Effect of PlGF-inhibition on survival in mice with hepatocellular carcinoma

Background: Inhibition of angiogenesis is currently hot topic in the search for an effective treatment for hepatocellular carcinoma (HCC). Up till recently, the focus was mainly on VEGF, an important regulator in the pathologic and physiologic angiogenesis. Although promising results are seen by inhibiting the VEGF-pathway, patients often suffer from major side effects. Placental growth factor (PlGF) is a VEGF analogue only involved in pathologic angiogenesis and its inhibition has the potential to restrain tumour growth, without affecting healthy organs. Therefore, we assessed whether administration of PlGF-antibodies could serve as a potential therapy for HCC in mice. Methods: 5-week-old male mice (sv129) received intraperitoneal (ip) injections once per week with N-nitrosodiethylamine (35 mg/kg bodyweight) or saline , which gives rise to HCC after 25W in WT. PlGF-knock-out mice (PlGF-/-) received weekly ip DEN-injections and were compared with their WT counterparts. At 26W, WT mice were treated with twice a week with murine monoclonal PlGF-antibodies (20 mg/kg anti-PlGF) or IgG for 5W and 10W. Results: By 25 weeks of DEN treatment, 29% of the WT mice but none of the PlGF-/- mice had succumbed to the disease (p = 0,056). Also, treatment of DEN-injected HCC mice from 25 weeks for 5 weeks with 5D11D4 (ThromboGenics N.V.) or IgG showed a significant difference in mortality. While 45% died in the control IgG group, only 23% mortality was observed in the anti-PlGF group (N=48; P < 0.05). Also, the liver/body weight ratio was 0.057 ± 0.003 in the control group versus 0.042 ± 0.004 in the 5D11D4 group (N=19; P < 0,05). After 10W treatment 90% died in the control IgG group, while only 41 % mortality was observed in the anti-PlGF group (N = 11, P < 0,05). No mortality was observed in mice injected with saline instead of DEN, followed by 5 wks of treatment with anti-PlGF or IgG. The liver/body weight ratio was 0.038 ± 0.001 in the saline and IgG group versus 0.041 ± 0.002 in the anti-PlGF group (N=12, P = 0,27). Figure 1: left: Mean survival of IgG and aPlGF treated mice ; right: mean survival of PlGF knock out mice and WT’s during DEN-induction Conclusion: Our study showed that administration of 20 mg/kg anti-PlGF twice a week, has a positive effect on survival in mice with HCC. The liver/bodyweight ratio of anti-PlGF treated mice was significantly lower than in the control IgG group, showing a specific effect on liver tumours. Treatment of anti-PlGF in healthy mice did not induce negative side effects. Therefore, treatment with PlGF antibodies might serve as a promising systemic treatment in hepatocellular carcinoma patients

Deformation and damage due to drying-induced salt crystallization in porous limestone

ACLInternational audienceThis paper presents a computational model coupling heat, water and salt ion transport, salt crystallization, deformation and damage in porous materials. We focus on crystallization-induced damage. The theory of poromechanics is employed to relate stress, induced by crystallization processes or hygro-thermal origin, to the material's mechanical response. A non-local formulation is developed to describe the crystallization kinetics. The model performance is illustrated by simulating the damage caused by sodium chloride crystallization in a porous limestone. The results are compared with experimental observations based on neutron and X-ray imaging. The simulation results suggest that the crystallization kinetics in porous materials have to be accurately understood in order to be able to control salt damage. The results show that the effective stress caused by salt crystallization depends not only on the crystallization pressure but also on the amount of salt crystals, which is determined by the spreading of crystals in the porous material and the crystallization kinetics. © 2013 Elsevier Ltd

Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin

Preservation of bone mass is crucial for healthy ageing and largely depends on adequate responses of matrix-embedded osteocytes. These cells control bone formation and resorption concurrently by secreting the WNT/-catenin antagonist sclerostin (SOST). Osteocytes reside within a low oxygen microenvironment, but whether and how oxygen sensing regulates their function remains elusive. Here, we show that conditional deletion of the oxygen sensor prolyl hydroxylase (PHD) 2 in osteocytes results in a high bone mass phenotype, which is caused by increased bone formation and decreased resorption. Mechanistically, enhanced HIF-1 signalling increases Sirtuin 1-dependent deacetylation of the Sost promoter, resulting in decreased sclerostin expression and enhanced WNT/-catenin signalling. Additionally, genetic ablation of PHD2 in osteocytes blunts osteoporotic bone loss induced by estrogen deficiency or mechanical unloading. Thus, oxygen sensing by PHD2 in osteocytes negatively regulates bone mass through epigenetic regulation of sclerostin and targeting PHD2 elicits an osteo-anabolic response in osteoporotic models.Research Foundation – Flanders (FWO: G.0A72.13, G.096414 and G0A4216N) and P.C. from long-term structural funding – Methusalem Funding by the Flemish Government

Adsorption and film forming of train of water droplets impacting porous stones

The phenomenon of droplets impacting porous media is ubiquitous in rain events. Rain is a major source of moisture in buildings. When a water droplet impacts a permeable surface, it spreads on the surface and is absorbed into the porous material due to capillary action. This paper presents an experimental investigation of the absorption and film forming during train of liquid droplets impacting porous stones, towards establishing the fate of rain droplets during rain events

Water uptake in masonry: effect of brick/mortar interface

Water transport in masonry walls composed of bricks and mortar joints can be strongly affected by the interface between brick and mortar. In this study, water uptake experiments and numerical simulations are performed to study the effect of interface resistance on moisture transport in masonry samples with horizontal and vertical interfaces. Neutron radiography is used to measure moisture content distribution in different masonry samples. An interface resistance is introduced to consider the imperfect contact between brick and mortar in the numerical model. A good agreement between measured and simulated moisture contents is found for different masonry samples. The orientation, horizontal or vertical, of the interface between brick and mortar has no influence on the value of the interface resistance. However we found that the interface resistance is affected by capillary pressure at the interface. A lower capillary pressure at the interface leads to a larger interface resistance

Indicators for the evaluation of test section flow quality

ABSTRACT: The flow in a wind tunnel test section must meet high standards to obtain accurate and reliable measurement data. Good flow quality demands a certain degree of spatial uniformity and temporal steadiness of velocity and pressure. In this paper, a set of six new indices is developed and presented that relate spatial aspects of the mean velocity field to flow quality. One index quantifies the degree of uniformity of the velocity field and can be used directly as a flow quality indicator. The five other indices are related to different types of deviations from spatially uniform flow; skewed flow and angularity (up-flow and down-flow, swirl, cross-flow, diverging and converging flow). The indices can be used to evaluate the flow quality in existing tunnels and to assess the impact of design modifications. They can also be used in the CFD-based design of new wind tunnels. KEYWORDS: Wind tunnel testing; Flow quality; Skewness; Angularity; Uniformity. INTRODUCTION Wind tunnel test section flow quality relates to temporal and spatial aspects of the flow. In this paper, only spatial aspects of the flow will be addressed. Strictly speaking, spatial uniformity is required in the entire empty test section of the wind tunnel. Deviations from spatial uniformity can have negative repercussions on the test results (Rae and Pope, 1984; Barlow and Rae, 1999). A skewed flow for example (i.e. with a streamwise velocity that is not symmetrically distributed over the width of the test section) will cause the static pressure over the front face of an object placed in the test section and the position of the stagnation point to be shifted. This can have a significant influence on all measured quantities around the object. Spatial flow uniformity is often documented by contour plots of velocity magnitude or static pressure that are shown in one or more cross-sectional planes of the wind tunnel (e.g. Selig and McGranahan, 2004). Other authors provide only numerical information in the form of a single mean value and spatial standard deviation for the quantity for the entire cross-sectional plane. The first method allows determining the presence or absence of skewness and angularity. However, multiple sections are required to obtain a complete view of the flow quality in the entire test section. Mean values and spatial standard deviations have the advantage that the flow in a specific (part of the) cross-section can be characterised numerically, although the interpretation of these characteristic values is not always clear. The existing techniques do not allow for a complete and straightforward evaluation of test section flow quality. However, it is important to be able to quantify wind tunnel test section flow quality and to assess and compare the impact of features such as honeycombs, corner or guide vanes, screens, etc. for wind tunnel and flow quality optimization. To this extent, a set of six new complementary indices describing spatial uniformity and the different types of spatial non-uniformity is developed in this paper

Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche.

Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or upregulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfa(δ/δ), where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfa(δ/δ) mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-Vegfa axis