tumours, an unnatural cultivation environment for human mini-tumours. The aim of the project "Development of human-based hydrogels as a substitute for mouse-derived Matrigel for cancer research" by Björn Papke from the Institute of Pathology and Karl Hillebrandt is to produce a cultivation structure without animal additives. For this purpose, a cultivation structure, also gel-like, is to be produced from tissue obtained from patients during surgical procedures, which better corresponds to the natural environment of the human mini-tumours.


Congratulations!
BMBF grant – GreifbAR
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The Federal Ministry of Education and Research (BMBF) funds the project "Tangible reality - skilful interaction of user hands and fingers with real tools in mixed reality worlds (GreifbAR)" – a cooperation of the Augmented Vision group of the DFKI (Prof. Dr. Didier Stricker), the Department of Psychology and Human-Machine Interaction of the University of Passau (Prof. Dr. Susanne Mayr), the company NMY Mixed Reality Communication (Christoph Lenk), and the Experimental Surgery of Charité – Universitätsmedizin Berlin (Prof. Dr. Igor M. Sauer).

The goal of the GreifbAR project is to make extended reality (XR) worlds, including virtual (VR) and mixed reality (MR), tangible and graspable by allowing users to interact with real and virtual objects with their bare hands. Hand accuracy and dexterity is paramount for performing precise tasks in many fields, but the capture of hand-object interaction in current XR systems is woefully inadequate. Current systems rely on hand-held controllers or capture devices that are limited to hand gestures without contact with real objects. GreifbAR solves this limitation by proposing a sensing system that detects both the full hand grip including hand surface and object pose when users interact with real objects or tools. This sensing system will be integrated into a mixed reality training simulator.

Competent handling of instruments and suture material is the basis of every surgical activity. The main instruments used in surgery are in the hands of the surgical staff. Their work is characterised by the targeted use of a large number of instruments that have to be operated and controlled in different ways. Until now, surgical knotting techniques have been learned by means of personal instruction by experienced surgeons, blackboard images and video-based tutorials. A training and teaching concept based on the acquisition of finger movement does not yet exist in surgical education and training. Learning surgical account techniques through participant observation and direct instruction by experienced surgeons is cost-intensive and hardly scalable. This type of training is increasingly reaching its limits in daily clinical practice, which can be attributed in particular to the changed economic, social and regulatory conditions in surgical practice. Students and trainees as well as specialist staff in further training are therefore faced with the problem of applying and practising acquired theoretical knowledge in a practice-oriented manner. Text- and image-based media allow scalable theoretical knowledge acquisition independent of time and place. However, gestures and work steps can only be passively observed and subsequently imitated. Moreover, the learning success cannot be quantitatively measured and verified.

The aim of the Charité's sub-project is therefore to develop a surgical application scenario for Mixed/Augmented Reality (MR/AR) for the spatial guidance and verifying recording of complex fine motor finger movements for the creation of surgical knots, the practical implementation and technical testing of the developed concept within the framework of a demonstrator, and the evaluation of the usability of the system for use in a clinical context.
Two new research grants by Berliner Krebsgesellschaft
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The Berliner Krebsgesellschaft will fund two very interesting research projects by Dr. Linda Feldbrügge and Dr. Karl Hillebrandt in collaboration with Dr. Björn Papke.

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„Purinergic immune regulation in peritoneal metastases of gastric cancer via CD39 and ENTPD3 – target for a novel immune Checkpoint inhibition?“ – PI: Dr. Linda Feldbrügge

Peritoneal metastasis, especially derived from gastric cancer (GC), has a poor prognosis with a median survival of only months. Treatment is usually confined to palliative systemic chemotherapy, complemented individually by checkpoint inhibitors that block PD1-signaling. Innovative therapies combining surgery with local drug application such as hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC) are still pending confirmation in clinical trials. Purinergic signaling, which involves ATP hydrolysis and generation of adenosine, regulated through CD39 (ENTPD1) and related enzymes, has been recognized as a critical immunoregulatory pathway in the tumor microenvironment (TME). The objective of the current project is to characterize the immune environment in the unique setting of peritoneal metastasis of gastric cancer with a focus on ectonucleotidases CD39 and ENTPD3 on T cells, macrophages and MDSC as well as mechanisms of ectonucleotidase-mediated immune regulation in tumor associated macrophages in vitro. As a high-volume center for surgical therapy of peritoneal malignancies and with years of experience in ectonucleotidase research, we aim to advance the understanding of peritoneal metastasis and contribute to improving treatment options for our patients.

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"The influence of decellularised tumour matrix heterogeneity in relation to KRAS/MAPK inhibition of in vitro colorectal liver metastases." PI: Dr. Karl Hillebrandt and Dr. Björn Papke (Dept. of Pathology)

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, with approximately 900,000 annual deaths. 30-50% of patients develop colorectal liver metastases (CRLM) during their disease. More than 50% of these tumors have mutations in the KRAS oncogene, making them usually poorly treatable. Despite multimodal therapy concepts have improved the outcome of these patients, a large proportion of patients suffer a recurrence of their disease. For better therapeutic concepts, we need to better understand the tumor biology and metastatic mechanisms of these diseases. In vitro models, such as two-dimensional cell culture, are primarily used for this purpose. These models can only reflect the physiological complexity to a limited extent. Recently, it was shown that the use of organ-specific and tumor-specific extracellular matrix (ECM) has an impact on the behavior of human CRC cell lines. Culture of cell lines with decellularized matrix resulted in cells adopting a metastatic cell state and forming significantly more metastases in a mouse model than cells cultured on plastic or collagen. The goal of our project is to study the growth (with and without inhibition of the RAS/MAPK signaling pathway) of patient-derived tumor organoids growing on different decellularized metastatic matrices (dMM) and decellularized liver matrices (dLM). These studies of tumor matrix heterogeneity are essential to define which starting materials, for in vitro modeling of our three-dimensional tumor organoid culture, can be used to develop the most physiological, personalized dLM/dMM-based CRLM in vitro model possible. Based on these results, we plan to conduct small-scale therapy evaluations for personalized tumor therapy using our in vitro dLM/dMM-based CRLM in the near future.

Congratulations!
ADBoard | Therapeutic Assist and Decision Algorithms for Hepatobiliary Tumor Boards
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The Gemeinsamer Bundesausschuss (Federal Joint Committee, G-BA) will fund a new collaborative project of the Charité's Dept. of Surgery and the Deutsches Forschungszentrum für Künstliche Intelligenz (German Research Center for Artificial Intelligence, DFKI), Speech and Language Technology.

The aim of the project Therapeutic Assist and Decision Algorithms for Hepatobiliary Tumor Boards (ADBoard) is the validation and evaluation of decision support systems based on linguistic and semantic methods of artificial intelligence (AI) for interdisciplinary tumour conferences in the care of tumour patients. Natural language processing (NLP) and machine learning (ML) will provide the technical basis for data extraction, data filtration and decision support for the automated generation of therapy recommendations. Interdisciplinary tumour board conferences are medical conferences, usually held on a weekly basis, which are required by the respective medical societies to determine a therapy or monitoring plan for patients with malignant diseases. Participants are representatives of the required medical disciplines who, taking into account the tumour characteristics and the general health of the patient, review the treatment options and make a therapy recommendation.

The Gemeinsamer Budesausschuss (Federal Joint Committee, G-BA) has the mandate to promote new forms of health care that go beyond the current standard provision of statutory health insurance, and health care research projects that are aimed at gaining knowledge to improve existing health care.

ADBoard is a collaboration of Priv.-Doz. Dr. Felix Krenzien, Priv.-Doz. Dr. Christian Benzing, Prof. Dr. Dominik Modest, Prof. Dr. Johann Pratschke (Charité – Universitätsmedizin Berlin) and Prof. Dr.-Ing. Sebastian Möller, Head of Research Department Speech and Language Technology, German Research Center for Artificial Intelligence.
Advanced Clinician Scientists
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Priv.-Doz. Dr. Nathanael Raschzok and Priv.-Doz. Dr. Felix Krenzien successfully applied for the BIH Charité Advanced Clinician Scientist Pilot Programme (AdCSP) in a highly competitive process.

The BIH Charité AdCSP is designed as a career-phase-specific, sustainable funding programme that aims to closely interlink individual and institutional funding. The primary goal of the programme is to simultaneously incentivise the fellows and recognise the permissive academic culture of the respective clinics or institutes. Like the BIH Charité Clinician Scientist Programme (CSP) and the "Digital Clinician Scientist Programme" (DCSP), which has been additionally funded by the DFG since 2019, it is intended to be open to all clinical disciplines and to offer multiple networking opportunities for the funded fellows and participating clinics and institutes.

Congratulations!
Grant provided by the Berliner Krebsgesellschaft e.V.
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Dr. med. M. Felsenstein receives a grant provided by the Berliner Krebsgesellschaft e.V. for his project "Deciphering the molecular determinants of pancreatic duct dysplasia by analysis of single-cell transcriptomics (RNAseq) in precursor lesions".

Besides great advances in the molecular and genetic understanding of pancreatic duct adenocarcinoma (PDAC), this tumor entity remains particularly aggressive with dismal prognosis. Recent single-cell sequencing studies underline the eminent urgency to understand tumor heterogeneity in the setting of PDAC. More detailed knowledge about the molecular mechanisms of pancreatic cancer evolution, carcinogenesis and heterogeneity could direct ideas for earlier detection and more effective targeted therapies, also preventing disease recurrence. Future therapeutic approaches in precision medicine will likely focus on the disease relevant sub-populations, specifically driving cancer progression, dissemination and exerting tumor escape mechanisms. In-depth transcriptomic data of single carcinoma environmental cells and respective cell clusters may help to discover novel biomarkers, which can be clinically instrumented for earlier detection and putatively increase the fraction of patients, amenable to curatively intended therapies. This study aims to analyze sorted single cells of macro-dissected precursor and cancerous lesions of the pancreas by single nuclei RNA sequencing (snRNAseq). In this feasibility study, we will include 10 patients, who will undergo resection of the pancreas due to “worrisome” or malignant lesions. We will perform in-depth transcriptomic analysis of pancreatic dysplasia in order to broaden our understanding of the molecular mechanisms of pancreatic carcinogenesis.

Congratulations!
Karl Hillebrandt | Charité 3R Tandem project for early career researchers
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Together with Dr. Björn Papke (Molecular tumour pathology), Dr. Karl Hillebrandt was able to acquire funding for a "Tandem project for early career researchers" from the Charité 3R. The project is entitled "A personalised therapy approach implementing individually matched matrix-based in vitro colorectal liver metastases to reduce metastatic mouse models".
Although modern multimodal therapy strategies have improved the clinical outcome of patients with colorectal liver metastases (CRLM), the overall prognosis is still poor. To further improve treatment options for patients, it is necessary to develop and test new targeted therapeutic approaches. To date, mouse models have often been used to study metastatic colorectal cancer. However, the rate of successful translation of animal models into clinical trials is less than 8%, highlighting the urgent need for alternative models to study the biology of metastatic cancer. This project aims to develop a novel personalised extracellular matrix-based in vitro model of human CRLM. This model will be validated against existing data from patient-derived organoids and xenografts (histology, single cell RNA sequencing and targeted gene sequencing). After internal comparison of our in vitro CRLM with the original CRLM, we will translate it into a personalised drug screening platform to test drug response from standard therapy to novel inhibitor combinations.
Two new (Junior) Clinician Scientitsts
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Dr. Simon Moosburner and Dr. Tomasz Dziodzio successfully applied for the BIH Charité (Junior) Clinician Scientist Program.

Dr. Dziodzio is studying pathomechanisms of obesity in the context of kidney transplantation and investigates the impact of obesity on the immune response in the kidney transplant recipient. In addition, a clinical trial will investigate whether surgical weight reduction in obese patients prior to kidney transplantation leads to improved graft function.

Dr. Moosburner is working on the extracorporeal evaluation of liver grafts from older donors. The aim is to characterise old liver grafts during normothermic machine perfusion. For this purpose, a model for normothermic ex vivo machine perfusion of small animal livers as well as liver transplantation in the rat model was established.

CASSANDRA | Clinical ASSist AND aleRt Algorithms
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The Innovationsausschuss beim Gemeinsamen Bundesausschuss (G-BA) is funding 33 new projects in healthcare research. A total of 186 project applications were received in response to the funding announcements of December 2019. Nine project proposals from the open topic area and 24 project proposals from the topic-specific area received a positive funding decision.

Our project CASSANDRA (Clinical ASSist AND aleRt Algorithms – Early detection of postoperative complications with machine learning algorithms) is one of the projects funded for three years.

The aim of the project is to evaluate Machine Learning (ML) in the detection of postoperative complications after major abdominal surgery. By means of digital records and ML-driven analysis of perioperative risk factors, postoperative parameters as well as telemedical vital parameter monitoring, it is to be examined whether complications requiring treatment – in particular infections of the abdominal cavity after liver, pancreas, stomach and intestinal surgery – can be automatically detected and predicted, in order to develop the basis for an autonomous real-time monitoring system on normal wards.
CASSANDRA is a collaboration of Axel Winter, Dr. Max Maurer, Prof. Dr. Igor M. Sauer (Charité – Universitätsmedizin Berlin) and Prof. Dr. Bert Arnrich, Head of the Chair, Professor for Digital Health - Connected Healthcare, Hasso Plattner Institut.
DICOM_XR | XR4ALL 2nd Open Call: Project Selected for Phase 1
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XR4ALL is an initiative by the European Commission to strengthen the European XR industry.

After 140 applications, 18 projects have been selected for Phase 1 of the 2nd Cut-off date of the XR4ALL Open Call. In this phase, projects need to expand upon and validate their concept from a business and a technical perspective during two months.
Based on an evaluation at the end of the first phase, only the best-rated projects will be admitted to Phase 2 and therefore be able to develop the proposed solution.

Our project DICOM_XR (PI: Christoph Rüger) is one of them (and one of three from Germany)!

One of the most common use-cases for XR in medicine is the visualization of medical imaging data like computed tomography (CT) scans. The well-established standard for storing and transferring such data is DICOM (Digital Imaging and Communications in Medicine). It is used in all major hospitals in the European Union – XR applications that involve medical images need to be built upon this standard. Existing open-source DICOM frameworks offer data interoperability and are compatible with 3D engines, like Unity. However, while DICOM is well-established and very feature rich, it is also a complex standard to work with as a developer. In addition to data interoperability provided by DICOM, most medical XR applications also require: 1) Data transfer from a machine with access to the hospital’s image network to mobile XR devices such as HMDs, 2) performant visualization, particularly for stereographic displays, and 3) view manipulation with 3D input (e.g. hand tracking) instead of mouse input. These requirements are, at best, additional workloads for technically skilled teams and, at worst, insurmountable hurdles for projects lacking programmers.
DICOM_XR is a framework aiming to solve all three of these requirements: data transfer, performant visualization and utilization of three-dimensional input. Building upon an existing open-source DICOM solution, DICOM_XR will offer a ‘plug and play’ solution for XR developers. It will significantly decrease technical hurdles for e.g. medical studies evaluating XR, which are still sorely needed. It can also streamline the development of commercial XR applications: Medical open-source projects such as SlicerIGT have been successfully used as a foundation for certified medical products. In short, DICOM_XR will allow medical XR developers to focus on features that their users want, rather than technical infrastructure.
EKFS grant | Metabolic reconditioning of steatotic rat liver grafts by normothermic ex vivo machine perfusion
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The Else Kröner Fresenius Stiftung will fund the project "Metabolic reconditioning of steatotic rat liver grafts by normothermic ex vivo machine perfusion" (PI: Priv.-Doz. Dr. Nathanael Raschzok) for two years.

Liver transplantation is the treatment of choice for end-stage liver disease, yet the number of transplant candidates constantly exceeds the organ supply. The imbalance between demand and supply of liver grafts is dramatically exacerbated by the rising prevalence of obesity and the metabolic syndrome, which both show a strong correlation with steatosis hepatis. Liver grafts with macrovesicular steatosis above 30% are associated with delayed graft function and lower graft and patient survival, and livers with >60% steatosis are generally discarded from transplantation. Within the next 10 years, the overall liver graft utilization could potentially be halved due to the rising prevalence of steatosis, emphasizing the urgent clinical need to find solutions to make steatotic livers acceptable for transplantation.

In this project the hypothesis is tested whether metabolic reprogramming of steatotic liver grafts will 1) restore hepatocyte function, 2) activate lipid catabolism, 3) increase resistance to ischemia reperfusion damage, and 4) alleviate overwhelming inflammatory processes in the early phase of post-transplant regeneration with beneficial long-term impact for graft function and recipient survival.
Brigitta Globke: Digital Clinician Scientist
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Dr. Brigitta Globke successfully applied for participation in the BIH Charite Digital Clinician Scientist Program.

The aim of the project is the development and evaluation of an augmented reality assist system for intraoperative photoplethysmographic control of perfusion. The project is carried out in collaboration with Benjamin Kossack, Fraunhofer | Heinrich Hertz Institute Computer Vision and Graphics.

Charité and BIH are jointly organizing the new "Digital Clinician Scientist Program" (D-CSP). The program is primarily aimed at physicians who are already working on innovative research projects to meet the technological challenges of data-driven medicine during their specialist training. The German Research Foundation (DFG) is funding the project for an initial period of three years.

The BIH Charité Digital Clinician Scientist Program will provide a new career path for the creators of digital change in medicine and will expand the successful Germany-wide model of the BIH Charité Clinician Scientist Program. In addition to the three-year individual funding, which is based on protected time for research, the focus is on modules for the acquisition of scientific skills (Big Data, bioinformatics or artificial intelligence) as well as mandatory mentoring. For the new program, various experts* from the Charité, the BIH, the Max Delbrück Center for Molecular Medicine (MDC), the Berlin Institute for Medical Systems Biology (BIMSB), the Einstein Center for Digital Future, and the Bernstein Center for Computational Neuroscience will be involved in the design of the D-CSP and in the recruitment and supervision of program participants.
Einstein BIH Visiting Fellow project, funded by Stiftung Charité
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The Stiftung Charité will fund our project “Vascular Composite Tissue Allotransplantation (VCA): An integrated, multidisciplinary basic and clinical research program for hand and uterus transplantation” (Einstein BIH Visiting Fellowship) within the framework of the Private Excellence Initiative Johanna Quandt for two more years!

The Charité has a long tradition as an international leader in transplantation. Prior to starting our Einstein BIH funded project in February 2017, Vascular Composite Tissue Allotransplantation (VCA) was neither object of scientific investigations, nor offered to patients. As an Einstein BIH Visiting Fellow Prof. Stefan G. Tullius, Harvard Medical School, ignited both: a basic research group in this field and a clinical research transplant program. During the first three years of our multidisciplinary basic and clinical research program, we have been able to implement complex small animal models (mouse hindlimb, heart, skin transplant models); a rat uterus transplant model is currently established. Those models offer unique opportunities to address basic research questions of translational relevance including: organ-specific alloimmune responses, immunogenicity, and the maternal-fetal interface in uterus transplantation.
An enthusiast clinical, multi-disciplinary has been established, led and mentored by Prof. Tullius that has brought preparatory surgical exercises and clinical algorithms for VCA at the Charité on the way.

Stiftung Charité is an independent charitable foundation. It was endowed in 2005 by entrepreneur Johanna Quandt, who entrusted it with the mission of supporting the innovative potential and excellence of Berlin’s university medicine, which can look back on a rich tradition in medical research and patient care. Thereby, the foundation is active in two focal areas: promoting technology transfer between the laboratory and the clinic as well as improving the framework conditions for innovation and entrepreneurship in medicine. Since 2014, Stiftung Charité is also funding the life sciences in Berlin by its Private Excellence Initiative Johanna Quandt.
EUROSTARS project
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Within the Eurostars project „Comprehensive qualitative/quantitative multi-pathogen IVD workflow for immunocompromised patients (Im-compr-IVD)“ an IVD workflow covering sample preparation up to clinical relevant diagnosis of infection in immunocompromised patients will be developed. Deliverables are:
  • Design, development and preclinical validation of QIC-Finder assay with novel primers and probes for qualitative and quantitative screening of 23 pathogens (bacterial, viral, fungal and parasitic);
  • Detection instrumentation and interpretation software optimized for assay performance;
  • Instructions for high quality DNA/RNA extraction from plasma.
Partners are Pathofinder (Netherlands, Coordinator), Ella Biotech (Germany), IT-IS International Ltd. (United Kingdom) and Charité - Universitätsmedizin Berlin.

Eurostars projects are co-funded by EUREKA member countries and the European Union Horizon 2020 Framework program.
DFG Research Grant for PD Dr. Moritz Schmelzle
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Priv.-Doz. Dr. Moritz Schmelzle receives additional financial support for his project "CD39-dependent regulation of innate immune responses and modulation of exacerbated sterile inflammation in acute-on-chronic liver failure" (DFG Research Grant 299534341, SCHM2661/3-2).
Acute on chronic liver failure (ACLF) is defined as an acute hepatic insult in patients with chronic liver disease and is characterized by high death rates. Systemic inflammation is considered a hallmark of ACLF and can be linked to progression of liver failure and clinical deterioration. Criteria for ACLF and the systemic inflammatory response syndrome (SIRS) substantially overlap and support the assumption of mechanistic similarities between both syndromes. Thus, modulating inflammation and the linked immune responses in ACLF might help to restore homeostasis and improve of regenerative capacities of the injured liver.We hypothesize that the catalyzed hydrolysis of purinergic damage-associated molecular patterns (DAMPS), such as extracellular ATP, by the ectonucleotidase CD39 is crucially involved in the regulation of innate immune responses and the modulation of exacerbated sterile inflammation in ACLF. We here aim to describe characteristics and functions of monocyte subsets in ACLF and to investigate implications of purinergic signaling. We further plan to investigate the therapeutical relevance of non-classical monocytes and the immune-type ectonucleotidase CD39 in experimental ACLF. Finally, we will evaluate the clinical significance of cellular and non-cellular immune responses in ACLF patients enrolled in the GRAFT Trial.
DFG grant for Linda Feldbrügge
Dr. Linda Feldbrügge receives a research grant from the Deutsche Forschungsgemeinschaft (DFG) for her project "Purinergic regulation of inflammation in liver fibrosis by ectonucleoside triphosphate diphosphohydrolase-3 (ENTPD3)“.

ENTPD3, expressed by macrophages and various other cell types, modulates inflammation and tissue regeneration by scavenging extracellular ATP and ADP. As demonstrated by her preliminary work, ENTPD3 appears to play a deleterious role in liver fibrosis. Her new project aims to define the mechanisms of ENTPD3 mediated modulation of macrophage function and regulation of liver fibrosis, and test their relevance in human liver fibrosis.

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DFG Research Grant
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Priv.-Doz. Dr. Nathanael Raschzok receives a research grant from the Deutsche Forschungsgemeinschaft (DFG) for his project "Defatting of steatotic liver grafts by normothermic ex vivo machine perfusion with DNP" in collaboration with Prof. Dr. med. Andreas Birkenfeld, Universitätsklinikum Carl Gustav Carus, Dresden.

Transplantation of steatotic marginal liver grafts is associated with a certain risk of graft dysfunction, primary non-function, and biliary complications, which results in a worse outcome compared to transplantation of unimpaired livers.
We hypothesize, that normothermic machine perfusion combined with adequate pharmacological intervention can prevent the deleterious effect of ischemia-reperfusion injury on macrovesicular grafts by a) minimizing the negative effect of cold storage, and by b) actively decreasing the intracellular fat content of the graft.
Mild mitochondrial uncoupling by DNP decreases the intrahepatic fat content of steatotic liver grafts during normothermic ex vivo machine perfusion. Efficient defatting can be safely achieved ex vivo with DNP concentrations that would be toxic in vivo. Systemic side effects of DNP are prevented by exclusive hepatic exposure through machine perfusion, and by washing DNP out of the liver graft at the end of the perfusion period. The synergetic effects of normothermic perfusion and defatting with DNP will prevent ischemia-reperfusion injury and make severely steatotic liver grafts acceptable for transplantation.
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SFB 1365 Renoprotection
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The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) is establishing ten new Collaborative Research Centres (CRCs, Sonderforschungsbereich, SFB) to further support top-level research in Germany.
Chronic kidney diseases and acute kidney damage are widespread and reduce the life expectancy of those affected. The CRC “Renoprotection” therefore aims to decode specific signalling pathways for kidney damage and develop new approaches to treatment in the long term (Charité Berlin – FU Berlin and HU Berlin, Spokesperson: Prof. Dr. Pontus Börje Persson).
With the project "Renoprotective role of Lipocalin-2 in allograft rejection following kidney transplantation" Priv.-Doz. Dr. Felix Aigner and Dr. Muhammad Imtiaz Ashraf, PhD will be part of this SFB/CRC!

To provide allograft renoprotection, novel strategies are needed, including (i) prevention of renal allograft IRI and (ii) targeted immunosuppression and thus; reduction and avoidance of steroid and CNI usage in the long-run. Using a mouse model of kidney transplantation, we recently demonstrated a renoprotective role of exogenously administered recombinant Lcn2:Siderophore:Fe complex (rLcn2). The rLcn2 mediated mechanism of allograft renoprotection is still unknown; however, the mechanistic insight is essential for comprehensive translation of the rLcn2 therapy into clinical practice. In the funded project, we aim at (i) understanding the route and mechanisms of immunoregulation and/or cytoprotection, mediated by exogenously administered rLcn2 during the allograft damage; and (ii) characterizing the source and nature of endogenous Lcn2 i.e. whether it is complexed with mammalian iron binding catechols and may contribute to allograft survival in the long-run. Our ultimate goal is to pave the way for transplant renoprotection via recombinant Lcn2.

More information…
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Mathilde Feist and Paul Ritschl: Clinician Scientists
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Dr. Mathilde Feist and Dr. Paul Ritschl successfully applied for the BIH Charité Clinician Scientist Program. Mathilde Feist will work on "Cytokine-armed oncolytic vaccinia virus for pancreatic cancer therapy". Mentors are Prof. Bahra, Prof. Sauer and Prof. Beling.
Paul Ritschl focusses on "The Impact of Donor Derived Microparticles Following Solid Organ Transplantation". Mentors are Priv.-Doz. Dr. Schmelzle and Priv.-Doz Dr. Öllinger.
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Wibke Schulte: BIH Charité Clinician Scientist
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Dr. med. Wibke Schulte successfully applied for the BIH Charité Clinician Scientist Program with her project „Die Rolle von MIF in der humanen akuten Peritonitis | Role of MIF in human acute peritonitis“. Mentors are Priv.-Doz. Dr. med. Felix Aigner and Prof. Dr. Igor M. Sauer.
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Barbara Kern: BIH Charité Clinician Scientist
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Dr. Barbara Kern successfully applied for the BIH Charité Clinician Scientist Program. With her project "Novel Treatment and Diagnostic Approaches Utilizing the Role of Dendritic Cells in Immune Responsivness" Barbara will be engaged in our Vascular Tissue Allotransplantation Initiative (Project VCA). The Clinician Scientist Program is a modern career pathway within academic medicine that allows physicians to pursue a structured residency with time set aside for clinical and basic research. At the end of the program, participants will have completed their residency and, ideally, their postdoctoral teaching qualification (Habilitation). The program is intended to produce a new generation of scientists with translational training who will help speed up the rate at which scientific findings are translated into application.
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ECRT - Advanced Scientist Grant
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PD Dr. Nathanael Raschzok receives one of the 2017 Einstein Center for Regenerative Therapies (ECRT) Kickbox – Advanced Scientist Grant.
Einstein Center for Regenerative Therapies Kickbox – advanced scientist grant. The project is entitled „Overcoming steatotic compromise – Reconstitution of endogenous repair in severely steatotic liver grafts by metabolic reconditioning“. The project will be conducted by Nathanael Raschzok, Angelika Kusch, Duska Dragun, and Igor M. Sauer.

In order to stimulate excellent and creative research ideas that might take regenerative therapies a vital step forward, the Einstein Center offers a special two-stage funding scheme. At first, the Kickbox seed grant provides a great framework to investigate initial ideas and to develop sound research concepts. Subsequently, the flexible funds enable the realisation of projects that evolved from the Kickbox initiation phase in order to reach the scientific goals of the Einstein Center. Congratulations!
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ECRT Kickbox - Junior Scientist Grant
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Karl Hillebrandt receives one of the 2017 Einstein Center for Regenerative Therapies (ECRT) Kickbox – Junior Scientist Grant. The project is entitled "Fighting liver cirrhosis? Establishment and analysis of decellularized human cirrhotic liver slices as a 3-dimensional model to study cell matrix interactions".

Liver cirrhosis is one of the main indications for liver transplantation. Due to the organ shortage, this therapy option is limited to the minority of patients suffering from cirrhosis. Therefore, there is a need of alternative treatment options.The aim of our project is to establish a decellularization protocol for human cirrhotic livers slices, which preserves the natural extracellular matrix (ECM) of cirrhotic livers. These decellularized liver slices will serve as a 3 dimensional model to study cell matrix interactions. If we are able to establish a protocol which will preserve the ECM, we will conduct in vitro recellularization experiments to study how the cirrhotic ECM will change the genotype and phenotype of different cell types. With this knowledge we aim to modify specific cell types in vivo or vitro for example prior to cell transplantation. Our ambition is to steer the cell matrix interaction via these modified cells after their transplantation and thereby halt or even reverse the progress of liver cirrhosis. This approach may offer an alternative treatment option in the future.

Team : Karl Hillebrandt, Oliver Klein, Ben Strücker, Igor Sauer  
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SPARK Berlin supports Fikatas Knot
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The Berlin Institute of Health (BIH) and Stiftung Charité teamed up with Stanford University School of Medicine to initiate SPARK Berlin.

We are very pleased to announce that Dr. Panagiotis Fikatas' project “Device for ready-prepared surgical knots” was selected for both, funding and mentorship. 

SPARK was created to overcome the hurdles associated with translating academic discoveries into therapeutics and diagnostics that address unmet medical needs.  The SPARK mission is to help academics overcome the obstacles involved in moving their early discoveries from bench to bedside, to educate faculty, postdoctoral fellows and graduate students on the translational research process and path to clinical application, so that development of promising discoveries becomes second nature to our institution, and to develop more cost-effective and innovative approaches to drug development .

Congratulations!
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Rebeka Major: BIH Promotionsstipendium
Rebeka Major successfully applied for the BIH-Promotionsstipendium grant. Her work will focus in the role of the INDY („I’m Not Dead Yet“) gene in liver regeneration – a project in cooperation with Prof. A. Birkenfeld, Universitätsklinikum Carl Gustav Carus in Dresden.
In the Berlin Institute of Health (BIH), the Max Delbrück Center for Molecular Medicine (MDC) and the Charité - Universitätsmedizin Berlin have joined forces. The core idea is to combine translational research with an overarching systems medicine approach to bridge the gap between basic research and clinical application.
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Our manuscript "Depletion of donor dendritic cells ameliorates immunogenicity of both skin and hind limb transplants" has been accepted for publication in Frontiers in Immunology, section Alloimmunity and Transplantation. Authors are Muhammad Imtiaz Ashraf, Joerg Mengwasser, Anja Reutzel-Selke, Dietrich Polenz, Kirsten Führer, Steffen Lippert, Peter Tang, Edward Michaelis, Rusan Catar, Johann Pratschke, Christian Witzel, Igor M. Sauer, Stefan G. Tullius, and Barbara Kern.

Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APC), particularly dendritic cells (DC), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DC (cDC) and APC on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation.
By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. While donor depletion of cDC and APC reduced frequencies, maturation, and activation of DC in all analysed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4+IL-17+) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APC and cDC mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA.

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