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Institute
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (16) (remove)
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.
Die bariatrische Chirurgie ist momentan die einzige Therapieoption der morbiden Adipositas mit der eine langfristige Gewichtsreduktion erreicht werden kann. Unter den Operationsmethoden gilt der RYGB als eine der wirksamsten Behandlungen bezogen auf den Gewichtsverlust und die Verbesserung von Begleiterkrankungen wie dem Diabetes mellitus Typ 2. Darüber hinaus belegt eine wachsende Zahl an Veröffentlichungen, dass der RYGB den Zustand chronischer Entzündung, wie er typischerweise mit Adipositas einhergeht, verringern kann. Diese sogenannte Endotoxämie geht unter anderem mit einer gestörten Integrität der intestinalen Epithelbarriere einher. Ziel der vorliegenden Arbeit war es eine Analyse der Veränderungen von für die Darmbarriere wichtigen Junktionsproteinen vorzunehmen, um eine Grundlage für künftige mechanistische Untersuchungen zu schaffen. Dafür wurden die Veränderungen von Barriereproteinen in Vollwandresektaten des Duodenums, des Jejunums, des Ileums sowie des Kolons von Ratten, die einen RYGB erhalten hatten, mittels Western Blot Untersuchungen quantifiziert. Als Kontrollgruppe dienten schein-operierte Ratten. Es kam zu tiefgreifenden Veränderungen der analysierten Barriereproteine in den Vollwandresektaten. Interessanterweise unterschieden sich die Verteilungsmuster der Veränderungen der Barriereproteinte deutlich zwischen den einzelnen Darmregionen. Um herauszufinden, ob diese Veränderungen durch regionale Veränderungen der Mikroumgebung nach RYGB- Operation induziert wurden, wurden im reduktionistischen Zellkultursystem Stuhl- Transferexperimente durchgeführt. Caco2-Zellkulturen dienten hierbei als Modell für die intestinale epitheliale Barriere. Es wurden funktionelle Messungen und quantitative Analysen der Veränderungen der Barriereproteine der Zellkultur durchgeführt. Die Funktionsmessungen zeigten, dass der Inhalt des Duodenums, des Jejunums sowie des Kolons deutliche barrierestabilisierende Effekte auf die Caco2-Zellmonolayer hatte. Zudem zeigten sich tiefgreifende Veränderungen der untersuchten Barriereproteine. Zusammenfassend wurde in der vorliegenden Arbeit erstmals eine regionenspezfische Regulation der intestinalen Barriereproteine in Korrelation mit funktionellen Messungen nach RYGB nachgewiesen.
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.
Der postoperative Hypoparathyreoidismus (PH) stellt eine der häufigsten Komplikationen nach Schilddrüsenoperationen dar. Ziel dieses systematischen Reviews und Metaanalyse ist die Erarbeitung einer einheitlichen Definition sowie die Ermittlung des bestmöglichen Ansatzes für eine frühzeitige Detektion des PH.
Nach Durchführung einer systematischen Literaturrecherche gemäß der PICo-Systematik unter Verwendung der Datenbanken Embase, Pubmed und der Cochrane Library, erfolgte die themenbezogene Aufarbeitung der eingeschlossenen Studien, sowie eine Bias-Bewertung und Metaanalyse geeigneter Arbeiten.
Von 13.704 Artikeln konnten 188 in die weitere Analyse eingeschlossen werden. In diesen fanden sich sehr heterogene Definitionen des PH. Sowohl in der systematischen Analyse als auch in der Metaanalyse zeigte sich eine genauere Vorhersagekraft des PH durch eine postoperative im Vergleich zu einer intraoperativen PTH-Messung. Keiner der analysierten Zeiträume innerhalb des ersten postoperativen Tages (POD1) zeigte eine signifikante Überlegenheit in der Vorhersage eines PH. Die PTH- Schwellenwerte 10 bzw. 15 pg/ml können einen PH zuverlässig detektieren. Als Entscheidungsgrundlage zwischen den beiden Werten kann die untere Normwertgrenze des angewendeten Testverfahrens herangezogen werden. Bei präoperativer PTH-Abnahme nach Anästhesieeinleitung ist ein relativer PTH-Abfall von prä- nach postoperativ von 73 ± 11% prädiktiv für die Entwicklung eines PH. Die Bestimmung des Calciumspiegels an POD1 ist obligat und optimiert insbesondere die Erkennung einer biochemischen Hypokalzämie.
Ein nicht nachweisbarer oder inadäquat niedriger postoperativer PTH-Spiegel im Zusammenhang mit einer biochemischen oder symptomatischen Hypokalzämie kann als einheitliche Definition des postoperativen Hypoparathyreoidismus vorgeschlagen werden. Die Messung des Parathormons sollte zwischen einer und sechs Stunden postoperativ, spätestens aber innerhalb von 24 Stunden erfolgen. Sowohl der Schwellenwert ≤ 15 pg/ml als auch ein relativer PTH-Abfall von prä- nach postoperativ sind zuverlässig in der Detektion gefährdeter Patienten.
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.
Die hier vorliegende Untersuchung beschäftigt sich mit dem Vergleich zweier minimalinvasiver operativer Therapiestrategien der distalen Unterarmfraktur als häufigster Fraktur im Kindesalter.
Für die vorliegende Studie erfolgte eine umfassende retrospektive Auswertung von 122 Fällen distaler kindlicher Unterarmfrakturen aus einem Zeitraum von elf Jahren, die in der kinderchirurgischen Abteilung des Universitätsklinikums Würzburg osteosynthetisch versorgt wurden. Ziel der Untersuchung war die Betrachtung der Epidemiologie des Verletzungsbildes und des Therapieerfolges in Abhängigkeit von der gewählten Osteosynthesetechnik. Die Kinder wurden dabei entweder allein durch eine Kirschner-Draht-Osteosynthese des Radius oder durch eine zusätzliche Fixierung der Ulna mittels elastisch stabiler intramedullärer Nagelung versorgt.
Durch beide Operationsstrategien konnte für die meisten Patientinnen und Patienten ein gutes Therapieergebnis erreicht werden. Hinsichtlich der Operations- und Hospitalisierungsdauer zeigte sich ein Vorteil für Kinder, die osteosynthetisch lediglich durch Kirschner-Drähte versorgt wurden. In anderen Studien beobachtete Komplikationen in Form sekundärer Dislokationen der Fraktur auch nach Osteosynthese oder Infektionen im Bereich der Drahtenden konnten im hier untersuchten Kollektiv seltener festgestellt werden.
Die vorliegende Untersuchung zeigt, dass, sofern die Indikation zur operativen Versorgung besteht, die Fixierung des Radius allein mittels Kirschner-Drähten eine adäquate Therapie distaler Frakturen von Ulna und Radius im Kindesalter darstellt. Von einer kombinierten Osteosynthese mittels Kirschner-Drähten und ESIN könnten besonders Patientinnen und Patienten profitieren, bei denen initial große Dislokationen der Fraktur, Begleitverletzungen des Arms oder eine Lokalisation im Bereich des diametaphysären Übergangs bestehen. Um diese Beobachtungen auch in größeren Kollektiven und prospektiv sowie randomisiert zu untersuchen, sind weitere Studien wünschenswert.
Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state.
(1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36–74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.
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.