Targeted nanoparticle-based technologies show increasing prevalence in radiotracer design. As a consequence, quantitative contribution of nonspecific accumulation in the target tissue, mainly governed by the enhanced permeability and retention (EPR) effect, becomes highly relevant for evaluating the specificity of these new agents. This study investigated the influence of different tumor phenotypes on the EPR effect, hypothesizing that a baseline level of uptake must be exceeded to visualize high and specific uptake of a targeted macromolecular radiotracer. Methods These preliminary studies use 89Zr-labeled mouse serum albumin (89Zr-desferrioxamine-mAlb) as a model radiotracer to assess uptake and retention in 3 xenograft models of human prostate cancer (CWR22rv1, DU-145, and PC-3). Experiments include PET and contrast-enhanced ultrasound imaging to assess morphology, vascularization, and radiotracer uptake; temporal ex vivo biodistribution studies to quantify radiotracer uptake over time; and histologic and autoradiographic studies to evaluate the intra- and intertumoral distribution of 89Zr-desferrioxamine-mAlb. Results Early uptake profiles show statistically significant but overall small differences in radiotracer uptake between different tumor phenotypes. By 20 h, nonspecific radiotracer uptake was found to be independent of tumor size and phenotype, reaching at least 5.0 percentage injected dose per gram in all 3 tumor models. Conclusion These studies suggest that minimal differences in tumor uptake exist at early time points, dependent on the tumor type. However, these differences equalize over time, reaching around 5.0 percentage injected dose per gram at 20 h after injection. These data provide strong support for the introduction of mandatory experimental controls of future macromolecular or nanoparticle-based drugs, particularly regarding the development of targeted radiotracers.

No abstract

Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin‐6 (IL‐6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL‐6 classic and the IL‐6 trans‐signaling pathway. Whereas IL‐6 classic signaling is important for innate and acquired immunity, IL‐6 trans‐signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL‐6 trans‐signaling, but not IL‐6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA‐damage‐induced hepatocyte apoptosis through suppression of p53 and enhances β‐catenin activation and tumor proliferation. Second, IL‐6 trans‐signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL‐6 trans‐signaling are largely protected from tumor formation in a diethylnitrosamine/3,3′,5,5′‐tetrachloro‐1,4‐bis(pyridyloxy)benzene model of HCC. Conclusion: IL‐6 trans‐signaling, and not IL‐6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL‐6 trans‐signaling, rather than total inhibition of IL‐6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL‐6 classic signaling‐driven protective immune responses. (Hepatology 2017;65:89‐103).

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human tumors, with radical surgical resection as the only curative treatment option. However, resection is only possible in a small fraction of patients, and about 80% of the patients develop recurrencies. PDAC development is facilitated by the cytokine interleukin-6 (IL-6), which acts via classic and transsignaling. Both pathways are inhibited by the anti-IL-6-receptor antibody tocilizumab, whereas the fusion protein sgp130Fc specifically blocks trans-signaling. Here, we show that conservative or adjuvant therapy with both inhibitors reduces tumor growth in an orthotopic model of human Colo357 cells in SCID/bg mice. In the conservative setting, median primary tumor weight was reduced 2.4-fold for tocilizumab and 4.4-fold for sgp130Fc. sgp130Fc additionally led to a decrease in microvessel density, which was not observed with tocilizumab. In the adjuvant therapeutic setting after surgical resection of the primary tumor, treatment with tocilizumab or sgp130Fc decreased the local recurrence rate from 87.5% in the control group to 62.5 or 50%, respectively. Furthermore, the median weight of the local recurrent tumors was clearly diminished, and both inhibitors reduced the number of distant metastases. A significant reduction of tumor weight and metastases-comparable to gemcitabine treatment-was also observed with both inhibitors in another model using the poorly differentiated PancTuI cells. Our findings demonstrate the inhibition of IL-6 as a new treatment option in PDAC.

Rhesus monkey embryonic stem (rhES) cells were grown on mouse embryonic fibroblast (MEF) feeder layers for up to 10 days to form multilayered colonies. Within this period, stem cell colonies differentiated transiently into complex structures with a disc-like morphology. These complex colonies were characterized by morphology, immunohistochemistry, and marker mRNA expression to identify processes of epithelialization as well as epithelial-mesenchymal transition (EMT) and pattern formation. Typically, differentiated colonies were comprised of an upper and a lower ES cell layer, the former growing on top of the layer of MEF cells whereas the lower ES cell layer spread out underneath the MEF cells. Interestingly, in the central part of the colonies, a roundish pit developed. Here the feeder layer disappeared, and upper layer cells seemed to ingress and migrate through the pit downward to form the lower layer while undergoing a transition from the epithelial to the mesenchymal phenotype, which was indicated by the loss of the marker proteins E-cadherin and ZO-1 in the lower layer. In support of this, we found a concomitant 10-fold upregulation of the gene Snail2, which is a key regulator of the EMT process. Conversion of epiblast to mesoderm was also indicated by the regulated expression of the mesoderm marker Brachyury. An EMT is a characteristic process of vertebrate gastrulation. Thus, these rhES cell colonies may be an interesting model for studies on some basic processes involved in early primate embryogenesis and may open new ways to study the regulation of EMT in vitro. Stem Cells 2005;23:805-816

ZUSAMMENFASSUNG Hintergrund Der extrakorporale hochintensive fokussierte Ultraschall (HIFU) ist ein vielversprechendes Verfahren zur nichtinvasiven Thermoablation gutartigen und bösartigen Gewebes. Derzeitige HIFU-Therapien nutzen Ultraschall (US-HIFU) oder MRT (MR-HIFU) zur Bildsteuerung mit der Möglichkeit zur integrierten Therapieplanung, Echtzeit-Therapiekontrolle (räumliche Orientierung und Temperatursteuerung) und Therapieevaluation. Methode Dieser Übersichtsartikel basiert auf Publikationen aus Fachzeitschriften, die die thermale Ablation mittels HIFU thematisieren, und beinhaltet zudem eigene klinische Ergebnisse. Es wird ein kurzer Überblick über die häufigsten CEzertifizierten klinischen Applikationen für MR-HIFU gegeben. Ergebnisse Im Laufe des letzten Jahrzehnts erhielten zahlreiche HIFU-basierte Applikationen die Zulassung in diversen Ländern. Im Speziellen ist MR-HIFU nun zugelassen für die Therapie von Uterusmyomen, Linderung von Knochenschmerzen, der Ablation der Prostata und die Therapie des essenziellen Tremors als erste neurologische Applikationsform. Schlussfolgerung MR-HIFU ist eine patientenfreundliche, nichtinvasive Methode zur Thermoablation, welche mittlerweile für mehrere klinische Applikationen zugelassen wurde. Insgesamt bestätigen die bisherigen klinischen Daten die Wirksamkeit und Sicherheit der Therapie sowie die Kosteneffizienz der Methode.Kernaussagen: ▪ HIFU stellt eine vielversprechende Technik zur nichtinvasiven Thermoablation von Gewebe dar. ▪ HIFU wird üblicherweise unter Bildkontrolle mittels Ultraschall (US-HIFU) oder MRT (MR-HIFU) durchgeführt. ▪ Die bevorzugte Bildkontrolle (US-HIFU vs. MR-HIFU) hängt von der geplanten Applikation ab. ▪ MRT bietet einen höheren Weichteilkontrast zur Therapieplanung, eine nahezu in Echtzeit und nichtinvasiv erfolgende Temperaturkontrolle und eine postinterventionelle Therapieevaluation. ▪ MR-HIFU ist CE-zertifiziert für die Therapie von Uterusmyomen, Linderung von Knochenschmerzen, Ablation der Prostata und Therapie des essenziellen Tremors. ABSTR AC TBackground Extracorporeal high-intensity focused ultrasound (HIFU) is a promising method for the noninvasive thermal ablation of benign and malignant tissue. Current HIFU treatments are performed under ultrasound (US-HIFU) or magnetic resonance (MR-HIFU) image guidance offering integrated therapy planning, real-time control (spatial and temperature guidance) and evaluation.Methods This review is based on publications in peer-reviewed journals addressing thermal ablation using HIFU and includes our own clinical results as well. The technical background of HIFU is explained with an emphasis on MR-HIFU applications. A brief overview of the most commonly performed CE-approved clinical applications for MR-HIFU is given.Results Over the last decade, several HIFU-based applications have received clinical approval in various countries. In particular, MR-HIFU is now approved for the clinical treatment of uterine fibroids, palliation of bone pain, ablation of the prostate and treatment of essential tre...

G-MSCs in conjunction with IL-1ra-loaded/unloaded HA-sECM show a significant periodontal regenerative potential.

Embryo implantation involves adhesion of trophoblast cells to the epithelial lining of the endometrium. Using an in-vitro model to simulate this initial interaction, we previously reported that attachment of human trophoblast-like JAR spheroids to human uterine epithelial RL95-2 cells provokes a Ca(2+) influx in RL95-2 cells depending on apically localized integrin receptors. Here, we demonstrate that adhesiveness of RL95-2 cells for JAR spheroids, measured by a centrifugal force-based adhesion assay, is dependent on Rho GTPases, most likely RhoA. Cellular expression and distribution of RhoA were studied by fluorescence confocal microscopy, focusing on the localization of RhoA and F-actin within the adhesion sites between JAR and RL95-2 cells. Contact areas contained high amounts of RhoA and F-actin fibres near the plasma membrane. To determine whether Rho GTPases may influence JAR cell binding, we treated RL95-2 cells with Clostridium difficile toxin A, which specifically inactivates Rho GTPases. Toxin A treatment changed the subcellular distribution of endogenous RhoA in RL95-2 cells and altered RhoA and F-actin colocalization. Adhesion of JAR spheroids to RL95-2 cells treated with toxin A was largely suppressed. These data indicate that Rho GTPases, most likely RhoA, play an important role in uterine epithelial RL95-2 cells for trophoblast binding, and suggest that RhoA may be involved in local signalling cascades during early embryo implantation in vivo.