Prospective, randomized, double-blind, multi-center, Phase III clinical study on transarterial chemoembolization (TACE) combined with Sorafenib® versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation – HeiLivCa [ISRCTN24081794]

<p>Abstract</p> <p>Background</p> <p>Disease progression of hepatocellular cancer (HCC) in patients eligible for liver transplantation (LTx) occurs in up to 50% of patients, resulting in withdrawal from the LTx waiting list. Transarterial chemoembolization (TACE) is used as bridging therapy with highly variable response rates. The oral multikinase inhibitor sorafenib significantly increases overall survival and time-to-progression in patients with advanced hepatocellular cancer.</p> <p>Design</p> <p>The HeiLivCa study is a double-blinded, controlled, prospective, randomized multi-centre phase III trial. Patients in study arm A will be treated with transarterial chemoembolization plus sorafenib 400 mg bid. Patients in study arm B will be treated with transarterial chemoembolization plus placebo. A total of 208 patients with histologically confirmed hepatocellular carcinoma or HCC diagnosed according to EASL criteria will be enrolled. An interim patients' analysis will be performed after 60 events. Evaluation of time-to-progression as primary endpoint (TTP) will be performed at 120 events. Secondary endpoints are number of patients reaching LTx, disease control rates, OS, progression free survival, quality of live, toxicity and safety.</p> <p>Discussion</p> <p>As TACE is the most widely used primary treatment of HCC before LTx and sorafenib is the only proven effective systemic treatment for advanced HCC there is a strong rational to combine both treatment modalities. This study is designed to reveal potential superiority of the combined TACE plus sorafenib treatment over TACE alone and explore a new neo-adjuvant treatment concept in HCC before LTx.</p

Spatial Segregation of BMP/Smad Signaling Affects Osteoblast Differentiation in C2C12 Cells

BACKGROUND: Bone morphogenetic proteins (BMPs) are involved in a plethora of cellular processes in embryonic development and adult tissue homeostasis. Signaling specificity is achieved by dynamic processes involving BMP receptor oligomerization and endocytosis. This allows for spatiotemporal control of Smad dependent and non-Smad pathways. In this study, we investigate the spatiotemporal regulation within the BMP-induced Smad transcriptional pathway. METHODOLOGY/PRINCIPAL FINDINGS: Here we discriminate between Smad signaling events that are dynamin-dependent (i.e., require an intact endocytic pathway) and dynamin-independent. Inhibition of dynamin-dependent endocytosis in fluorescence microscopy and fractionation studies revealed a delay in Smad1/5/8 phosphorylation and nuclear translocation after BMP-2 stimulation of C2C12 cells. Using whole genome microarray and qPCR analysis, we identified two classes of BMP-2 induced genes that are differentially affected by inhibition of endocytosis. Thus, BMP-2 induced gene expression of Id1, Id3, Dlx2 and Hey1 is endocytosis-dependent, whereas BMP-2 induced expression of Id2, Dlx3, Zbtb2 and Krt16 is endocytosis-independent. Furthermore, we demonstrate that short term inhibition of endocytosis interferes with osteoblast differentiation as measured by alkaline phosphatase (ALP) production and qPCR analysis of osteoblast marker gene expression. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that dynamin-dependent endocytosis is crucial for the concise spatial activation of the BMP-2 induced signaling cascade. Inhibition of endocytic processes during BMP-2 stimulation leads to altered Smad1/5/8 signaling kinetics and results in differential target gene expression. We show that interfering with the BMP-2 induced transcriptional network by endocytosis inhibition results in an attenuation of osteoblast differentiation. This implies that selective sensitivity of gene expression to endocytosis provides an additional mechanism for the cell to respond to BMP in a context specific manner. Moreover, we suggest a novel Smad dependent signal cascade induced by BMP-2, which does not require endocytosis

Analytical and numerical bedrock reconstruction in glacier flows from free surface elevation data

This paper presents a simple analytical and numerical approach to reconstruct the bedrock in glacier flows from given free surface data. The approach relies on the Shallow Ice Approximation in one space dimension to describe the glacier flow dynamics. Remarkably, we show that this complex, non-linear partial differential equation can be integrated once to yield and explicit relationship between the ice free surface elevation and the ice depth and therefore the bedrock. The applicability of the proposed approach is broadened by proposing a transient numerical scheme capable of reconstructing the ice depth and underlying bedrock topography

Direct Reconstruction of Three-dimensional Glacier Bedrock and Surface Elevation from Free Surface Velocity

This study presents a new algorithm to reconstruct both the ice-surface elevation and the altitude of the bedrock of a glacier from the knowledge of the ice-surface velocity which could potentially be obtained from satellite data. It requires the prior knowledge of the surface mass balance and basal conditions. The algorithm is realized in two steps: the first one involves the solution of a partial differential equation obtained from a rearrangement of the shallow-ice approximation and the second one involves the mere downslope integration of a non-linear function of the ice velocity and ice thickness. It is therefore an efficient algorithm which is in principle easy to implement. The algorithm is tested on synthetic data and is shown to be very successful with an ideal dataset and robust even when significant noise is added to the input data. Importantly, the inversion algorithm does not appear to amplify the input error in the dat

Nonlinear resonance in viscous films on inclined wavy planes

We study nonlinear resonance in viscous gravity-driven films flowing over undulated substrates. Numerical solution of the full, steady Navier-Stokes equations is used to follow the emergence of the first few free-surface harmonics with increasing wall amplitude, and to study their parametric dependence on film thickness, inertia and capillarity. Bistable resonance is computed for steep enough bottom undulations. As an analytic approach, we apply the integral boundary-layer method and derive an asymptotic equation valid for rather thin films. The analysis recovers the key numerical findings and provides qualitative understanding. It shows that higher harmonics are generated by a nonlinear coupling of the wall with lower-order harmonics of the free surface. It also accounts for bistable resonance, and produces a minimum model whose solution is similar to that of the Duffing oscillator. All rights reserved (C) 2008 Elsevier Ltd.