TY - JOUR A1 - Baur, Johannes A1 - Otto, Christoph A1 - Steger, Ulrich A1 - Klein-Hessling, Stefan A1 - Muhammad, Khalid A1 - Pusch, Tobias A1 - Murti, Krisna A1 - Wismer, Rhoda A1 - Germer, Christoph-Thomas A1 - Klein, Ingo A1 - Müller, Nora A1 - Serfling, Edgar A1 - Avots, Andris T1 - The transcription factor NFaTc1 supports the rejection of heterotopic heart allografts JF - Frontiers in Immunology N2 - The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8\(^+\) T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation. KW - NFATc1 KW - transplantation KW - heterologous KW - CD8+ T cells KW - ChIPseq KW - metabolism Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221530 VL - 9 ER - TY - THES A1 - Stratmann [geb. Hirster], Tizia T1 - Veränderung der gesundheitsbezogenen Lebensqualität nach leberchirurgischen Operationen T1 - Health-related Quality of Life after hepatic resection N2 - Es zeigte sich, dass die unmittelbare postoperative gesundheitsbezogene Lebensqualität erwartungsgemäß deutlich eingeschränkt, jedoch nach circa sechs Monaten wieder auf dem Ausgangsniveau der präoperativen Ebene angekommen war. Sowohl die Symptomskalen als auch die Funktionsskalen zeigten statistisch signifikante Unterschiede der erhobenen Werte bezüglich des Vergleichs der präoperativen zu den postoperativen Daten, dasselbe ließ sich über die Werte im Rahmen der Verlaufskontrolle nach circa sechs Monaten erheben. Eine kurzfristige Einbuße der Lebensqualität durch einen stationären Krankenhausaufenthalt sowie einer operativen Versorgung erscheint logisch. Für die zukünftige Entscheidung vor allem auch für Personen, welche aufgrund einer benignen Leberraumforderung eine operative Versorgung erhalten sollen, ist zu sagen, dass die globale gesundheitsbezogene Lebensqualität postoperativ nach circa sechs Monaten gleich bzw. etwas gebessert ausfiel und somit eine Rechtfertigung der operativen Versorgung auch bei benignen Erkrankungen darstellen kann. Ein wesentlicher Aspekt der Arbeit ist, dass gezeigt werden konnte, dass auch bei komplexen Lebereingriffen eine schnelle Rekonvaleszenz - mindestens auf das Niveau vor dem Eingriff - innerhalb der ersten sechs Monate zu erwarten ist. Die systematische Erfassung der Lebensqualität hilft die postoperativen Einschränkungen und die Rekonvaleszenz zu normieren. N2 - It has been shown that the immediate postoperative health-related quality of life was reduced significantly, as expected. After six months the health-related quality of life returned to the preoperative level. The data indicates that even in complex liver procedures, fast recovery - at least to the preoperative level - can be expected within six months. The systematic assessment of quality of life helps to objectify postoperative limitations and recovery. KW - Leberresektion KW - Lebensqualität KW - gesundheitsbezogene Lebensqualität KW - health-related quality of life KW - hrQOL KW - hepatic resection KW - hepatic surgery KW - Leberchirurgie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-359977 ER - TY - JOUR A1 - Anany, Mohamed A. A1 - Kreckel, Jennifer A1 - Füllsack, Simone A1 - Rosenthal, Alevtina A1 - Otto, Christoph A1 - Siegmund, Daniela A1 - Wajant, Harald T1 - Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis JF - Cell Death & Disease N2 - TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221104 VL - 9 ER - TY - THES A1 - Döhler, Ida T1 - Reduktion von Blutungskomplikationen bei Patientinnen und Patienten mit oraler Antikoagulation in der elektiven Allgemein- und Viszeralchirurgie durch individuelles Risiko-adjustiertes Bridging T1 - Reduction of bleeding complications in patients on oral anticoagulation in elective general and visceral surgery by individual risk-adjusted bridging N2 - Zahlreiche Studien zeigten, dass perioperatives Bridging der oralen Antikoagulation zu einem erhöhten Blutungsrisiko führt. Ursache hierfür könnte eine zu aggressive Herangehensweise bezüglich der Dosierung des Bridgings sein. Daher war das Ziel dieser Arbeit herauszufinden, ob ein Risiko-adjustiertes Bridging-Schema in der elektiven Allgemein- und Viszeralchirurgie zu einem geringeren Auftreten von postoperativen Blutungsereignissen führt und ob trotzdem ein adäquater Schutz vor thromboembolischen Ereignissen gegeben ist. Hierfür wurde retrospektiv und monozentrisch das Auftreten der genannten postoperativen Ereignisse in zwei Zeiträumen untersucht. Das erste Studienintervall erstreckte sich von Januar 2011 bis Dezember 2014 und spiegelt die Ereignisraten vor der internen Leitlinienänderung wider. Es wurden 263 Personen eingeschlossen. Das zweite Intervall begann im Januar 2017 und endete im Dezember 2019, in diesem wurden 271 Personen untersucht. Zwischen diesen beiden Zeiträumen wurde eine überarbeitete klinikinterne Bridging-Leitlinie etabliert, welche an das individuelle thromboembolische Risiko, Alter, Gewicht und die Nierenfunktion der Patientinnen und Patienten angepasst war. Postoperative Major- (8.4% vs. 4.1%, p=0.039) und Minor-Blutungen (13.7% vs. 6.3%, p=0.004) nahmen im zweiten Intervall signifikant ab, während das thromboembolische Risiko weiterhin niedrig blieb (0.8% vs. 1.1%, p=1). Außerdem zeigte sich, dass es zu keiner signifikanten Zunahme der Mortalität, der Reoperationen, der Länge des postoperativen stationären Aufenthalts oder der Erythrozytenkonzentrat-Transfusionen kam. Die Ergebnisse dieser Arbeit zeigen, dass die differenzierte Bridging-Leitlinie für die Allgemein- und Viszeralchirurgie mit einer signifikant erniedrigten Blutungsrate assoziiert ist und eine Anpassung des Bridgings an die patientenspezifischen Risikofaktoren wichtig ist. N2 - Multiple studies have shown that perioperative bridging of oral anticoagulation leads to an increased risk of bleeding. This could be due to an overly aggressive approach to bridging dosing. Therefore, the aim of this study was to find out whether a risk-adjusted bridging regimen in elective general and visceral surgery leads to a lower incidence of postoperative bleeding events and whether adequate protection against thromboembolic events is still provided. For this purpose, the occurrence of the aforementioned postoperative events was examined retrospectively and monocentrically in two time periods. The first study interval extended from January 2011 to December 2014 and reflects the event rates before the internal guideline change. 263 people were included. The second interval began in January 2017 and ended in December 2019, in which 271 people were examined. Between these two periods, a revised internal clinical bridging guideline was established, which was adapted to the individual thromboembolic risk, age, weight and renal function of the patients. Postoperative major (8.4% vs. 4.1%, p=0.039) and minor bleeding complications (13.7% vs. 6.3%, p=0.004) decreased significantly in the second interval, while the thromboembolic risk remained low (0.8% vs. 1.1%, p=1). In addition, there was no significant increase in mortality, reoperations, length of postoperative hospital stay or red blood cell transfusions. The results of this study show that the differentiated bridging guideline for general and visceral surgery is associated with a significantly lower bleeding rate and that it is important to adapt bridging to patient-specific risk factors. KW - Heparin KW - Blutung KW - Chirurgie KW - Perioperatives Bridging KW - Risikoadjustiertes Bridging KW - Blutungskomplikationen KW - Allgemein-/Viszeralchirurgie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370639 ER - TY - THES A1 - Engelbrecht, Elisabeth T1 - Retrospektive Auswertung des Therapieerfolges einer PTCD-Anlage bei Insuffizienz der Pankreatojejunostomie nach Pankreaskopfresektionen T1 - Retrospective evaluation of effective treatment of biliopancreatic fistulas due to leakage of the pancreatojejunostomy after pancreatic head resection by transhepatic biliary drainage N2 - Trotz stetiger Weiterentwicklung und Verbesserungen in chirurgischen Anastomosetechniken treten postoperative Pankreasfisteln (POPF) in 20 - 25 % der Patienten und Patientinnen als Komplikation nach partieller Pankreatikoduodenektomie (PPD) auf. Kommt es zu einer kombinierten Leckage aus Gallen- und Pankreassekret, wurde in dieser Arbeit die Definition einer komplizierten POPF (CPPF) eingeführt, welche eine seltene, aber schwerwiegende und gefährliche postoperative Komplikation darstellt. Neben einer Relaparotomie kann eine Restpankreatektomie als ultima ratio zur Beherrschung dieser schweren Komplikation notwendig werden, welche mit einer Mortalität von 50 % verbunden ist. Die Internationale Studiengruppe der Pankreaschirurgie (ISGPS) entwickelte ein Klassifikationssystem für POPF, welches auf Abweichungen der üblichen postoperativen Behandlungsstrategie beruht. Jedoch wurden keine spezifischen Behandlungsalgorithmen bzw. Therapiekonzepte, insbesondere im Falle einer CPPF, vorgeschlagen. In dieser Arbeit soll die therapeutische Effektivität einer perkutanen transhepatischen Cholangiodrainage (PTCD) bei Patienten und Patientinnen mit einer CPPF evaluiert werden. Dazu wurde eine retrospektive Analyse an Patienten und Patientinnen durchgeführt, welche eine CPPF nach PPD entwickelten. Die Patienten und Patientinnen wurden hinsichtlich der gewählten Behandlungsstrategie, des Outcomes, postoperativer Komplikationen nach Clavien-Dindo-Klassifikation, des CCI (Comprehensive Complication Index), der 30- und 90-Tage-Mortalität sowie Restpankreatektomie, postoperativer Arrosionsblutungen und der Hospitalisierungsdauer nach Behandlung einer CPPF analysiert. Zwischen 2007 und 2018 entwickelten 56 (19,1 %) von insgesamt 293 Patienten und Patientinnen eine relevante POPF (ISGPS Grad B/C) nach einer Pankreaskopfresektion. Darunter wurden 17 Patienten und Patientinnen mit einer komplizierten POPF (CPPF) identifiziert. 11 Patienten und Patientinnen erhielten als Behandlung eine PTCD und sechs Patienten und Patientinnen erhielten eine chirurgisch eingebrachte transhepatische Cholangiodrainage (CTCD) im Rahmen eines Revisionseingriffes. Es wurde keine Restpankreatektomie oder Reoperation nach einer initialen PTCD Therapie notwendig. In 4 von 17 Fällen kam es zu postoperativen Blutungen nach Einbringen einer transhepatischen Cholangiodrainage, der mediane CCI lag bei 44 ± 17,3, die mediane Hospitalisierungsdauer betrug 36 ± 19,2 Tage, die 30-Tage-Mortalität war 0 % und die 90-Tage-Mortalität 17,7 %. Es wurde kein Sterbefall in Verbindung mit einer PTCD beobachtet. Mit Hilfe dieser Studie kann gezeigt werden, dass eine PTCD eine praktikable, sichere und effektive Behandlungsoption für Patienten und Patientinnen mit einer CPPF bietet. Die Separierung von Galle und Pankreassaft stellt eine neuartige Behandlungsoption in ausgewählten Patienten und Patientinnen mit ausreichend drainierter CPPF nach PPD dar. N2 - Despite continuous advancements and improvements in surgical anastomosis techniques, postoperative pancreatic fistulas (POPF) occur as complications in 20-25 % of patients after partial pancreaticoduodenectomy (PPD). In cases of combined leakage of bile and pancreatic secretions, this work introduces the definition of a complicated POPF (CPPF), which is a rare but severe and dangerous postoperative complication. Besides a relaparotomy, a remaining pancreatectomy may be necessary as a last resort to control this severe complication, which is associated with a mortality rate of 50 %. The International Study Group of Pancreatic Surgery (ISGPS) developed a classification system for POPF based on deviations from the usual postoperative treatment strategy. However, no specific treatment algorithms or therapeutic concepts, especially in the case of a CPPF, have been proposed. This study aims to evaluate the therapeutic effectiveness of percutaneous transhepatic biliary drainage (PTCD) in patients with a CPPF. For this purpose, a retrospective analysis was conducted on patients who developed a CPPF after PPD. The patients were analyzed regarding the chosen treatment strategy, outcome, postoperative complications according to the Clavien-Dindo classification, the Comprehensive Complication Index (CCI), the 30- and 90-day mortality rates, as well as remaining pancreatectomy, postoperative erosive bleeding and hospitalization duration after treatment of a CPPF. Between 2007 and 2018, 56 (19.1%) out of a total of 293 patients developed a relevant POPF (ISGPS Grade B/C) after pancreatic head resection. Among them, 17 patients with a complicated POPF (CPPF) were identified. Eleven patients received PTCD as treatment, and six patients received surgically placed transhepatic biliary drainage (CTCD) as part of a revision procedure. No remaining pancreatectomy or reoperation was necessary after initial PTCD therapy. In 4 out of 17 cases, postoperative bleeding occurred after the introduction of a transhepatic biliary drainage; the median CCI was 44 ± 17.3, the median hospitalization duration was 36 ± 19.2 days, the 30-day mortality was 0%, and the 90-day mortality was 17.7%. No deaths associated with PTCD were observed. This study demonstrates that PTCD offers a feasible, safe and effective treatment option for patients with a CPPF. The separation of bile and pancreatic juice presents an innovative treatment option in selected patients with adequately drained CPPF after PPD. KW - Bauchspeicheldrüsenkrebs KW - Postoperative Komplikation KW - Pankreasfistel KW - PTCD KW - postoperative Pankreasfistel KW - Anastomoseninsuffizienz Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370395 ER - TY - JOUR A1 - Baluapuri, Apoorva A1 - Hofstetter, Julia A1 - Dudvarski Stankovic, Nevenka A1 - Endres, Theresa A1 - Bhandare, Pranjali A1 - Vos, Seychelle Monique A1 - Adhikari, Bikash A1 - Schwarz, Jessica Denise A1 - Narain, Ashwin A1 - Vogt, Markus A1 - Wang, Shuang-Yan A1 - Düster, Robert A1 - Jung, Lisa Anna A1 - Vanselow, Jens Thorsten A1 - Wiegering, Armin A1 - Geyer, Matthias A1 - Maric, Hans Michael A1 - Gallant, Peter A1 - Walz, Susanne A1 - Schlosser, Andreas A1 - Cramer, Patrick A1 - Eilers, Martin A1 - Wolf, Elmar T1 - MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation JF - Molecular Cell N2 - The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth. KW - MYC KW - SPT5 KW - SUPT5H KW - SPT6 KW - RNA polymerase II KW - transcription KW - elongation rate KW - processivity KW - directionality KW - tumorigenesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221438 VL - 74 ER - TY - JOUR A1 - Colunga, Thomas A1 - Hayworth, Miranda A1 - Kreß, Sebastian A1 - Reynolds, David M. A1 - Chen, Luoman A1 - Nazor, Kristopher L. A1 - Baur, Johannes A1 - Singh, Amar M. A1 - Loring, Jeanne F. A1 - Metzger, Marco A1 - Dalton, Stephen T1 - Human Pluripotent Stem Cell-Derived Multipotent Vascular Progenitors of the Mesothelium Lineage Have Utility in Tissue Engineering and Repair JF - Cell Reports N2 - In this report we describe a human pluripotent stem cell-derived vascular progenitor (MesoT) cell of the mesothelium lineage. MesoT cells are multipotent and generate smooth muscle cells, endothelial cells, and pericytes and self-assemble into vessel-like networks in vitro. MesoT cells transplanted into mechanically damaged neonatal mouse heart migrate into the injured tissue and contribute to nascent coronary vessels in the repair zone. When seeded onto decellularized vascular scaffolds, MesoT cells differentiate into the major vascular lineages and self-assemble into vasculature capable of supporting peripheral blood flow following transplantation. These findings demonstrate in vivo functionality and the potential utility of MesoT cells in vascular engineering applications. KW - stem cells KW - mesothelium KW - vascular progenitor KW - tissue engineering KW - regenerative medicine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223217 VL - 26 ER - TY - JOUR A1 - Mühlemann, Markus A1 - Zdzieblo, Daniela A1 - Friedrich, Alexandra A1 - Berger, Constantin A1 - Otto, Christoph A1 - Walles, Heike A1 - Koepsell, Hermann A1 - Metzger, Marco T1 - Altered pancreatic islet morphology and function in SGLT1 knockout mice on a glucose-deficient, fat-enriched diet JF - Molecular Metabolism N2 - Objectives Glycemic control by medical treatment represents one therapeutic strategy for diabetic patients. The Na+-d-glucose cotransporter 1 (SGLT1) is currently of high interest in this context. SGLT1 is known to mediate glucose absorption and incretin secretion in the small intestine. Recently, inhibition of SGLT1 function was shown to improve postprandial hyperglycemia. In view of the lately demonstrated SGLT1 expression in pancreatic islets, we investigated if loss of SGLT1 affects islet morphology and function. Methods Effects associated with the loss of SGLT1 on pancreatic islet (cyto) morphology and function were investigated by analyzing islets of a SGLT1 knockout mouse model, that were fed a glucose-deficient, fat-enriched diet (SGLT1−/−-GDFE) to circumvent the glucose-galactose malabsorption syndrome. To distinguish diet- and Sglt1−/−-dependent effects, wildtype mice on either standard chow (WT-SC) or the glucose-free, fat-enriched diet (WT-GDFE) were used as controls. Feeding a glucose-deficient, fat-enriched diet further required the analysis of intestinal SGLT1 expression and function under diet-conditions. Results Consistent with literature, our data provide evidence that small intestinal SGLT1 mRNA expression and function is regulated by nutrition. In contrast, pancreatic SGLT1 mRNA levels were not affected by the applied diet, suggesting different regulatory mechanisms for SGLT1 in diverse tissues. Morphological changes such as increased islet sizes and cell numbers associated with changes in proliferation and apoptosis and alterations of the β- and α-cell population are specifically observed for pancreatic islets of SGLT1−/−-GDFE mice. Glucose stimulation revealed no insulin response in SGLT1−/−-GDFE mice while WT-GDFE mice displayed only a minor increase of blood insulin. Irregular glucagon responses were observed for both, SGLT1−/−-GDFE and WT-GDFE mice. Further, both animal groups showed a sustained release of GLP-1 compared to WT-SC controls. Conclusion Loss or impairment of SGLT1 results in abnormal pancreatic islet (cyto)morphology and disturbed islet function regarding the insulin or glucagon release capacity from β- or α-cells, respectively. Consequently, our findings propose a new, additional role for SGLT1 maintaining proper islet structure and function. KW - glucose transporter SGLT1 KW - pancreatic islet cytomorphology KW - pancreatic islet function KW - β-cell KW - α-cell Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224230 VL - 13 ER -