Simulation of tumor-induced angiogenesis and its response to anti-angiogenic drug treatment: mode of drug delivery and clearance rate dependencies

Tumor cells secrete diffusible substances collectively called tumor angiogenic factors (TAFs), most notably vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which in turn stimulate endothelial cell migration and thus angiogenesis, or new blood vessel formation. Anti-angiogenic drugs for cancer treatment are receiving much attention, with endostatin identified as one of the potent inhibitors. Although the mechanisms of action of endostatin are yet to be fully elucidated, there is evidence that bFGF and endostatin may bind competitively to heparan sulfate proteoglycan receptors on endothelial cells, or endostatin may otherwise downregulate bFGF or VEGF and its receptors, putatively inhibiting cell proliferation. To test these and other hypotheses of inhibitory action that can be similarly formulated, for other TAF inhibitors as well as endostatin, we have developed a mathematical model of extratumoral angiogenesis in cancer in response to specific anti-angiogenic drug treatment. It is built on previous work, a modification and augmentation of published models, and is expressed as four nonlinear partial differential equations, with specific terms for endothelial cell proliferation, degradation, and endostatin-TAF inhibition, and a stochastic, discretized version of this model to represent vessel growth. Our extended model reproduces the simulated kinetics of angiogenesis in a mouse tumor model reported earlier. We assessed the anti-angiogenic kinetic behavior of our extended model by simulating dynamic responses to exogenous endostatin treatment in the same mouse model, using four dosage regimens, two of these reported for in vivo pre-clinical or clinical studies, and two 10 times greater: daily single bolus injections of 20 mg/kg per day and 200 mg/kg per day, and constant infusions of 20 mg/kg per day and 200 mg/kg per day, each for 20 simulated days. We also explored the effects of drug clearance, over an eightfold range of clearance rates that include scaled clearances for endostatin, a sister-drug angiostatin, or similar drugs with clearances in this range. Predictively, our simulation results suggest ineffectiveness of the bolus injection protocols, consistent with in vivo data with angiostatin treatment, whereas simulated constant infusion of endostatin in the mouse model effectively suppresses angiogenesis after only 3 days of treatment, at the lowest dose, over a wide range of drug clearance rates.     

EphA/ephrin-A interactions during optic nerve regeneration: restoration of topography and regulation of ephrin-A2 expression

During visual system development, interactions between Eph tyrosine kinase receptors and their ligands, the ephrins, guide retinal ganglion cell (RGC) axons to their topographic targets in the optic tectum. Here we show that Eph/ephrin interactions are also involved in restoring topography during RGC axon regeneration in goldfish. Following optic nerve crush, EphA/ephrin-A interactions were blocked by intracranial injections of recombinant Eph receptor (EphA3-AP) or phospho-inositol phospholipase-C. Topographic errors with multiple inputs to some tectal loci were detected electrophysiologically and increased projections to caudal tectum demonstrated by RT-97 immunohistochemistry. In EphA3-AP-injected fish, ephrin-A2-expressing cells in the retino-recipient tectal layers were reduced in number compared to controls and their distribution was no longer graded. The findings, supported by in vitro studies, implicate EphA/ephrin-A interactions in restoring precise topography and in regulating ephrin-A2 expression during regeneration.     

Dependence of human forearm skin postocclusive reactive hyperemia on occlusion time

INTRODUCTION: Human postocclusive forearm skin reactive hyperemia is not only a potential means of identifying early signs of cardiovascular diseases, it can also be used in the assessment of local microvascular response to topically applied compounds on skin. The method is not fully characterized. In this study, we investigated the influence of occlusion time on postocclusive forearm skin reactive hyperemia using laser Doppler fluximetry (LDF). METHODS: Twenty healthy male volunteers were studied on three separate days (at least 24 h apart) via a randomized design. Volunteers were studied in a supine position while fasted. Laser Doppler probes were placed on the volar surface of the antebrachium. In preliminary studies, 3 min of upper arm blood flow occlusion at suprasystolic pressure was found to be the upper limit of tolerability. Subsequently, volunteers were randomized to receive 1, 2, or 3 min occlusion on 3 different days. Skin blood flux was measured before, during, and after occlusion using LDF. The primary outcome calculated was maximal change in skin blood flux before and after occlusion, expressed in arbitrary units (AU). RESULTS: Skin blood flux changes (mean+/-S.E.M.) after 1, 2, and 3 min occlusion period were 15.39+/-1.27 AU, 24.84+/-1.62 AU, and 32.14+/-1.73 AU, respectively. Using repeated-measures analysis of variance (ANOVA), significant difference (P<.05) in skin blood flux changes were revealed between these three occlusion durations, where 3 min occlusion produced significantly greater in skin blood flux occlusion change compared to 1 and 2 min occlusion. DISCUSSION: Three minutes of occlusion produces the greater postocclusive reactive hyperemia. It is recommended that studies using postocclusive forearm skin reactive hyperemia should occlude the forearm for at least 3 min.     

Training on a visual task improves the outcome of optic nerve regeneration

Optic nerve regeneration in a lizard, Ctenophorus ornatus, is dysfunctional despite survival of most retinal ganglion cells and axon regeneration to the optic tectum. The regenerated retino-tectal projection at 6 months has crude topography but by 1 year is disordered; visually-elicited behavior is absent via the experimental eye. Here, we assess the influence of training on the outcome of optic nerve regeneration. Lizards were trained to catch prey presented within the monocular field of either eye. One optic nerve was then severed and visual stimulation resumed throughout regeneration. In the trained group, presentation was restricted to the eye undergoing optic nerve regeneration; for the untrained group, the unoperated eye was stimulated. Pupil responses returned in trained but not in untrained animals. At 1 year, trained animals oriented to and captured prey; untrained animals demonstrated minimal orienting and failed to capture prey. Regenerated retino-tectal projections were topographic in the trained but not in the untrained group as assessed by in vitro electrophysiological recording and by carbocyanine dye tracing. In vitro electrophysiological recording during application of neurotransmitter antagonists to the tectum revealed that the level of GABAergic inhibition was modest in trained animals but elevated in the untrained group; responses were mainly AMPA-mediated in both groups. We conclude that training improves the behavioral outcome of regeneration, presumably by stabilizing and refining the transient retino-tectal map and preventing a build-up of tectal inhibition. The results suggest that for successful central nerve regeneration to occur in mammals, it may be necessary to introduce training to complement procedures stimulating axon regeneration.     

An investigation of noise levels in Alberta sawmills

BACKGROUND: Noise exposure in the sawmill industry is an area of concern. This study documents the level of noise exposure in nine sawmills in the province of Alberta, Canada. METHODS: Personal noise monitoring data were collected in nine Alberta sawmills, in winter and in summer (n = 213). Exposures were considered in light of an estimated "real world" noise reduction rating (NRR) calculation assuming use of conventional hearing protection. Limited comparisons were made with spot area monitoring data. RESULTS: Only 10% of the personal monitoring measurements were below the Alberta 8-hr exposure limit of 85 dBA. Twenty-seven percent of the personal monitoring measurements were 95 dBA or higher. Worker enclosures played a large role in reducing noise exposure. There were no significant differences between seasons in noise category distributions (P = 0.61). The planermen and planer infeed operators had the highest percentage of personal monitoring measurements 95 dBA or higher (62% and 82%, respectively). CONCLUSIONS: Based on a conservative formula, a risk of excess noise exposure could exist even when wearing required hearing protection due to very high noise levels found in planing operations in sawmills.     

UK Food Standards Agency Optimal Nutrition Status Workshop: environmental factors that affect bone health throughout life

The UK Food Standards Agency (FSA) convened a group of expert scientists to discuss and review UK FSA- and Department of Health-funded research on diet and bone health. This research focused on the lifestyle factors that are amenable to change and may significantly affect bone health and the risk of osteoporotic fracture. The potential benefits of fruits and vegetables, meat, Ca, vitamins D and K and phyto-oestrogens were presented and discussed. Other lifestyle factors were also discussed, particularly the effect of physical activity and possible gene-nutrient interactions affecting bone health.     

"Helicobacter rappini" isolates from 2 homosexual men.

We report 2 cases of bacteremia due to "Helicobacter rappini" in 2 young, homosexual men, including the first report of H. rappini in a human immunodeficiency virus-positive patient. Blood cultures showed a spiral, fusiform, gram-negative bacterium with bipolar sheathed flagella.