Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma

BACKGROUND: Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N\u27-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis. The aims of the studies were to determine 1) whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2) whether the treatment schedule would have a crucial impact on controlling GBM. METHODS: U251 human glioma cells (4×10(5)) were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8-21 days treatment) of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0-21 days treatment) was to mimic cases following radiation therapy or surgery. There were four different treatment groups: vehicle, vatalanib (oral treatment 50 mg/kg/d), HET0016 (intraperitoneal treatment 10 mg/kg/d), and combined (vatalanib and HET0016). Following scheduled treatments, all animals underwent magnetic resonance imaging on day 22, followed by euthanasia. Brain specimens were equally divided for immunohistochemistry and protein array analysis. RESULTS: Our results demonstrated a trend that HET0016, alone or in combination with vatalanib, is capable of controlling the tumor growth compared with that of vatalanib alone, indicating attenuation of the unwanted effect of vatalanib. When both vatalanib and HET0016 were administered together on the day of the tumor implantation (0-21 days treatment), tumor volume, tumor blood volume, permeability, extravascular and extracellular space volume, tumor cell proliferation, and cell migration were decreased compared with that of the vehicle-treated group. CONCLUSION: HET0016 is capable of controlling tumor growth and migration, but these effects are dependent on the timing of drug administration. The addition of HET0016 to vatalanib may attenuate the unwanted effect of vatalanib

Measurement of rat brain tumor kinetics using an intravascular MR contrast agent and DCE‐MRI nested model selection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109323/1/jmri24469.pd

Swimming in circles: Motion of bacteria near solid boundaries

Near a solid boundary, E. coli swims in clockwise circular motion. We provide a hydrodynamic model for this behavior. We show that circular trajectories are natural consequences of force-free and torque-free swimming, and the hydrodynamic interactions with the boundary, which also leads to a hydrodynamic trapping of the cells close to the surface. We compare the results of the model with experimental data and obtain reasonable agreement. In particular, we show that the radius of curvature of the trajectory increases with the length of the bacterium body.Comment: Also available at http://people.deas.harvard.edu/~lauga

Discrete cilia modelling with singularity distributions

We discuss in detail techniques for modelling flows due to finite and infinite arrays of beating cilia. An efficient technique, based on concepts from previous ‘singularity models’ is described, that is accurate in both near and far-fields. Cilia are modelled as curved slender ellipsoidal bodies by distributing Stokeslet and potential source dipole singularities along their centrelines, leading to an integral equation that can be solved using a simple and efficient discretisation. The computed velocity on the cilium surface is found to compare favourably with the boundary condition. We then present results for two topics of current interest in biology. 1) We present the first theoretical results showing the mechanism by which rotating embryonic nodal cilia produce a leftward flow by a ‘posterior tilt,’ and track particle motion in an array of three simulated nodal cilia. We find that, contrary to recent suggestions, there is no continuous layer of negative fluid transport close to the ciliated boundary. The mean leftward particle transport is found to be just over 1 μm/s, within experimentally measured ranges. We also discuss the accuracy of models that represent the action of cilia by steady rotlet arrays, in particular, confirming the importance of image systems in the boundary in establishing the far-field fluid transport. Future modelling may lead to understanding of the mechanisms by which morphogen gradients or mechanosensing cilia convert a directional flow to asymmetric gene expression. 2) We develop a more complex and detailed model of flow patterns in the periciliary layer of the airway surface liquid. Our results confirm that shear flow of the mucous layer drives a significant volume of periciliary liquid in the direction of mucus transport even during the recovery stroke of the cilia. Finally, we discuss the advantages and disadvantages of the singularity technique and outline future theoretical and experimental developments required to apply this technique to various other biological problems, particularly in the reproductive system

Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPßCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups (p \u3c 0.05). Similar growth inhibition was observed in syngeneic GL261 GBM (p \u3c 0.05). Survival studies using patient derived xenografts of GBM811, showed prolonged survival to 26 weeks in animals treated with focal radiation, in combination with HET0016 and TMZ (p \u3c 0.05). We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA), in addition to inflammation and angiogenesis markers in the treatment group (p \u3c 0.05). Our results indicate that HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HPßCD-HET0016 significantly prolonged survival in PDX GBM811 model

Stress-induced lipocalin-2 controls dendritic spine formation and neuronal activity in the amygdala.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Behavioural adaptation to psychological stress is dependent on neuronal plasticity and dysfunction at this cellular level may underlie the pathogenesis of affective disorders such as depression and post-traumatic stress disorder. Taking advantage of genome-wide microarray assay, we performed detailed studies of stress-affected transcripts in the amygdala - an area which forms part of the innate fear circuit in mammals. Having previously demonstrated the role of lipocalin-2 (Lcn-2) in promoting stress-induced changes in dendritic spine morphology/function and neuronal excitability in the mouse hippocampus, we show here that the Lcn-2 gene is one of the most highly upregulated transcripts detected by microarray analysis in the amygdala after acute restraint-induced psychological stress. This is associated with increased Lcn-2 protein synthesis, which is found on immunohistochemistry to be predominantly localised to neurons. Stress-naïve Lcn-2(-/-) mice show a higher spine density in the basolateral amygdala and a 2-fold higher rate of neuronal firing rate compared to wild-type mice. Unlike their wild-type counterparts, Lcn-2(-/-) mice did not show an increase in dendritic spine density in response to stress but did show a distinct pattern of spine morphology. Thus, amygdala-specific neuronal responses to Lcn-2 may represent a mechanism for behavioural adaptation to psychological stress.Marie Curie Excellence Grant from the European Commission.Medical Research Council Project GrantCOST Action ECMNe

A separated vortex ring underlies the flight of the dandelion

Wind-dispersed plants have evolved ingenious ways to lift their seeds1,2. The common dandelion uses a bundle of drag-enhancing bristles (the pappus) that helps to keep their seeds aloft. This passive flight mechanism is highly effective, enabling seed dispersal over formidable distances3,4; however, the physics underpinning pappus-mediated flight remains unresolved. Here we visualized the flow around dandelion seeds, uncovering an extraordinary type of vortex. This vortex is a ring of recirculating fluid, which is detached owing to the flow passing through the pappus. We hypothesized that the circular disk-like geometry and the porosity of the pappus are the key design features that enable the formation of the separated vortex ring. The porosity gradient was surveyed using microfabricated disks, and a disk with a similar porosity was found to be able to recapitulate the flow behaviour of the pappus. The porosity of the dandelion pappus appears to be tuned precisely to stabilize the vortex, while maximizing aerodynamic loading and minimizing material requirements. The discovery of the separated vortex ring provides evidence of the existence of a new class of fluid behaviour around fluid-immersed bodies that may underlie locomotion, weight reduction and particle retention in biological and manmade structures

Age-Related Memory Impairment Is Associated with Disrupted Multivariate Epigenetic Coordination in the Hippocampus

Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape