Selektive Zelloberflächenmodulation von Nierenzellkarzinomen mit Glykosylphosphatidylinositol-verankertem TIMP-1 hemmt die TGF-β1-Aktivierung und senkt die Expression regulatorischer ID-Gene

Das zugunsten von Matrix Metalloproteinasen (MMP) verschobene Proteasen/Inhibitoren-Verhältnis begründet unter anderem die Malignität von Nierenzellkarzinomen. „Tissue Inhibitor of Metalloproteinases 1“ (TIMP-1), ein löslicher Gewebeinhibitor für Metalloproteinasen der extrazellulären Matrix, kontrolliert die Aktivität von MMP durch 1:1 stochiometrische Bindung. Durch Fusion von humanen TIMP-1 mit einem Glykosylphosphatidylinositol- (GPI-)Anker wird die TIMP-1-Aktivität von der extrazellulären Matrix auf die Zelloberfläche verschoben und eine lokale Applikation von definierten TIMP-1-Konzentrationen ermöglicht. Mit TIMP-1-GPI behandelte Nierenkarzinomzellen zeigten im Vergleich zu Vehikel und nativen TIMP-1-Kontrollgruppen signifikant erhöhte Apoptose- und reduzierte Proliferationsraten. Ziel der Arbeit ist mithilfe von transkriptomischem Profiling und Signaltransduktionsweg-Mapping verantwortliche Genregulationsmechanismen für TIMP-1-GPI-spezifische Effekte zu identifizieren. Mithilfe dieser Techniken zeigten wir, dass eine TIMP-1-GPI-Behandlung zu einer signifikanten Änderung der Regulation von „Inhibitor der DNA Bindung“ (ID), TGF-β/SMAD und BMP Signaltransduktionswege führte. Die unterdrückte ID-Proteinexpression ist auf die durch TIMP-1-GPI gehemmte proteolytische Aktivierung von pro-TGF-β1 und dadurch verursachte reduzierte TGF-β1-Signalaktivität zurückzuführen. Eine mögliche Erklärung für die Überlegenheit von TIMP-1-GPI gegenüber nativem TIMP-1 ist die fokale Konzentration auf der Zelloberfläche, die eine effektivere Hemmung von autosezernierten TGF-β1 ermöglicht. Diese besonderen Eigenschaften von TIMP-1-GPI könnten in der Therapie von Nierenzellkarzinomen als Adjuvanz bei der modernen chirurgischen Nierenteilresektion oder bei der Therapie mit Angiogenese-Hemmern zunutze gemacht werden, um mögliche Tumorrezidive zu verhindern

Selektive Zelloberflächenmodulation von Nierenzellkarzinomen mit Glykosylphosphatidylinositol-verankertem TIMP-1 hemmt die TGF-β1-Aktivierung und senkt die Expression regulatorischer ID-Gene

Das zugunsten von Matrix Metalloproteinasen (MMP) verschobene Proteasen/Inhibitoren-Verhältnis begründet unter anderem die Malignität von Nierenzellkarzinomen. „Tissue Inhibitor of Metalloproteinases 1“ (TIMP-1), ein löslicher Gewebeinhibitor für Metalloproteinasen der extrazellulären Matrix, kontrolliert die Aktivität von MMP durch 1:1 stochiometrische Bindung. Durch Fusion von humanen TIMP-1 mit einem Glykosylphosphatidylinositol- (GPI-)Anker wird die TIMP-1-Aktivität von der extrazellulären Matrix auf die Zelloberfläche verschoben und eine lokale Applikation von definierten TIMP-1-Konzentrationen ermöglicht. Mit TIMP-1-GPI behandelte Nierenkarzinomzellen zeigten im Vergleich zu Vehikel und nativen TIMP-1-Kontrollgruppen signifikant erhöhte Apoptose- und reduzierte Proliferationsraten. Ziel der Arbeit ist mithilfe von transkriptomischem Profiling und Signaltransduktionsweg-Mapping verantwortliche Genregulationsmechanismen für TIMP-1-GPI-spezifische Effekte zu identifizieren. Mithilfe dieser Techniken zeigten wir, dass eine TIMP-1-GPI-Behandlung zu einer signifikanten Änderung der Regulation von „Inhibitor der DNA Bindung“ (ID), TGF-β/SMAD und BMP Signaltransduktionswege führte. Die unterdrückte ID-Proteinexpression ist auf die durch TIMP-1-GPI gehemmte proteolytische Aktivierung von pro-TGF-β1 und dadurch verursachte reduzierte TGF-β1-Signalaktivität zurückzuführen. Eine mögliche Erklärung für die Überlegenheit von TIMP-1-GPI gegenüber nativem TIMP-1 ist die fokale Konzentration auf der Zelloberfläche, die eine effektivere Hemmung von autosezernierten TGF-β1 ermöglicht. Diese besonderen Eigenschaften von TIMP-1-GPI könnten in der Therapie von Nierenzellkarzinomen als Adjuvanz bei der modernen chirurgischen Nierenteilresektion oder bei der Therapie mit Angiogenese-Hemmern zunutze gemacht werden, um mögliche Tumorrezidive zu verhindern

Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF-beta 1 activation and reduces regulatory ID gene expression

Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase activity through 1:1 stoichiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol (GPI) anchor (TIMP-1-GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1-GPI treated renal cell carcinoma cells show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify the potential mechanisms driving these effects. Significant changes in the DNA binding inhibitors, TGF-beta 1/SMAD and BMP pathways resulted from TIMP-1-GPI treatment. These events were linked to reduced TGF-beta 1 signaling mediated by inhibition of proteolytic processing of latent TGF-beta 1 by TIMP-1-GPI

Recombinant GPI-anchored TIMP-1 stimulates growth and migration of peritoneal mesothelial cells.

Mesothelial cells are critical in the pathogenesis of post-surgical intraabdominal adhesions as well as in the deterioration of the peritoneal membrane associated with long-term peritoneal dialysis. Mesothelial denudation is a pathophysiolocigally important finding in these processes. Matrix metalloproteinase (MMP) biology underlies aspects of mesothelial homeostasis as well as wound repair. The endogenous tissue inhibitors of metalloproteinases (TIMPs) moderate MMP activity. METHODS AND FINDING: By modifying human TIMP-1 through the addition of a glycosylphosphatidylinositol (GPI) anchor, a recombinant protein was generated that efficiently focuses TIMP-1 on the cell surface. Treatment of primary mesothelial cells with TIMP-1-GPI facilitates their mobilization and migration leading to a dramatic increase in the rate of wound experimental closure. Mesothelial cells treated with TIMP-1-GPI showed a dose dependent increase in cell proliferation, reduced secretion of MMP-2, MMP-9, TNF-α and urokinase-type plasminogen activator (uPA), but increased tissue plasminogen activator (t-PA). Treatment resulted in reduced expression and processing of latent TGF-β1. TIMP-1-GPI stimulated rapid and efficient in vitro wound closure. The agent enhanced mesothelial cell proliferation and migration and was bioactive in the nanogram range. The application of TIMP-1-GPI may represent a new approach for limiting or repairing damaged mesothelium

Submillisievert Computed Tomography of the Chest Using Model-Based Iterative Algorithm: Optimization of Tube Voltage With Regard to Patient Size

Objective: The aim of this study was to define optimal tube potential for soft tissue and vessel visualization in dose-reduced chest CT protocols using model-based iterative algorithm in average and overweight patients. Methods: Thirty-six patients receiving chest CTaccording to 3 protocols (120 kVp/noise index [NI], 60;100 kVp/NI, 65;80 kVp/NI, 70) were included in this prospective study, approved by the ethics committee. Patients' physical parameters and dose descriptors were recorded. Images were reconstructed with model-based algorithm. Two radiologists evaluated image quality and lesion conspicuity;the protocols were intraindividually compared with preceding control CT reconstructed with statistical algorithm (120 kVp/NI, 20). Mean and standard deviation of attenuation of the muscle and fat tissues and signal-to-noise ratio of the aorta were measured. Results: Diagnostic images (lesion conspicuity, 95%-100%) were acquired in average and overweight patients at 1.34, 1.02, and 1.08 mGy and at 3.41, 3.20, and 2.88 mGy at 120, 100, and 80 kVp, respectively. Data are given as CT dose index volume values. Conclusions: Model-based algorithm allows for submillisievert chest CT in average patients;the use of 100 kVp is recommended

Imaging characteristics of intravascular spherical contrast agents for grating-based x-ray dark-field imaging - effects of concentrations, spherical sizes and applied voltage

This study investigates the x-ray scattering characteristics of microsphere particles in x-ray-grating-based interferometric imaging at different concentrations, bubble sizes and tube voltages (kV). Attenuation (ATI), dark-field (DFI) and phase-contrast (PCI) images were acquired. Signal-to-noise (SNR) and contrast-to-noise ratios with water (CNRw) and air as reference (CNRa) were determined. In all modalities, a linear relationship between SNR and microbubbles concentration, respectively, microsphere size was found. A significant gain of SNR was found when varying kV. SNR was significantly higher in DFI and PCI than ATI. The highest gain of SNR was shown at 60kV for all media in ATI and DFI, at 80kV for PCI. SNR for all media was significantly higher compared to air and was slightly lower compared to water. A linear relationship was found between CNRa, CNRw, concentration and size. With increasing concentration and decreasing size, CNRa and CNRw increased in DFI, but decreased in PCI. Best CNRa and CNRw was found at specific combination of kV and concentration/size. Highest average CNRa and CNRw was found for microspheres in ATI and PCI, for microbubbles in DFI. Microspheres are a promising contrast-media for grating-based-interferometry, if kV, microsphere size and concentration are appropriately combined

Qualitative and Quantitative Imaging Evaluation of Renal Cell Carcinoma Subtypes with Grating-based X-ray Phase-contrast CT

Current clinical imaging methods face limitations in the detection and correct characterization of different subtypes of renal cell carcinoma (RCC), while these are important for therapy and prognosis. The present study evaluates the potential of grating-based X-ray phase-contrast computed tomography (gbPC-CT) for visualization and characterization of human RCC subtypes. The imaging results for 23 ex vivo formalin-fixed human kidney specimens obtained with phase-contrast CT were compared to the results of the absorption-based CT (gbCT), clinical CT and a 3T MRI and validated using histology. Regions of interest were placed on each specimen for quantitative evaluation. Qualitative and quantitative gbPC-CT imaging could significantly discriminate between normal kidney cortex (54 +/- 4 HUp) and clear cell (42 +/- 10), papillary (43 +/- 6) and chromophobe RCCs (39 +/- 7), p < 0.05 respectively. The sensitivity for detection of tumor areas was 100%, 50% and 40% for gbPC-CT, gbCT and clinical CT, respectively. RCC architecture like fibrous strands, pseudocapsules, necrosis or hyalinization was depicted clearly in gbPC-CT and was not equally well visualized in gbCT, clinical CT and MRI. The results show that gbPC-CT enables improved discrimination of normal kidney parenchyma and tumorous tissues as well as different soft-tissue components of RCCs without the use of contrast media

Correction to: Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI.

The article Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI

Correction to: Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI.

The article Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI

Imaging of hip and thigh muscle injury: a pictorial review

Abstract Muscle injuries of the hip and thigh are a highly relevant issue in competitive sports imaging. The gold standard in diagnostic imaging of muscle injuries is magnetic resonance imaging (MRI). Radiologists need to be familiar with typical MRI findings in order to accurately detect and classify muscle injuries. Proper interpretation of the findings is crucial, especially in elite athletes. In soccer players, muscle injuries of the hip and thigh are the most common reason for missing a game. The present pictorial review deals with the diagnostic assessment, especially MRI, of muscle injuries of the hip and thigh. Typical MR findings in muscle injuries include edema, hematoma, and tendinous avulsion as well as partial or complete muscle tear. To estimate the time to return to play, a grading into three groups—muscle strain, partial tear, complete tear—has traditionally been used. Taking into account the most recent literature, there are other prognostic factors such as the longitudinal length of a tear, the tendon’s intramuscular component, or persisting edema