A Novel Synthetic Smoothened Antagonist Transiently Inhibits Pancreatic Adenocarcinoma Xenografts in a Mouse Model

Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials.Using Shh-Light II (Shh-L2) and alkaline phosphatase (AP) based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low µM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo.We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists

Interplay between ultrastructural findings and atherothrombotic complications in type 2 diabetes mellitus

Accelerated atherosclerosis is the main underlying factor contributing to the high risk of atherothrombotic events in patients with diabetes mellitus and atherothrombotic complications are the main cause of mortality. Like with many bodily systems, pathology is observed when the normal processes are exaggerated or uncontrolled. This applies to the processes of coagulation and thrombosis as well. In diabetes, in fact, the balance between prothrombotic and fibrinolytic factors is impaired and thus the scale is tipped towards a prothrombotic and hypofibrinolytic milieu, which in association with the vascular changes accompanying plaque formation and ruptures, increases the prevalence of ischaemic events such as angina and myocardial infarction. Apart from traditional, modifiable risk factors for cardiovascular disease like hypertension, smoking, elevated cholesterol; rheological properties, endogenous fibrinolysis and impaired platelet activity are rapidly gaining significance in the pathogenesis of atherosclerosis especially in diabetic subjects. Blood clot formation represents the last step in the athero-thrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. It is no surprise that just like platelets and fibrin networks, erythrocytes have been shown to play a role in coagulation as well. This is in striking contrast to their traditional physiological role of oxygen transport. In fact, emerging evidence suggests that erythrocytes enhance functional coagulation properties and platelet aggregation. Among the spectrum of haematological abnormalities in diabetes, erythrocyte aggregation and decreased deformability of erythrocytes predominate. More importantly, they are implicated in the pathogenesis of microvascular complications of diabetes. The morphology of platelets, fibrin networks and erythrocytes are thus essential role players in unravelling the pathogenesis of cardiovascular complications in diabetic subjects.National Research Foundation of South Africa (UNIQUE GRANT NO: 92709) and the MRC: E Pretorius (fund number A0X331).http://www.cardiab.comhb201

The Use of Lidar Data and VHR Imagery to Estimate the Effects of Tree Roots on Shallow Landslides Assessment

The study of geo-hazards has been benefited from the technological advances in the field of Remote Sensing (RS) techniques as the ALS (Airborne Laser Scanners) Systems with Very High Resolution (VHR) cameras. Recently, the LiDAR (Light Detection and Ranging) is an active sensor technique used for a variety of geoscientific applications including slope monitoring to retrieve ground surface displacements at high spatial resolution. Additionally, LiDAR has been widely used in order to collect high-resolution information on forests structure for the determination and characterization of vegetation cover due its ability to capture multiple returns and to reach the ground, even in forested areas, allowing the generation of Digital Terrain Models (DTMs) for the estimation of forest variables. In this paper, a LiDAR dataset and VHR imagery from aerial survey was used in the southwest zone of Medellín City-Colombia where the most frequent landslides are shallow and triggered by rainfall. Slopes with gradients up to 30% on residual soils characterize the study area, having about of 30% of forest cover consisting predominantly of Eucalyptus and Coniferous forests. For the estimation of the tree roots effects on the shallow landslides assessment on a natural slope, interpolation processes were developed from the LiDAR 3D point cloud, obtaining DTMs of 1 m-pixel. Additionally, orthophotos with the same spatial resolution were acquired in the aerial campaign. The proposed workflow was implemented on a GIS platform, and considers the extraction of the tree heights by generating a Canopy Height Model (CHM), while for the delineation of the tree crown a process of image segmentation was developed. Once the vegetation has been characterized using LiDAR products and dendrometric relationships, the Limit Equilibrium Method (LEM) was used to evaluate slope stability considering the effect of vegetation (trees). The results indicate that the proposed workflow allows to obtain adequate stability indicators for the estimation of tree roots contribution and additionally, this RS technique allows saving resources in this kind of analysis. © Published under licence by IOP Publishing Ltd