Combined determination of plasma MMP2, MMP9, and TIMP1 improves the non-invasive detection of transitional cell carcinoma of the bladder

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a major role in the maintenance of extracellular matrix homeostasis and are involved in the process of tumour invasion and metastasis in several malignant tumour entities. The goal of this study is to evaluate the diagnostic value of various circulating MMPs and TIMPs in blood plasma for a non-invasive detection of transitional cell carcinoma of the bladder (TCC). METHODS: In this study the concentrations of MMP1, MMP2, MMP3, MMP9, their inhibitors TIMP1, TIMP2, and the MMP1/TIMP1-complex (MTC1) were quantified in blood plasma with the sandwich enzyme-linked immunosorbent assay (ELISA). Blood plasma samples were investigated from 68 patients (non-metastasized, n = 57 and metastasized, n = 11) with TCC of the bladder and from 79 healthy controls. The mROC program was used to calculate the best two- and three- marker combinations. The diagnostic values for all single markers and the marker combinations were estimated both by the overall diagnostic performance index area under the ROC curve (AUC) and the sensitivity and specificity at cutoff limits with the highest diagnostic accuracy and at the 90% and 95% limits of sensitivity and specificity, respectively. RESULTS: The median MMP2 concentration was elevated in blood plasma in all patient groups with TCC in comparison to the controls (p < 0.001). The concentrations of TIMP1, TIMP2, and MTC1 in plasma probes were significantly lower from patients with non-metastasized TCC compared to the controls. MMP2 tested alone reached the highest sensitivity and specificity at 75%, respectively. The sensitivity and specificity increased when tested in combination with MMP9 and TIMP1 (97%, 94%, respectively). The combination of MMP9 and TIMP1 also showed an improved sensitivity (80%) and specificity (99%) than tested alone. CONCLUSION: MMP2 is a statistically significant marker in blood plasma for bladder cancer detection with an increased diagnostic value in combination with MMP9 and TIMP1. This study showed that the highest sensitivities and specificities are not obtained by testing each marker alone. As shown by the best two-marker combination, which includes MMP9 and TIMP1, the optimized combination does not always include the best single markers

The Effect of High-Impact Exercise on Stress Urinary Incontinence in Physically Active Women

Stress urinary incontinence (SUI) is a condition in which increased abdominal pressure with coughing, laughing, sneezing, or exercise can cause unintentional leakage of urine in the female population. CrossFit and other high impact aerobic exercises, are popular forms of exercise amongst women all age groups. The purpose of this study was to examine specific high impact exercises that can affect SUI in women

Comparing the Vaginal Wall Sling with Autologous Rectus Fascia and Polypropylene Sling on Outcome and Patient Satisfaction

Since 2011 FDA safety update on transvaginal synthetic mesh for treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP), providers are encouraged to counsel patients on risks related to synthetic mesh slings, such as dyspareunia, erosion, and extrusion. As an alternative to synthetic slings patients often choose autologous slings. We aim to compare outcome and patient satisfaction in patients, who received an autologous vaginal wall sling (VWS), rectus fascia sling (RFS), or synthetic suburethral sling (SSS) for treatment of SUI

The impact of stromal-epithelial interaction in bladder tissue and its influence on carcinogenesis

Deckblatt, Inhaltsverzeichnis, Abkuerzungsverzeichnis, Danksagung, Eidesstattliche Erklaerung, Anhang und Eigene Publikationsliste Vorbemerkungen Einleitung Eigene Literatur Ergebnisse eigener Arbeiten Diskussion und Ausblick Zusammenfassung LiteraturverzeichnisDie vorliegende Habilitationsarbeit fasst eigene Forschungsergebnisse, die ich als Erst-, Letztautor und Co-Autor in peer-reviewed Journalen veröffentlicht habe, zusammen. Gegenstand der Habilitationsschrift ist die stromal- epitheliale Interaktion im Gewebe der Harnblase. Es wird auf intra- und interzellulärer Ebene die Bedeutung dieser Wechselwirkungen im Harnblasengewebe und der Einfluss auf die Karzinogenese des Harnblasenkarzinoms diskutiert. Wir haben mit Hilfe konditionierter Medien in vitro gezeigt, dass von Fibroblasten spezielle Substanzen sezerniert werden, die das Urothelwachstum angeregen. In dieser Studie stellen wir fest, dass die urotheliale Stimulation mittels konditionierter Medien Organ und Spezies spezifisch ist. Weiterhin ist es gelungen, die Kultivierung primärer Urothelzellen zu verbessern, um ausreichend Zellmaterial für weiterführende in vivo-Projekte zur Verfügung zu haben, beispielsweise zum Tissue engineering oder zur Durchführung von Rekombinationsexperimenten. In eigenen Arbeiten konnten wir die Bedeutung proteolytischer Enzyme beim Harnblasenkarzinom nachweisen. Bisher existierten in der Literatur kaum Untersuchungen zu diesen proteolytischen Enzymen beim Harnblasenkarzinom. Die Proteasen Cathepsin B, H und L sowie der Plasminogenaktivator vom Urokinase-Typ zeigten in malignen Blasenzelllinien, in Harnblasenkarzinomgewebe bzw. in Urin von Patienten mit einem Blasenkarzinom, eine erhöhte Aktivität oder Expression. Durch Einführung der Zellrekombinationstechnik an der Klinik für Urologie der Charité, Campus Mitte konnten wir in vivo verdeutlichen, dass zellulär sezernierte Substanzen den urothelialen Phänotyp verändern. Damit haben wir einen Weg aufgezeigt mit dem Ziel, Substanzen in vivo zu identifizieren, die differenzierend auf das Urothel wirken. Mit dieser etablierten Rekombinationsmethode untersuchen wir in zukünftigen Projekten, molekulare Regulationsmechanismen, die zur Karzinogenese der Harnblase beitragen.This thesis combines and summarizes own research results, which are published as first and last author in peer reviewed journals. The focus of the thesis is the evaluation of stromal-epithelial interactions in bladder tissue and their influence on the carcinogenesis in bladder cancer. In conditioned media studies we showed that fibroblast-conditioned media yielded an increased urothelial cell growth. The ability of urinary fibroblasts to stimulate urothelial cell proliferation resides in an unidentified soluble factor secreted into the medium, independent of the presence of fibroblasts. This factor is relatively organ and species-specific. Further, we could improve primary urothelial cell culturing techniques to obtain sufficient cell material for future in vivo studies, e.g. for tissue engineering and for tissue recombination experiments. We demonstrated the impact of proteolytic enzymes on the carcinogenesis in bladder cancer. So far the literature only presents limited publications in this field. The proteases cathepsin B, H, and L, and the urokinase type plasminogen activator showed in our studies an increased activity and expression in tissue and in urine of patients, which were diagnosed with bladder carcinoma. Due to the introduction of the cell recombination technique to the Department of Urology, Charite Medical School, we could clarify in vivo how the secretion of cellular substances changes the urothelial phenotype. In the future we will investigate further molecular mechanisms which might contribute in the carcinogenesis of bladder cancer by applying the cell recombination technique

Außenpolitische Strategie und ökonomische Interessen Deutschlands nach dem Irak-Krieg 2003

Szukala A, Jäger T. Außenpolitische Strategie und ökonomische Interessen Deutschlands nach dem Irak-Krieg 2003. In: Staack M, Voigt R, eds. Europa nach dem Irak-Krieg. Ende der transatlantischen Epoche?. Baden-Baden: Nomos; 2004: 231-255

Hyperbaric Oxygen Therapy to Promote Vaginal Wall Healing after Salvage Surgery for Mesh-related Complication

Patients with multiple failed vaginal surgeries utilizing synthetic mesh present a therapeutic challenge. We present a case of a 75-year-old woman with severe stress urinary incontinence and mesh extrusion after two failed synthetic sling surgeries. Surgical reconstruction consisted of mesh excision, urethral reconstruction with vaginal tubularization, autologous rectus fascia sling placement. The patient developed a vaginal hematoma and wound dehiscence post-operatively, which was treated with surgical debridement and hyperbaric oxygen (HBO). The patient’s wound healed well, and she regained full continence, which was sustained at 10 months postoperatively. HBO therapy promotes wound healing after complex transvaginal reconstructive surgery

The Large Scale European XFEL Control System: Overview and Status of the Commissioning

The European XFEL is a 3.4 km long X-ray Free Electron Laser in the final construction and commissioning phase in Hamburg. It will produce 27000 bunches per second at 17.5 GeV. Early 2015 a first electron beam was produced in the RF-photo-injector and the commissioning of consecutive sections will follow during this and next year. The huge number and variety of devices for the accelerator, beam line, experiment,cryogenic and facility systems pose a challenging control task. Multiple systems, including industrial solutions, must be interfaced to each other. The large number of bunches requires a tight time synchronization (down to picoseconds) and high performance data acquisitionsystems. Fast feedbacks from front-ends, the DAQs and online analysis system with a seamless integration of controls are essential for the accelerator and the initially 6 experimental end stations. It turns out that the European XFEL will be the first installation exceeding 2500 FPGAcomponents in the MicroTCA form factor and will run one of the largest PROFIBUS networks. Many subsystem prototypes are already successfully in operation. An overview and status of the XFEL control system will be given