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Cytokine production of human CD4+ memory T cells
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Nature Communication accepted the manuscript "Progressive expression of killer-like receptors and GPR56 defines the cytokine production of human CD4+ memory T cells" for publication. Authors are Kim-Long Truong, Stephan Schlickeiser, Katrin Vogt, David Boës, Katarina Stanko, Christine Appelt, Mathias Streitz, Gerald Grütz, Nadja Stobutzki, Christian Meisel, Christina Iwert, Stefan Tomiuk, Julia Polansky, Andreas Pascher, Nina Babel, Ulrik Stervbo, Igor Sauer, Undine Gerlach, and Birgit Sawitzki.

All memory T cells mount an accelerated response on antigen reencouter, but significant functional heterogeneity is present within the respective memory T cell subsets as defined by CCR7 and CD45RA expression, thereby warranting further stratification. Here we show that several surface markers, KLRB1, KLRG1, GPR56 and KLRF1, help define “low”, “high” or “exhausted” cytokine producers within human peripheral and intra-hepatic CD4+ memory T cells. Highest simultaneous production of TNF and IFN-γ is observed in KLRB1+KLRG1+GPR56+ CD4 T cells. By contrast, KLRF1 expression is associated with reduced TNF/IFN-γ production and T cell exhaustion. Lastly, TCRbeta repertoire analysis and in vitro differentiation support a regulated, successive expression for these markers during CD4+ memory T cell differentiation. Our results thus help refine the classification of human memory T cells to provide insights on inflammatory disease progression and immunotherapy development.
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Die Zukunft der Medizin [The Future of Medicine]
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A new book "Die Zukunft der Medizin [The Future of Medicine]" (editors: E. Böttinger and J. Zu Putlitz) highlights new developments and technologies transforming healthcare in the 21st century.
M. Aach, R. Averill, G. Barreto, E. Böttinger, M. Braun, D. Champeaux, A. Cornejo Müller, P. Dabrock. I. de Cremoux, J. Deerberg-Wittram, L. Determann, H. Estiri, T. Ganslandt, T. Gayvoronskaya, A. Gharabaghi, J. Graalmann, D. Grasmücke, P. Haas, R. Herzog, M.C. Hirsch, J. Jacubeit, D. Jäger, C. Johner, J.N. Kather, J.G. Klann, F. Knieps, J.C. Kvedar, M.D. Majmudar, C. Meinel, A. Mühle, S. Müllauer, S.N. Murphy, M. Müschenich, R. Novak, H. Pak, R. Philipp, M. Pogorzhelskiy, F. Post, J. Pratschke, H.-U. Prokosch, J. zu Putlitz, M. Queisner, L. Reisman, R. Rittweger, T. Rödiger, I.M. Sauer, S. von Schorlemer, S. Schürle-Finke, M. Sedlmayr, A. Stett, K.B. Wagholikar, L. Wamprecht, and C.-C. Weiß contributed to this interesting book.

Igor Maximilian Sauer, Moritz Queisner, Michael Pogorzhelskiy and Johann Pratschke are authors of the chapter "Operieren im digitalen Raum – Mixed Reality in der Chirurgie [Operating within the digital space – mixed reality in surgery]".
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Percoll purification after isolation of Primary Human Hepatocytes
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The manuscript "Isolation of Primary Human Hepatocytes: Is Percoll Purification Really Necessary?" was accepted for publication in Scientific Reports.
Authors are Rosa Horner, Jospeh G.M.V. Gassner, Martin Kluge M, Peter Tang, Steffen Lippert, Karl H. Hillebrandt, Simon Moosburner, Anja Reutzel-Selke, Johann Pratschke, Igor M. Sauer and Nathanael Raschzok.

Research and therapeutic applications create a high demand for primary human hepatocytes. The limiting factor for their utilization is the availability of metabolically active hepatocytes in large quantities. Centrifugation through Percoll, which is commonly performed during hepatocyte isolation, has so far not been systematically evaluated in the scientific literature. 27 hepatocyte isolations were performed using a two-step perfusion technique on tissue obtained from partial liver resections. Cells were seeded with or without having undergone the centrifugation step through 25% Percoll. Cell yield, function, purity, viability and rate of bacterial contamination were assessed over a period of 6 days. Viable yield without Percoll purification was 42.4 x 106 (SEM ± 4.6 x 106) cells/g tissue. An average of 59% of cells were recovered after Percoll treatment. There were neither significant differences in the functional performance of cells, nor regarding presence of non-parenchymal liver cells. In five cases with initial viability of <80%, viability was significantly increased by Percoll purification (71.6 to 87.7%, p=0.03). Considering our data and the massive cell loss due to Percoll purification, we suggest that this step can be omitted if the initial viability is high, whereas low viabilities can be improved by Percoll centrifugation.
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Critical Care for Potential Liver Transplant Candidates
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The book Critical Care for Potential Liver Transplant Candidates
(D. Bezinover and F. Saner [Eds.]) focuses on patients with end-stage-liver disease (ESLD) who could possibly qualify for liver transplant. This patient cohort raises many problems: who should be treated and also, when is it too late for transplant? The authors are all dedicated experts in the field of ESLD/liver transplantation, but from different disciplines with different views of the problem.
In the past 15 years many things have changed in the treatment for these patients: cardiac assessment, treatment of porto-pulmonary hypertension, hemodynamics, coagulation assessment and management, diagnosis of kidney failure, and the timing of dialysis. These issues are comprehensively discussed in this book, in order to provide physicians starting in the field of transplantation an overview of different areas of concern.
This book is aimed at specialists and trainees in critical care, hepatology, anesthesia, surgery, and nephrology.

N. Raschzok, K.H. Hillebrandt and I.M. Sauer contributed with the chapter "Liver Assist Systems for Bridging to Transplantation: Devices and Concepts".

More information via this link.
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Composite tissue allotransplantation: opportunities and challenges
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"Composite tissue allotransplantation: opportunities and challenges" is available in Cellular & Molecular Immunology (Cell Mol Immunol. 2019 Mar 6. doi: 10.1038/s41423-019-0215-3. [Epub ahead of print]). Authors are J. Iske, Y. Nian, R. Maenosono, M. Maurer, I.M. Sauer & S.G. Tullius.

Vascularized composite allotransplants (VCAs) have unique properties because of diverse tissue components transplanted en mass as a single unit. In addition to surgery, this type of transplant also faces enormous immunological challenges that demand a detailed analysis of all aspects of alloimmune responses, organ preservation, and injury, as well as the immunogenicity of various tissues within the VCA grafts to further improve graft and patient outcomes. Moreover, the side effects of long-term immunosuppression for VCA patients need to be carefully balanced with the potential benefit of a non-life-saving procedure. In this review article, we provide a comprehensive update on limb and face transplantation, with a specific emphasis on the alloimmune responses to VCA, established and novel immunosuppressive treatments, and patient outcomes.
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Human stem cells promote liver regeneration after partial hepatectomy
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"Human Stem Cells Promote Liver Regeneration After Partial Hepatectomy in BALB/C Nude Mice" will be published in J Surg Res. 2019 (Mar 4;239:191-200. doi: 10.1016/j.jss.2019.02.010. [Epub ahead of print]).
Authors are S. Wabitsch, Ch. Benzing, F. Krenzien, K. Splith, P.K. Haber, A. Arnold, M. Nösser, C. Kamalia, F. Hermann, Ch. Günther, D. Hirsch, I.M. Sauer, J. Pratschke, and M. Schmelzle.

Mesenchymal stem cells (MSCs) have been suggested to augment liver regeneration after surgically and pharmacologically induced liver failure. To further investigate this we processed human bone marrow-derived MSC according to good manufacturing practice (GMP) and tested those cells for their modulatory capacities of metabolic alterations and liver regeneration after partial hepatectomy in BALB/c nude mice.

Human bone marrow-derived MSC attenuate metabolic alterations and improve liver regeneration after partial hepatectomy in BALB/c nude mice. Obtained results using GMP-processed human MSC suggest functional links between fat accumulation and hepatocyte proliferation, without any evidence for cellular homing. This study using GMP-proceeded MSC has important regulatory implications for an urgently needed translation into a clinical trial.
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Diffusion-weighted magnetic resonance imaging using a preclinical 1 T PET/MRI
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"Diffusion-weighted magnetic resonance imaging using a preclinical 1 T PET/MRI in healthy and tumor-bearing rats" was published in EJNMMI Res. 2019 Feb 22;9(1):21. doi: 10.1186/s13550-019-0489-6.
Authors are J. Albrecht, D. Polenz, A.A. Kühl, J.M.M. Rogasch, A. Leder, I.M. Sauer, M. Babos, G. Mócsai, N. Beindorff, I.G. Steffen, W. Brenner, and E.J. Koziolek.

Hybrid positron emission tomography and magnetic resonance imaging (PET/MRI) scanners are increasingly used for both clinical and preclinical imaging. Especially functional MRI sequences such as diffusion-weighted imaging (DWI) are of great interest as they provide information on a molecular level, thus, can be used as surrogate biomarkers. Due to technical restrictions, MR sequences need to be adapted for each system to perform reliable imaging. There is, to our knowledge, no suitable DWI protocol for 1 Tesla PET/MRI scanners.
We established a respiratory-gated DWI protocol for a preclinical 1 T PET/MRI scanner allowing to monitor growth-related changes in ADC values of orthotopic HCC liver tumors. By monitoring the changes in tumor ADCs over time, different cellular stages were described. However, each study needs to adapt the protocol further according to their question to generate best possible results.
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Comparison of AR HMDs in Visceral Surgery
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"Real World Usability Analysis of two Augmented Reality Headsets in Visceral Surgery" was accepted for publication in Artificial Organs. Authors are S. Moosburner, C. Remde, P. Tang, M. Queisner, N. Haep, J. Pratschke, and I.M. Sauer.

Recent developments in the field of augmented reality (AR) have enabled new use cases in surgery. Initial set-up of an appropriate infrastructure for maintaining an AR surgical workflow requires investment in appropriate hardware. We compared the usability of the Microsoft HoloLens and Meta 2 head mounted displays (HMDs). Fifteen medicine students tested each device and were questioned with a variant of the System Usability Scale (SUS). Two surgeons independently tested the devices in an intraoperative setting.
In our adapted SUS, ergonomics, ease of use and visual clarity of the display did not differ significantly between HMD groups. The field of view (FOV) was smaller in the Microsoft HoloLens than the Meta 2 and significantly more study subjects (80% vs. 13.3%; p < 0.001) felt limited through the FOV. Intraoperatively, decreased mobility due to the necessity of an AC adapter and additional computing device for the Meta 2 proved to be limiting. Object stability was rated superior in the Microsoft HoloLens than the Meta 2 by our surgeons and lead to increased use.
We examined the Meta 2 and the Microsoft HoloLens and found key advantages in the Microsoft HoloLens which provided palpable benefits in a surgical setting.
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Nanomolar sensing of NAD
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"The nanomolar sensing of nicotinamide adenine dinucleotide in human plasma using a cycling assay in albumin modified simulated body fluids." was published in Nature Scientific Reports.
Authors are P. Brunnbauer, A. Leder, C. Kamali, K. Kamali, E. Keshi, K. Splith, S. Wabitsch, P. Haber, G. Atanasov, L. Feldbrügge, I.M. Sauer, J. Pratschke, M. Schmelzle, and F. Krenzien.

Nicotinamide adenine dinucleotide (NAD), a prominent member of the pyridine nucleotide family, plays a pivotal role in cell-oxidation protection, DNA repair, cell signalling and central metabolic pathways, such as beta oxidation, glycolysis and the citric acid cycle. In particular, extracellular NAD+ has recently been demonstrated to moderate pathogenesis of multiple systemic diseases as well as aging. Herein we present an assaying method, that serves to quantify extracellular NAD+ in human heparinised plasma and exhibits a sensitivity ranging from the low micromolar into the low nanomolar domain. The assay achieves the quantification of extracellular NAD+ by means of a two-step enzymatic cycling reaction, based on alcohol dehydrogenase. An albumin modified revised simulated body fluid was employed as standard matrix in order to optimise enzymatic activity and enhance the linear behaviour and sensitivity of the method. In addition, we evaluated assay linearity, reproducibility and confirmed long-term storage stability of extracellular NAD+ in frozen human heparinised plasma. In summary, our findings pose a novel standardised method suitable for high throughput screenings of extracellular NAD+ levels in human heparinised plasma, paving the way for new clinical discovery studies.
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Normothermic ex vivo machine perfusion
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"Improvement of normothermic ex vivo machine perfusion of rat liver grafts by dialysis and Kupffer Cell inhibition with glycine" was accepted for publication in Liver Transplantation.
Authors are J. Gassner, M. Nösser, S. Moosburner, R. Horner, P. Tang, L. Wegener, D. Wyrwal, F. Claussen, R. Arsenic, J. Pratschke, I.M. Sauer, and N. Raschzok.

Normothermic ex vivo liver machine perfusion might be a superior preservation strategy for liver grafts from extended criteria donors. However, standardized small animal models are not available for basic research on machine perfusion of liver grafts. A laboratory-scaled perfusion system was developed consisting of a custom-made perfusion chamber, a pressure-controlled roller pump, and an oxygenator. Male Wistar rat livers were perfused via the portal vein for 6 hours using oxygenated culture medium supplemented with rat erythrocytes. A separate circuit was connected via a dialysis membrane to the main circuit for plasma volume expansion. Glycine was added to the flush solution, the perfusate, and the perfusion circuit. Portal pressure and transaminase release were stable over the perfusion period. Dialysis significantly decreased the potassium concentration of the perfusate and led to significantly higher bile and total urea production. Hematoxylin and eosin staining and immunostaining for ssDNA and activated caspase 3 showed less sinusoidal dilatation and tissue damage in livers treated with dialysis and glycine. While Kupffer cells were preserved, tumor necrosis factor α mRNA levels were significantly decreased by both treatments. For proof of concept, the optimized perfusion protocol was tested with DCD grafts, resulting in significantly lower transaminase release into the perfusate and preserved liver architecture compared to baseline perfusion.
Our laboratory-scale normothermic portovenous ex vivo liver perfusion system enables rat liver preservation for 6 hours. Both dialysis and glycine treatment were shown to be synergistic for preservation of the integrity of normal and DCD liver grafts.
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