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Institute
- Medizinische Klinik und Poliklinik II (526) (remove)
Schriftenreihe
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (3)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
- Betriebsärztlicher Dienst der Universität Würzburg (1)
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (1)
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- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
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- Experimentelle Tumorimmunologie, Frauenklinik, Universität Würzburg (1)
- Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany (1)
ResearcherID
- N-2030-2015 (1)
Diese Dissertation untersucht das Phänomen Stress im Zusammenhang mit der Tako-Tsubo-Kardiomyopathie. Sie ist eine der ersten Arbeiten, die insbesondere die Stressverarbeitung der Betroffenen mit standardisierten Messverfahren analysiert. In einer retrospektiven Querschnittsstudie wurden mit Hilfe von zwei Fragebögen soziodemographische, medizinische und psychologische Aspekte dieser Erkrankung erfasst; insbesondere wurde die Stressverarbeitung der Betroffenen mit Hilfe des standardisierten Fragebogens SVF-120 von G. Erdmann und W. Janke erfasst. Es zeigt sich, dass entgegen unserer Erwartung die Stressverarbeitung von Patienten mit Apical Ballooning Syndrom sich nicht von derjenigen von Gesunden oder Myokardinfarkt-Patienten unterscheidet. Jedoch gaben 80 % unserer befragten Patienten an unter akuten oder längerfristigen Stressoren zum Zeitpunkt des Anfalls gelitten zu haben. Ein Zusammenhang zwischen Stress und der Stressherzerkrankung ist also naheliegend, jedoch scheint eine pathologische Stressverarbeitungsweise nicht der entscheidende Aspekt in der Pathogenese zu sein.
Background
Anastomotic leakage (AL) is one of the most common and serious complications following visceral surgery. In recent years, endoluminal vacuum therapy has dramatically changed therapeutic options for AL, but its use has been limited to areas easily accessible by endoscope.
Case presentation
We describe the first use of endoluminal vacuum therapy in the small intestine employing a combined surgical and endoscopic “rendezvous technique” in which the surgeon assists the endoscopic placement of an endoluminal vacuum therapy sponge in the jejunum by means of a pullback string. This technique led to a completely closed AL after 27 days and 7 changes of the endosponge.
Conclusion
The combined surgical and endoscopic rendezvous technique can be useful in cases of otherwise difficult endosponge placement.
Gastrointestinale Lymphome des MALT sind heute als eigenständige Entität anerkannt. Sie zeichnen sich durch morphologische, molekularbiologische, ätiopathogenetische und biologische Besonderheiten aus, die sie von den nodalen Lymphomen abgrenzen lassen. Im Rahmen der Würzburger Multicenterstudie „Gastrointestinale Lymphome II“ soll die Frage geklärt werden, ob in den lokalisierten Stadien I und II primärer Magenlymphome unter Berücksichtigung der posttherapeutischen Lebensqualität der operativen oder einer primär konservativen Therapie (Chemo- oder Radiotherapie) Vorzug gegeben werden soll. Von 1998 bis 2002 wurden dazu 49 Patienten mit neu diagnostiziertem niedrig- (n=19) oder hochmalignen (n=30) NHL des Magens in die Studie eingeschlossen. Nach zentraler Randomisierung wurden die Patienten mit low grade NHL der Operation (n=10) oder der Radiotherapie (n=9) zugeteilt. Die Patienten mit high grade NHL erhielten Operation plus Chemotherapie (n=16) oder alleinige Chemotherapie (n=14). Das mediane follow up betrug 74 Monate. Sowohl das operative als auch das konservative Vorgehen zeigten bei beiden Lymphomhistologien überaus hohe Remissionsraten in den Stadien EI und EII (CR um 90%). Unterschiede zwischen den Behandlungsmethoden konnten, evtl. auch bedingt durch die kleinen Gruppengrößen, nicht nachgewiesen werden. Insgesamt verstarben sechs Patienten, die sich in etwa gleichmäßig auf die Gruppen verteilten. Die Auswertung der Fragebögen zur Lebensqualität ergab gemäß SF-36 durchaus hohe Werte zur posttherapeutischen Lebensqualität. Eine Differenzierung der Patienten nach Behandlungsmethode oder Malignitätsgrad (low, high grade) war nicht möglich. Der Lebensqualitätsindex nach Troidl ließ einen prä-post-therapeutischen Vergleich zu: Betrachtet man die Kombination von Therapie und Malignitätsgrad, so fallen konservativ therapierte Patienten (unabhängig vom Malignitätsgrad) durch deutlich ansteigende Lebensqualität auf. Es lässt sich festhalten, dass bei primär gastrointestinalen Lymphomen sowohl mit operativem als auch konservativem Vorgehen hohe Remissionsraten erzielt werden können. Jedoch sind im Hinblick auf Organerhalt und die höhere post-therapeutische Lebensqualität die primäre Radio- und/oder Chemotherapie dem operativen Vorgehen vorzuziehen.
Zinc is an essential trace element for all living organisms. In mammals, including humans and mice, it is required for normal growth, development, hematopoiesis and immune defense. This thesis investigates the influence of zinc on the development of megakaryocytes (MKs), the cells responsible for bone marrow-derived platelet production. Furthermore, a detailed analysis of the expression of zinc import and export transporters (Slc39a/Slc30a genes) is carried out, firstly over the course of MK differentiation and secondly dependent on extracellular zinc.
Die Zelladhäsion von Leukozyten/ Metastasenzellen an Endothelzellen bei Entzündungsreaktionen/ Arteriosklerose und Tumormetastasierung ist ein mehrstufiger Prozess. Im ersten Schritt kommt es zu einer Interaktion zwischen E-Selektin-Rezeptoren auf den Endothelzellen und komplexen Kohlenhydraten, den Polylaktosaminen und ihren Derivaten, den Lewis-Antigenen. Im Rahmen dieser Arbeit wurden durch transiente Transfektion fünf rekombinante Glykoproteine erzeugt (hLysII/IV-FucTIII-VII). Durch hLysII/IV-FucTVI konnte die Zelladhäsion von U937 an HUVEC Zellen signifikant gehemmt werden. Fukosyltransferase VI scheint in der Lage zu sein, die Bildung von endständigen sLex-Antigenen an den Polylaktosaminketten von hLys zu ermöglichen. Auch durch eine Transfektion der Kolonkarzinomzelllinie SW480 und Colo 206 konnten Lysozymmutanten hergestellt werden, mit denen eine signifikante Adhäsionblockade möglich ist. Man kann sich hLysII/IV-FucTVI- SW480 und- Colo206 als potentielle therapeutische Substanzen vorstellen, die zum Beispiel zur Entzündungs- oder Metastasierungshemmung eingesetzt werden.
In CHO-FucTVI- Zellen wurde hLysII/IV stabil transfiziert, mit Puromycin selektioniert und hLysII/IV-FucTVI von den stabil transfizierten CHO-FucTVI- Zelle überexprimiert. Durch Immunaffinitätschromatographie und Ultrafiltration wurde das überexprimierte hLysII/IV-FucTVI aufgereinigt und aufkonzentriert. Durch den Lysozymtest nach Osserman und Lawlor und einen ELISA konnte die Lysozymmenge in den unterschiedlichen Schritten bestimmt werden. Im anschließenden Zelladhäsionsassay konnten bei Konzentrationen von 1 ng/ml, 10 ng/ml und 100 ng/ml hLysII/IV-FucTVI signifikante Reduktionen der Zelladhäsion von U937- Zellen an HUVEC- Zellen festgestellt werden. Die ermittelte mittlere Hemmkonzentration (IC50) von hLysII/IV-FucTVI liegt bei 7*10-12 M. Dies entspricht bei einem Molekulargewicht von 30 kDa der Menge von 0,21 ng/ml und hLysII/IV-FucTVI wäre damit der stärkste bisher bekannte E-Selektin-Antagonist. In dieser Funktion könnte hLysII/IV-FucTVI im Rahmen einer antiinflammatischen oder antineoplastischen Therapie eingesetzt werden.
Mutations in the oncogenic PIK3CA gene are found in 10-20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA-mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA-mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA-mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome-or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC.
Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [\(^{68}\)Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [\(^{68}\)Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.
Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease
(2021)
The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7%) of patients did not have an established diagnosis, whereas in 7/34 (20.6%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5%) and PMR in the remaining 6/34 (17.6%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95%CI, 0.95–1.1) vs. PMR, 0.92 ± 0.1 (95%CI, 0.85–0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95–1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95%CI, 0.83–1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95%CI, 0.55–0.61)) and GCA + PMR (0.64 ± 0.09 (95%CI, 0.57–0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.
Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (−0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.