Endosialin/CD248 may be a potential therapeutic target to prevent the invasion and metastasis in osteosarcoma.

Endosialin/CD248/tumor endothelial marker 1 is classified as a C-type lectin-like transmembrane receptor, found on the plasma membrane of activated mesenchymal cells, which binds to fibronectin. Although endosialin is expressed at high levels in stem-like cells of sarcomas, its role has not been fully uncovered. The present study aimed to determine whether endosialin expression is associated with tumor progression and metastasis, and whether endosialin has the potential to act as a novel therapeutic target in osteosarcoma (OS) using MORAb-004/ontuxizumab, a humanized monoclonal antibody, which targets the type C lectin domain of endosialin. The results demonstrated that endosialin was highly expressed in OSs with metastatic disease. Furthermore, MORAb-004 had no cytostatic effect on OS cells in vitro and did not change the expression of stem cells and differentiation markers; however, it inhibited migration of OS cells. Taken together, these results suggest that endosialin may play a role in migration, and may be involved in the metastatic process of OSs. Furthermore, MORAb-004 reduces the motility of OS cells, and suppresses invasion and the development of metastatic lesions.

Effect of mesenchymal stem cells on hypoxia-induced desensitization of ß2-adrenergic receptors in rat osteosarcoma cells.

The ß2-adrenergic receptor (ß2AR) mediates the effects of chronic stress in several neoplasms, however, ß2AR signaling is impaired by hypoxia in various tissues. While hypoxia is a common feature significant in the progression of solid tumors, little is known about the effect of hypoxia on ß2AR signaling in the tumor microenvironment. Previously, it has been reported that the systemic administration of mesenchymal stem cells (MSCs) increased the engraftment and metastatic colonization of rat osteosarcoma (OS) cells. In the current study, the effect of MSCs on the hypoxia-induced desensitization of the ß2AR in OS cells was investigated. Epinephrine, norepinephrine and isoproterenol increased the cellular proliferation of the rat OS cell line COS1NR and rat MSCs in a dose-dependent and ß2AR antagonist-sensitive manner. While isoproterenol had significant proliferative effects on MSCs under normoxic and hypoxic conditions, COS1NR cells did not respond under hypoxic conditions. A sensitivity assay for the ß2AR revealed that hypoxia impaired the sensitivity of COS1NR cells, whereas hypoxia did not affect MSCs. An immunoassay revealed no significant change in the expression of hypoxia-inducible factor-1α (HIF1α) in COS1NR cells, whilst an immunoassay demonstrated a 15% increase in MSCs following isoproterenol stimulation. In COS1NR cells co-cultured with MSCs under hypoxic conditions, isoproterenol caused a significant increase in proliferation and this effect was inhibited by an anti-interleukin (IL)-6 antibody. A tumor formation assay in syngeneic rats revealed that the systemic administration of MSCs enhances the growth of OS and the effect of MSCs was inhibited by IL-6 neutralization. In conclusion, MSCs are resistant to the hypoxia-induced desensitization to ß2AR. Hypoxia caused a siginificant desensitization of the ß2AR in COS1NR cells alone, whereas MSCs may support tumor progression through cellular interactions.

Changes in brain activation associated with use of a memory strategy: a functional MRI study.

It has been confirmed that some kinds of what are called memory strategies dramatically improve the performance of memory recall. However, there has been no direct research to examine changes in brain activity associated with the use of the method of loci within individuals. In the present study, using fMRI, we compared brain activations before and after instruction in the method of loci during both the encoding and recall phases. The resulting behavioral data showed that the use of the method of loci significantly increased scores for memory recall. The imaging data showed that encoding after instruction in the method of loci, relative to encoding before it, was associated with signal increases in the right inferior frontal gyrus, bilateral middle frontal gyrus, left fusiform gyrus, and bilateral lingual gyrus/posterior cingulate gyrus. Comparison of recall after instruction in the method of loci with that before it showed significant activation in the left parahippocampal gyrus/retrosplenial cortex/cingulate gyrus/lingual gyrus, left precuneus, left fusiform gyrus, and right lingual gyrus/cingulate gyrus. The present study demonstrated the changes in brain activation pattern associated with the use of the method of loci; left fusiform and lingual activity was associated with both the encoding and recall phases, bilateral prefrontal activity with the encoding phase, and activity of the posterior part of the parahippocampal gyrus, retrosplenial cortex, and precuneus with the recall phase. These findings suggest that brain networks mediating episodic encoding and retrieval vary with how individuals encode the same stimuli.

[Visual search training for a case of homonymous field defect with multiple visual dysfunctions].

A 72-year-old right handed man developed right homonymous hemianopia without macular sparing, left homonymous lower quadranopia with macular sparing, cerebral amblyopia, cerebral achromatopsia, impaired form vision, and mild right hemispatial neglect, after multiple cerebral infarctions, involving bilateral occipital cortices. His intelligence and memory were deteriorated moderately. He failed to notice objects located in the affected visual field, because of his severely impaired visual search. When ordinary lighting was used, he showed severe right-sided omissions on the line cancellation test. However, omissions were less marked under the brighter lighting. By using a modified method of Kerkhoff and Vianen (1994), he was trained to make saccadic eye movements toward affected regions to find a target and to search and point at targets arranged randomly. As the sensitivity for contrast of isoluminante red and green stimuli was preserved well at high spatial frequencies despite the decreaced contrast sensitivity for brightness, we used green targets as the training stimuli. After the training, search field and pointing range that could be covered by the patient increased in size for both green and white targets, and daily activities improved. Moreover, after the training, he no longer showed discrepancy in line cancellation performances between ordinary and brighter lighting conditions. In the follow up period, the search field and the performance on the line cancellation test were maintained, while the performance of pointing targets array declined. The family members complained of mild re-deterioration of daily activities. Then, the training for searching and pointing re-introduced at home. After the training, his pointing performance and daily activities, evaluated by questionnaires to his family members, improved again. In conclusion, it was suggested that disordered visual search after a homonymous field defect can be treated effectively, even if multiple visual dysfunctions were associated.

[Unawareness for homonymous visual field defect].

BACKGROUND: There was no report which dealt with the relationship between emotional state, degree of defective visual search, severity of hemianopic dyslexia, the episode when the patient became aware of the defect, and unawareness of visual loss in homonymous hemifield. OBJECTIVE: To investigate the relationship between degree of awareness and those factors that might be responsible for the unawareness, including the aspects listed above. METHODS: Four patients with visual field defects caused by a brain lesion after a stroke was investigated. Self rating of emotional state, search performance for an object among many placed on a table, and for text reading, as well as visual field, visual positive phenomena, and hemispatial neglect were evaluated. Degree of unawareness for field loss was evaluated by modified version of the method of Bisiach et al. (1985). In addition, the episodes when the patient became aware of the defect were asked. RESULT: In accordance with the previous studies, we found no relationship between the degree of awareness of field defect and anatomic lesions, co-existence of hemispatial neglect, or the degree of awareness of hemiplegia. However, the patient with neglect was unaware of their troubles in vision at all, whereas the patients without neglect were aware of the troubles but misinterpreted them as problems of the eyes including acuity. In accordance with previous studies, co-existence of visual hallucinations or illusions seemed to be associated with awareness of visual field defect. No relationship was found between the degree of awareness of field defect and emotional state, degree of field loss, degree of defective visual search, or severity of hemianopic dyslexia. Their responses to the inquiry about the degree of awareness of field defect were not consistent. Thus, the awareness of the field defect seemed to be difficult to be kept firmly in their mind. On the other hand, the patients could remember the episode when they became aware of the defect for the first time, being able to specify time, place, and situation. CONCLUSION: Levine (1990) suggested that the sensory loss in this sort of patients was never phenomenally immediate but instead must be discovered by observation and inference. Non-specificity of the lesion, qualitative difference in awareness between the patient with and without hemispatial neglect, association of positive visual phenomena and awareness, fluctuation of awareness, and dependence of awareness on personal experiences found in our patients, can be explained with this 'discovery' hypothesis.