Cluttered environments: Differential effects of obstacle position on grasp and gaze locations.

Previous research has investigated the effects of nontarget objects (NTOs) on reach trajectories, but their effects on eye-hand coordination remain to be determined. The current investigation utilized an eye-hand coordination paradigm, where a reaching and grasping task was performed in the presence of an NTO positioned exclusively in the right or left workspace of each right-handed participant. NTOs varied in their closeness to the subject and reach-path, between the starting location of the hand and the target-object of the reach. A control condition, where only the target was present, was also included. When an NTO was presented on the right (ipsilateral to the reaching hand), it pushed the final grasp and gaze locations on the target, shifting them to the left-away from the "obstacle." The impact of the ipsilateral NTO was increased as it was moved into positions closer to the participant that were of greater obstruction to the hand and arm. In contrast, when the NTO was contralateral, the risk of collision was low and participants developed a set reach plan that was repeated nearly identically for each contralateral NTO position. Our findings also indicate that the "invasiveness" of the NTO positions had a greater effect on grasp than it did on gaze position-demonstrating how the arrangement of clutter in an environment can differentially affect gaze and grasp when reaching for an object. (PsycINFO Database Record

Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo.

INTRODUCTION: Bone metastasis remains incurable with treatment restricted to palliative care. Cabozantinib (CBZ) is targeted against multiple receptor tyrosine kinases involved in tumour pathobiology, including hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR-2). CBZ has demonstrated clinical activity in advanced prostate cancer with resolution of lesions visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of CBZ effects. We characterised the effects of short-term administration of CBZ on bone in a range of in vivo models to determine how CBZ affects bone in the absence of tumour. METHODS: Studies were performed in a variety of in vivo models including male and female BALB/c nude mice (age 6-17-weeks). Animals received CBZ (30 mg/kg, 5× weekly) or sterile H2O control for 5 or 10 days. Effects on bone integrity (µCT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and bone marrow composition were assessed. Effects of longer-term treatment (15-day & 6-week administration) were assessed in male NOD/SCID and beige SCID mice. RESULTS: CBZ treatment had significant effects on the bone microenvironment, including reduced osteoclast and increased osteoblast numbers compared to control. Trabecular bone structure was altered after 8 administrations. A significant elongation of the epiphyseal growth plate, in particular the hypertrophic chondrocyte zone, was observed in all CBZ treated animals irrespective of administration schedule. Both male and female BALB/c nude mice had increased megakaryocyte numbers/mm(2) tissue after 10-day CBZ treatment, in addition to vascular ectasia, reduced bone marrow cellularity and extravasation of red blood cells into the extra-vascular bone marrow. All CBZ-induced effects were transient and rapidly lost following cessation of treatment. CONCLUSION: Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironment in vivo highlighting a potential role in mediating treatment responses.

Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib.

BACKGROUND: Prostate cancer is incurable once it has metastasized to the bone. Appropriate preclinical models are lacking. The therapeutic efficacy of the multikinase inhibitor cabozantinib was assessed in an orthotopic xenograft model of castration-resistant prostate cancer (CRPC) bone metastasis using noninvasive, multimodality functional imaging. METHODS: NOD/SCID mice were injected intratibially with luciferase-expressing ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) rearranged VCaP human prostate carcinoma cells. The response of VCaP xenografts (n = 7 per group) to cabozantinib was investigated using bioluminescence imaging and anatomical and diffusion weighted magnetic resonance imaging. This enabled quantitation of tumor volume and apparent diffusion coefficient (ADC). Bone uptake of technetium-methylene diphosphonate ((99m)Tc-MDP) was assessed by single-photon emission computed tomography. Ex vivo micro computed tomography was used to quantify bone volume and correlated with appropriate histopathology. Statistical significance was determined using the two-sided Mann-Whitney test or Wilcoxon signed rank test. RESULTS: VCaP xenografts were predominantly osteosclerotic with some osteolytic activity. Fluorescent in situ hybridization analysis confirmed retention of ERG oncogene rearrangements. Cabozantinib induced a statistically significant 52% reduction in tumor luminance (P = .02) and stasis in tumor volume after 15 days of treatment. Tumor ADC statistically significantly increased with cabozantinib and was associated with extensive necrosis (after 10 days, mean tumor ADC ± SD = 556±43×10(-6) mm(2)/s vs pretreatment ADC = 485±43×10(-6) mm(2)/s; P = .02 ). Tumor-associated uptake of (99m)Tc-MDP was statistically significantly reduced after 3 days of treatment (P = .02), sustained over 15 days treatment, and associated with a statistically significant (P = .048) reduction in bone growth on the tibial cortex, yet a highly statistically significant (P = .001) increase in trabecular bone volume. CONCLUSIONS: The intratibial VCaP model faithfully emulates clinical disease. Cabozantinib exerts potent effects on both tumor and tumor-induced bone matrix remodeling, and quantitation of ADC provides a clinically translatable imaging biomarker for early, sensitive assessment of treatment response in CRPC bone metastasis.

Characterization of a novel mouse model of multiple myeloma and its use in preclinical therapeutic assessment.

To aid preclinical development of novel therapeutics for myeloma, an in vivo model which recapitulates the human condition is required. An important feature of such a model is the interaction of myeloma cells with the bone marrow microenvironment, as this interaction modulates tumour activity and protects against drug-induced apoptosis. Therefore NOD/SCIDγc(null) mice were injected intra-tibially with luciferase-tagged myeloma cells. Disease progression was monitored by weekly bioluminescent imaging (BLI) and measurement of paraprotein levels. Results were compared with magnetic resonance imaging (MRI) and histology. Assessment of model suitability for preclinical drug testing was investigated using bortezomib, melphalan and two novel agents. Cells engrafted at week 3, with a significant increase in BLI radiance occurring between weeks 5 and 7. This was accompanied by an increase in paraprotein secretion, MRI-derived tumour volume and CD138 positive cells within the bone marrow. Treatment with known anti-myeloma agents or novel agents significantly attenuated the increase in all disease markers. In addition, intra-tibial implantation of primary patient plasma cells resulted in development of myeloma within bone marrow. In conclusion, using both myeloma cell lines and primary patient cells, we have developed a model which recapitulates human myeloma by ensuring the key interaction of tumour cells with the microenvironment.

Feature head-start: Conjunction search following progressive feature disclosure.

When a colour/orientation conjunction search display is immediately preceded by a display that shows either the colour or the orientation of each upcoming search item, search is faster after colour-preview than after orientation-preview. One explanation for this feature asymmetry is that colour has priority access to attentional selection relative to features such as orientation and size. In support of this hypothesis, we show that this asymmetry persists even after colour and orientation feature search performance is equated. However, this notion was ruled out by our subsequent experiments in which the target was defined by conjunction of colour and size; colour-preview was less helpful than size-preview (even though colour-feature search was faster than size-feature search, for these feature values). A final set of experiments tested size-preview vs. orientation-preview for size/orientation conjunction search, using stimuli for which orientation-feature search was easier than size-feature search. Size-preview produced much faster search than orientation-preview, demonstrating again that ease of feature search does not predict effects of a feature-preview. Overall, size produced the most facilitation when presented as a feature-preview (for both colour/size and size/orientation conjunctions), followed by colour (for colour/orientation conjunction but not for colour/size conjunction) and then orientation (which never facilitated search). Whilst each feature-preview may potentially facilitate search, the transition from feature-preview display to search display could disrupt search processes, because of luminance and/or colour changes. We see evidence for some sort of disruption when the feature-preview slows search. An explanation of this set of results must focus on both facilitation and disruption: these effects are not mutually exclusive, and neither suffices alone, since performance after feature-preview can be significantly better or significantly worse than conjunction baseline.