F. Claussen, J.M.G.V. Gassner, S. Moosburner, D. Wyrwal, M. Nösser, P. Tang, L. Wegener, J. Pohl, A. Reutzel-Selke, R. Arsenic, J. Pratschke, I.M. Sauer, and N. Raschzok published their trecent work on "Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation" in PLoS One 2020;15(7): e0235635.

Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP).

Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion.

Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend.

Our miniaturized dNEVLP system enables normothermic dual vessel rat liver perfusion. The administration of metamizole effectively ameliorates arterial vasospasm allowing for six hours of dNEVLP, with superior outcome compared to sNEVLP.

The Department of Surgery of the Charité (Director: Prof. Dr. Johann Pratschke) at the Charité Center 8 (CharitéCenter for Surgery) invites applications for the position of the Junior Professorship for Digital Surgery and interdisciplinary Technology Research (Salary Group: W1 BBesG-ÜfBE, non-tenured) with the reference number: Prof. 546/2020.

The initial appointment is for three years with the optional extension for another three years follow-ing successful evaluation. It is aimed to turn the Junior Professorship into a W2-Professorship (Salary Group: W2 BBesG-ÜfBE) after six years.The successful candidate has to fulfill the appointment requirements in accordance with § 102a of the Berlin Higher Education Act (Berliner Hochschulgesetz, Gem. § 102a BerlHG) and needs to credibly demonstrate through his/her previous scientific work that he/she is able to fulfill the expectations of the junior professorship.

One of the tasks of this Junior Professorship is the appropriate representation of the research area mentioned above. Within the framework of the Cluster of Excellence Matters of Activity – Image Space Material, he/she is expected to evaluate, accompany and advance the digital transformation in surgery and related disciplines as well as expand the repertoire of methods and initiate innovations. In cooperation with the research areas Cutting and Material Form Function of the Cluster of Excellence, new surgical cutting techniques are to be investigated and developed. It is planned to be linked to the currently being established institutions, The Simulated Human Being (Si-M) and the Berlin Simulation and Training Centre (BeST). In addition to the tasks mentioned, the following three fields of activity are to be covered:

Interdisciplinary Knowledge Transfer

• Implementation of new applications from areas such as deep learning, extended reality (mixed and virtual reality) or robotics in surgical practice requires an intensification of interdisciplinary cooperation
• Continuous exchange between industry and practice as well as with adjacent disciplines (e.g. Radiology)
• Integration of a growing number of applications and competencies from areas outside established medical technology, e.g.game design, computer science or human factor studies

Technology Assessment

• Sustainable implementation of digital technologies through opportunity and risk assessment
• Advising the Department of Surgery on investment decisions through appropriate risk and media competency

Innovation

• Identification of concrete application locations and practices of digital surgery within the clinic and experimental research (e.g. use of technologies in the context of biomedical research approaches to organ replacement as well as oncological models) for future Living Labs and to demonstrate these to the public
• Integration of users, research projects and start-ups also outside the Clinic

The successful candidate will be engaged in teaching activities of the medical education curriculum at Charité, supervise Master and Doctoral candidates, and participate in academic self-organization. In addition, the candidate should present concepts for a good supervision of doctoral students as well as for the integration of his/her research activities into the teaching of the Charité. Appointment requirements are governed by article 102a of the Berlin Higher Education Act (Berliner Hochschulgesetz:§ 102a BerlHG). Completed university degree in Natural Sciences, Humanities and/or Life Sciences or any other related field of Medicine or non-medicine is required. In addition, a Doctorate (Ph.D and/or M.D.) and significant post-doctoral experience are required. Basic medical knowledge is desired.

The Charité is an equal opportunity employer committed to excellence through diversity. As women are under-represented in academics, we explicitly encourage women to send in their application. Women will be given preference over equally qualified men (within the framework of the legal possibilities). We value diversity and therefore welcome all applications – regardless of gender, nationality, social background, religion or age. Equally qualified applicants with disabilities will be given preference.

Written applications according to the format specified on https://career.charite.de/am/calls/application_notes.pdf should be submittedby June 19th, 2020 under https://career.charite.de. For further questions on details, please contact Prof. Dr. Igor Maximilian Sauer.

Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangio-carcinoma (eCC) represent two cancer entities with devastating prognoses. Despite recent progress in research and treatment, therapy remains challenging. Cancer stem cells (CSCs) have been shown to play an important role in metastasis and chemoresistance. Therefore, CSCs may play a promising role as a potential therapeutic target.
A total of 31 patients (23 PDAC, 8 eCC) were included in the study. CSCs were analyzed in a single-cell suspension of tumor samples via fluorescence-activated cell scanning (FACS) with a functional Hoechst 33342 staining as well as a cell surface marker staining of the CSC-panel (CD24, CD44 and EpCAM) and markers to identify fibroblasts, leukocytes and components of the notch signaling pathway. Furthermore, the potential presence of CSCs among primary cancer-associated fibroblasts (CAFs) was assessed using the same FACS-panel.
We showed that CSCs are present in patient-derived dissociated tumor tissue. The functional and surface marker profile of CSC-detection did in fact correlate. The amount of CSCs was significantly correlated with tumor characteristics such as a higher UICC stadium and nodal invasion. CSCs were not restricted to the epithelial cell fraction in tumor tissues, which has been verified in independent analysis of primary cell cultures of CAFs.
Our study confirms the in vivo presence of CSCs in PDAC and eCC, stating a clinical significance thereof and thus their plausibility as therapeutic targets. In addition, stem-like cells also seem to constitute a part of the CAFs.

"Characterization of Pancreatic and Biliary Cancer Stem Cells in Patient-derived Tissue" was published in Anticancer Research. Authors are J. Gogolok, E. Seidel, A. Strönisch, A. Reutzel-Selke, I.M. Sauer, J. Pratschke, M. Bahra, and R.B. Schmuck.

Hepatocyte transplantation (HcTx) is a promising approach for the treatment of metabolic diseases in newborns and children. The most common application route is the portal vein, which is difficult to access in the newborn. Transfemoral access to the splenic artery for HcTx has been evaluated in adults, with trials suggesting hepatocyte translocation from the spleen to the liver with a reduced risk for thromboembolic complications. Using juvenile Göttingen minipigs, we aimed to evaluate feasibility of hepatocyte transplantation by transfemoral splenic artery catheterization, while providing insight on engraftment, translocation, viability, and thromboembolic complications. Four Göttingen Minipigs weighing 5.6 kg to 12.6 kg were infused with human hepatocytes (two infusions per cycle, 1.00E08 cells per kg body weight). Immunosuppression consisted of tacrolimus and prednisolone. The animals were sacrificed directly after cell infusion (n=2), 2 days (n=1), or 14 days after infusion (n=1). The splenic and portal venous blood flow was controlled via color-coded Doppler sonography. Computed tomography was performed on days 6 and 18 after the first infusion. Tissue samples were stained in search of human hepatocytes. Catheter placement was feasible in all cases without procedure-associated complications. Repetitive cell transplantations were possible without serious adverse effects associated with hepatocyte transplantation. Immunohistochemical staining has proven cell relocation to the portal venous system and liver parenchyma. However, cells were neither present in the liver nor the spleen 18 days after HcTx. Immunological analyses showed a response of the adaptive immune system to the human cells. We show that interventional cell application via the femoral artery is feasible in a juvenile large animal model of HcTx. Moreover, cells are able to pass through the spleen to relocate in the liver after splenic artery infusion. Further studies are necessary to compare this approach with umbilical or transhepatic hepatocyte administration.

"Hepatocyte Transplantation to the Liver via the Splenic Artery in a Juvenile Large Animal Model" was published in Cell Transplantation.
Authors are J. Siefert, K.H. Hillebrandt, S. Moosburner, P. Podrabsky, D. Geisel, T. Denecke, J.K. Unger, B. Sawitzki, S. Gül-Klein, S. Lippert, P. Tang, A. Reutzel-Selke, M.H. Morgul, A.W. Reske, S. Kafert-Kasting, W. Rüdinger, J. Oetvoes, J. Pratschke, I.M. Sauer, and N. Raschzok.

Today, Simon Moosburner successfully defended his doctoral thesis entitled "Erweiterung der Spenderpopulation bei Lebertransplantation: Klinischer Bedarf und Entwicklung eines Kleintier-Lebermaschinenperfusionssystems (Expanding the donor pool for liver transplantation: clinical need and development of small animal liver perfusion system)" summa cum laude !

Congratulations!

Three‐dimensional tissue cultures are important models for the study of cell‐cell and cell‐matrix interactions, as well as, to investigate tissue repair and reconstruction pathways. Therefore, we designed a reproducible and easy to handle printable bioreactor system (Teburu), that is applicable for different approaches of pathway investigation and targeted tissue repair using human tissue slices as a three‐dimensional cell culture model. Here, we definitively describe Teburu as a controlled environment to reseed a 500‐µm thick decellularized human liver slice using human mesenchymal stroma cells. During a cultivation period of eight days, Teburu, as a semi‐open and low consumption system, was capable to maintain steady pH and oxygenation levels. Its combination with additional modules delivers an applicability for a wide range of tissue engineering approaches under optimal culture conditions.

"Teburu—Open source 3D printable bioreactor for tissue slices as dynamic three‐dimensional cell culture models" was published in Artif Organs. 2019 Jun 18. doi: 10.1111/aor.13518. [Epub ahead of print]. Authors are A. Daneshgar, P. Tang, C. Remde, M. Lommel, S. Moosburner, U. Kertzscher, O. Klein, M. Weinhart, J. Pratschke, I.M. Sauer, and K.H. Hillebrandt.

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.

The new book "Die Zukunft der Medizin: Disruptive Innovationen revolutionieren Medizin und Gesundheit" is available. Igor Maximilian Sauer, Moritz Queisner, Michael Pogorzhelskiy and Johann Pratschke contributed with the chapter "Operieren im digitalen Raum – Mixed Reality in der Chirurgie".
Editors are Erwin Böttinger and Jasper zu Putlitz.

Dr. Karl Hillebrandt and Dr. Matthäus Felsenstein successfully applied for the BIH Charité Junior Clinician Scientist Program. Karl Hillebrandt will continue his work on human decellularized liver slices as 3D platform for in vitro models of cholangiocellular carcinoma. Matthäus Felsenstein focusses on derivation of normal pancreatic duct cells from human primary tissue and their stepwise genetic modification in vitro using CRISPR/Cas9 .

Congratulations!

Martin Kluge is wearing excellent suits and successfully defended his doctoral thesis magna cum laude! He examined the effects of the magnetic field of magnetic resonance imaging (MRI) systems on cells labeled with micrometer-sized iron oxide particles.

Congratulations!

Christoph Rüger successfully defended his thesis entitled "Ergonomische Untersuchungen zu Augmented Reality Head-Mounted Displays in der Ultraschallgeschützen Leberdiagnostik".

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