A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo

<p>Abstract</p> <p>Background</p> <p>Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, volociximab (M200), inhibits endothelial cell growth and movement <it>in vitro</it>, independent of the growth factor milieu, and inhibits tumor growth <it>in vivo </it>in the rabbit VX2 carcinoma model. Although volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models.</p> <p>Methods</p> <p>We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of volociximab. Hybridoma clones were screened for analogous function to volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis <it>in vitro</it>. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models.</p> <p>Results</p> <p>A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC₅₀= 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (<it>p </it>< 0.05) and this inhibition correlates with a concomitant decrease in vessel density.</p> <p>Conclusion</p> <p>The results herein demonstrate that 339.1, like volociximab, exhibits potent anti-α5β1 activity and confirms that inhibition of integrin α5β1 impedes angiogenesis and slows tumor growth <it>in vivo</it>.</p

Foreign body reaction to calcium hydroxylapatite vocal fold augmentation

We report a case of inflammation with foreign body cell reaction following injection of the true vocal folds (TVFs) with Radiesse (Bioform Inc, San Mateo, Calif), a synthetic calcium hydroxylapatite (CaHA) material. The patient underwent injection laryngoplasty for a 10-year history of persistent hoarseness and documented bilateral vocal fold paresis. Initial postoperative examination revealed overaugmentation with migration of the material. The material was removed in 2 successive procedures. Results of histological examination revealed the presence of chronic inflammation and foreign body giant cells (FBGCs). This is, to our knowledge, the first published case of an apparent FBGC reaction to vocal fold augmentation with Radiesse and leads us to conclude that rare CaHA rejection reactions can occur in human subjects. ©2006 American Medical Association. All rights reserved

An interactive teaching device simulating intussusception reduction

Intussusception is relatively uncommon, occurring in 0.5 to 2.3 cases per 1,000 live births in the USA. Radiology residents, therefore, have few opportunities to participate in intussusception reduction during training, and practicing radiologists encounter it infrequently. Training is essential, as successful reduction avoids surgery. The judgment involved in reducing an intussusception is best gained with experience. We developed a training device that simulates fluoroscopic intussusception reduction with air. The device consists of a doll that contains a cylinder with similar stress and strain characteristics to the human colon. The trainee pumps air into the cylinder through a rectal tube using a standard hand-held air reduction pump. A sensor measures the pressure within the chamber and transmits readings to a computer, which displays images from actual intussusception reductions based on the pressure maintained within the device. A random component in the software gives the user a new experience each time and models uncertainties in the actual reduction process, including perforation. This intussusception reduction simulator can enhance resident education, giving residents the opportunity to practice this technique before employing it on a real patient. The simulator can also help practicing radiologists become more comfortable with intussusception air reduction

An interactive teaching device simulating intussusception reduction

Intussusception is relatively uncommon, occurring in 0.5 to 2.3 cases per 1,000 live births in the USA. Radiology residents, therefore, have few opportunities to participate in intussusception reduction during training, and practicing radiologists encounter it infrequently. Training is essential, as successful reduction avoids surgery. The judgment involved in reducing an intussusception is best gained with experience. We developed a training device that simulates fluoroscopic intussusception reduction with air. The device consists of a doll that contains a cylinder with similar stress and strain characteristics to the human colon. The trainee pumps air into the cylinder through a rectal tube using a standard hand-held air reduction pump. A sensor measures the pressure within the chamber and transmits readings to a computer, which displays images from actual intussusception reductions based on the pressure maintained within the device. A random component in the software gives the user a new experience each time and models uncertainties in the actual reduction process, including perforation. This intussusception reduction simulator can enhance resident education, giving residents the opportunity to practice this technique before employing it on a real patient. The simulator can also help practicing radiologists become more comfortable with intussusception air reduction

Chemical weathering in active mountain belts controlled by stochastic bedrock landsliding

International audienceA link between chemical weathering and physical erosion exists at the catchment scale over a wide range of erosion rates1,2. However, in mountain environments, where erosion rates are highest, weathering may be kinetically limited3,4,5 and therefore decoupled from erosion. In active mountain belts, erosion is driven by bedrock landsliding6 at rates that depend strongly on the occurrence of extreme rainfall or seismicity7. Although landslides affect only a small proportion of the landscape, bedrock landsliding can promote the collection and slow percolation of surface runoff in highly fragmented rock debris and create favourable conditions for weathering. Here we show from analysis of surface water chemistry in the Southern Alps of New Zealand that weathering in bedrock landslides controls the variability in solute load of these mountain rivers. We find that systematic patterns in surface water chemistry are strongly associated with landslide occurrence at scales from a single hillslope to an entire mountain belt, and that landslides boost weathering rates and river solute loads over decades. We conclude that landslides couple erosion and weathering in fast-eroding uplands and, thus, mountain weathering is a stochastic process that is sensitive to climatic and tectonic controls on mass wasting processes