Refine
Has Fulltext
- yes (510)
Is part of the Bibliography
- yes (510)
Year of publication
Document Type
- Doctoral Thesis (258)
- Journal article (236)
- Conference Proceeding (12)
- Other (2)
- Habilitation (1)
- Master Thesis (1)
Keywords
- Chirurgie (31)
- obesity (11)
- cytokines (10)
- Dickdarmkrebs (9)
- Medizin (9)
- Transplantation (9)
- inflammation (9)
- Immunbiologie (8)
- Langerhans-Inseln (8)
- colorectal cancer (8)
Institute
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (510) (remove)
Sonstige beteiligte Institutionen
- Krankenhaushygiene und Antimicrobial Stewardship (2)
- Abteilung für Molekulare Onkoimmunologie (1)
- Harvard Medical School, Boston, USA (1)
- Institut für Medizinische Lehre und Ausbildungsforschung, Universität Würzburg (1)
- Klinikum Fulda (1)
- Klinikum Main-Spessart Lohr (1)
- Krankenhaushygiene und Antimicrobial Stewardship (Universitätsklinikum) (1)
- Krankenhaushygiene und Antimicrobial Stewardship, Universitätsklinikum Würzburg (1)
- Lehrkrankenhaus der Universität Würzburg: Klinikum Main-Spessart (1)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin der Universität Würzburg (1)
Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
(2023)
Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.
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.
Eine gefürchtete Komplikation nach Resektionen am Kolon mit Wiederherstellung der Kontinuität ist das Auftreten einer Anastomoseninsuffizienz (AI). Der Prozess der Diagnosestellung und das therapeutische Vorgehen sind zentrumsspezifisch und sehr heterogen. Ziel dieser Promotionsarbeit war die deskriptive Darstellung der Prävalenz, Diagnostik und Therapie von AI, um anhand dieser Daten ein bestimmtes zu favorisierendes Vorgehen zur AI-Behandlung herauszuarbeiten.
Es wurde eine retrospektive unizentrische Analyse durchgeführt. Diese umfasste eine Kohorte von 744 Patienten, welche von 2009 bis 2013 am Universitätsklinikum Würzburg unter Kontinuitätserhalt kolorektal reseziert wurden. Es erfolgte eine deskriptive und statistische Auswertung mittels uni- und multivariater Analysen in Bezug auf Demographie, Risikofaktoren für die Entwicklung einer AI und den Erfolg der einzelnen Therapiekonzepte.
Während der Nachbeobachtungsphase vom im Mittel 2,5 Jahren entwickelten 10,48% der Patienten eine AI. 60% der Insuffizienzen wurden während der ersten 7 postoperativen Tage detektiert. Als Risikofaktoren konnten indikationsunabhängig männliches Geschlecht, offener Zugangsweg und pulmonale Erkrankungen herausgearbeitet werden. Indikationsspezifisch zeigte sich eine Zunahme des AI-Risikos bei Divertikulitis-Patienten mit pulmonalen Erkrankungen (OR 4,5) und Cortisoneinnahme (OR 5,4). Auffällig wurden Patienten mit AI durch heterogene und teils unspezifische Symptome – am häufigsten durch Fieber (28,21%) und auffällige Laborwerte (48,72%). Eine folgende CT-Diagnostik bestätigte die Diagnose in 76,32% der Fälle und war in 24,48% falsch negativ. Patienten mit schlechtem AZ bei Diagnose der AI zeigten eine signifikant höhere Mortalität. Ein protektives Stoma konnte eine AI nicht verhindern, aber ihre Symptome und die Schwere des Verlaufs abmildern. Gemessen an der Überlebensrate und der Revisionspflichtigkeit unterschieden sich die durchgeführten Maßnahmen beim Versuch der kontinuitätserhaltenden Therapie nicht in Bezug auf den Erfolg der Therapie.
Wie Insuffizienz- und Mortalitätsrate nach AI zeigen, ist diese unizentrische Analyse international vergleichbar. Die Ableitung einer generellen Empfehlung zur therapeutischen Vorgehensweise bei AI ist nicht möglich. Vielmehr sind alle dargestellten Maßnahmen zur Beherrschung der AI sinnvoll, während die Wahl der Vorgehensweise weiterhin eine Individualentscheidung bleibt.
Background
With the emergence of photon-counting CT, ultrahigh-resolution (UHR) imaging can be performed without dose penalty. This study aims to directly compare the image quality of UHR and standard resolution (SR) scan mode in femoral artery angiographies.
Methods
After establishing continuous extracorporeal perfusion in four fresh-frozen cadaveric specimens, photon-counting CT angiographies were performed with a radiation dose of 5 mGy and tube voltage of 120 kV in both SR and UHR mode. Images were reconstructed with dedicated convolution kernels (soft: Body-vascular (Bv)48; sharp: Bv60; ultrasharp: Bv76). Six radiologists evaluated the image quality by means of a pairwise forced-choice comparison tool. Kendall’s concordance coefficient (W) was calculated to quantify interrater agreement. Image quality was further assessed by measuring intraluminal attenuation and image noise as well as by calculating signal-to-noise ratio (SNR) and contrast-to-noise ratios (CNR).
Results
UHR yielded lower noise than SR for identical reconstructions with kernels ≥ Bv60 (p < 0.001). UHR scans exhibited lower intraluminal attenuation compared to SR (Bv60: 406.4 ± 25.1 versus 418.1 ± 30.1 HU; p < 0.001). Irrespective of scan mode, SNR and CNR decreased while noise increased with sharper kernels but UHR scans were objectively superior to SR nonetheless (Bv60: SNR 25.9 ± 6.4 versus 20.9 ± 5.3; CNR 22.7 ± 5.8 versus 18.4 ± 4.8; p < 0.001). Notably, UHR scans were preferred in subjective assessment when images were reconstructed with the ultrasharp Bv76 kernel, whereas SR was rated superior for Bv60. Interrater agreement was high (W = 0.935).
Conclusions
Combinations of UHR scan mode and ultrasharp convolution kernel are able to exploit the full image quality potential in photon-counting CT angiography of the femoral arteries.
Relevance statement
The UHR scan mode offers improved image quality and may increase diagnostic accuracy in CT angiography of the peripheral arterial runoff when optimized reconstruction parameters are chosen.
Key points
• UHR photon-counting CT improves image quality in combination with ultrasharp convolution kernels.
• UHR datasets display lower image noise compared with identically reconstructed standard resolution scans.
• Scans in UHR mode show decreased intraluminal attenuation compared with standard resolution imaging.
Objectives
We developed a novel human cadaveric perfusion model with continuous extracorporeal femoral perfusion suitable for performing intra-individual comparison studies, training of interventional procedures and preclinical testing of endovascular devices. Objective of this study was to introduce the techniques and evaluate the feasibility for realistic computed tomography angiography (CTA), digital subtraction angiography (DSA) including vascular interventions, and intravascular ultrasound (IVUS).
Methods
The establishment of the extracorporeal perfusion was attempted using one formalin-fixed and five fresh-frozen human cadavers. In all specimens, the common femoral and popliteal arteries were prepared, introducer sheaths inserted, and perfusion established by a peristaltic pump. Subsequently, we performed CTA and bilateral DSA in five cadavers and IVUS on both legs of four donors. Examination time without unintentional interruption was measured both with and without non-contrast planning CT. Percutaneous transluminal angioplasty and stenting was performed by two interventional radiologists on nine extremities (five donors) using a broad spectrum of different intravascular devices.
Results
The perfusion of the upper leg arteries was successfully established in all fresh-frozen but not in the formalin-fixed cadaver. The experimental setup generated a stable circulation in each procedure (ten upper legs) for a period of more than six hours. Images acquired with CT, DSA and IVUS offered a realistic impression and enabled the sufficient visualization of all examined vessel segments. Arterial cannulating, percutaneous transluminal angioplasty as well as stent deployment were feasible in a way that is comparable to a vascular intervention in vivo. The perfusion model allowed for introduction and testing of previously not used devices.
Conclusions
The continuous femoral perfusion model can be established with moderate effort, works stable, and is utilizable for medical imaging of the peripheral arterial system using CTA, DSA and IVUS. Therefore, it appears suitable for research studies, developing skills in interventional procedures and testing of new or unfamiliar vascular devices.
Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model
(2023)
Background
Transplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4–6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an “out-of-hospital” sudden unexpected death with subsequent “in-hospital” cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin–streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V–A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia–reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem.
Results
BGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6%, − 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice.
Conclusions
Thus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma.
Loss of intestinal epithelial barrier function is a hallmark in digestive tract inflammation. The detailed mechanisms remain unclear due to the lack of suitable cell-based models in barrier research. Here we performed a detailed functional characterization of human intestinal organoid cultures under different conditions with the aim to suggest an optimized ex-vivo model to further analyse inflammation-induced intestinal epithelial barrier dysfunction. Differentiated Caco2 cells as a traditional model for intestinal epithelial barrier research displayed mature barrier functions which were reduced after challenge with cytomix (TNFα, IFN-γ, IL-1ß) to mimic inflammatory conditions. Human intestinal organoids grown in culture medium were highly proliferative, displayed high levels of LGR5 with overall low rates of intercellular adhesion and immature barrier function resembling conditions usually found in intestinal crypts. WNT-depletion resulted in the differentiation of intestinal organoids with reduced LGR5 levels and upregulation of markers representing the presence of all cell types present along the crypt-villus axis. This was paralleled by barrier maturation with junctional proteins regularly distributed at the cell borders. Application of cytomix in immature human intestinal organoid cultures resulted in reduced barrier function that was accompanied with cell fragmentation, cell death and overall loss of junctional proteins, demonstrating a high susceptibility of the organoid culture to inflammatory stimuli. In differentiated organoid cultures, cytomix induced a hierarchical sequence of changes beginning with loss of cell adhesion, redistribution of junctional proteins from the cell border, protein degradation which was accompanied by loss of epithelial barrier function. Cell viability was observed to decrease with time but was preserved when initial barrier changes were evident. In summary, differentiated intestinal organoid cultures represent an optimized human ex-vivo model which allows a comprehensive reflection to the situation observed in patients with intestinal inflammation. Our data suggest a hierarchical sequence of inflammation-induced intestinal barrier dysfunction starting with loss of intercellular adhesion, followed by redistribution and loss of junctional proteins resulting in reduced barrier function with consecutive epithelial death.
Background
Perioperative bridging of oral anticoagulation increases the risk of bleeding complications after elective general and visceral surgery. The aim of this study was to explore, whether an individual risk-adjusted bridging regimen can reduce bleeding events, while still protecting against thromboembolic events.
Methods
We performed a quality improvement study comparing bridging parameters and postoperative outcomes before (period 1) and after implementation (period 2) of a new risk-adjusted bridging regimen. The primary endpoint of the study was overall incidence of postoperative bleeding complications during 30 days postoperatively. Secondary endpoints were major postoperative bleeding, minor bleeding, thromboembolic events, postoperative red blood cell transfusion, perioperative length-of-stay (LOS) and in-hospital mortality.
Results
A total of 263 patients during period 1 and 271 patients during period 2 were compared. The included elective operations covered the entire field of general and visceral surgery. The overall incidence of bleeding complications declined from 22.1% during period 1 to 10.3% in period 2 (p < 0.001). This reduction affected both major as well as minor bleeding events (8.4% vs. 4.1%; p = 0.039; 13.7% vs. 6.3%; p = 0.004). The incidence of thromboembolic events remained low (0.8% vs. 1.1%). No changes in mortality or length-of-stay were observed.
Conclusion
It is important to balance the individual thromboembolic and bleeding risks in perioperative bridging management. The risk adjusted bridging regimen reduces bleeding events in general and visceral surgery while the risk of thromboembolism remains comparably low.
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.
Ziele: Das Ziel dieser Dissertation ist es, die empirischen antibiotische Therapien (PAT) bei komplizierten intraabdominellen Infektionen (cIAI) in den Jahren 2016 – 2018 in einem großen deutschen Maximalversorger zu evaluieren. Aktuelle Studien legen nahe, dass viele Patienten keine Nachteile durch kürzere Therapien mit schmaler wirksamen Antibiotika oder das vermeiden einer nicht notwendigen antibiotischen Therapie haben.
Methoden: Es wurde eine retrospektive Kohortenstudie durch Analyse von elektronischen Patientenakten an einem 1500-Betten-Universitätsklinikum in Deutschland durchgeführt, bei der die Dauer der Antibiotikatherapie nach Notfalloperationen erhoben und mit antibiotischen Leitlinien durch die hausinterne Antibiotic-Stewardship-Abteilung (AMS) verglichen.
Ergebnisse: 767 Patienten konnten eingeschlossen werden, davon erhielten 404 (52.7%) eine PAT. Die Gesamtanzahl der Therapietage pro 100 Patiententagen ging von 47,0 auf 42,2 Tage zurück (p = 0,035) ohne einen Anstieg an Komplikationen. Patienten ohne Sepsis, bei denen eine initiale chirurgischer Fokuskontrolle möglich war profitierten nicht von einer Therapiedauer über 4 Tage (160 vs 100 Patienten). Bei Patienten, bei denen diese Bedingungen nicht gegeben waren, zeigte sich ebenfalls kein Vorteil bei längeren Behandlungen (über >7 Tage, 74 lang vs. 32 kurz behandelte Patienten). Es zeigte sich ebenfalls kein Vorteil von empirischen Therapien mit Carbapenem statt mit Piperacillin-Tazobactam (n=51 C vs n=40 vs Pip/Taz).
Schlussfolgerung: Die Reduktion unnötiger, zu breiter und zu langer antibiotischer Therapien bei cIAI ist ohne einen Anstieg der postoperativen Komplikationen möglich. Weitere RCTs sind notwendig, um das Wissen um sichere Behandlungen zu vergrößern.