values in versus PBS-treated mice demonstrated that rhGas6 were more effective for remyelination compared

Although the dose of 400 ng/ml of rhGas6 did not produce MG132 statistically significant results, these mice also had more MBP immunoreactivity than PBS-treated mice, indicating that enhanced clearance of debris and reduced number of axonal spheroids was associated with successful remyelination. EM showed increased numbers of myelinated axons and a decreased g-ratio in rhGas6-treated mice indicative of increased myelin thickness. Thus, the data from EM are consistent with results obtained by MBP immunostaining. It was shown that following acute demyelination after cuprizone intoxication, many small caliber axons become preferentially remyelinated. We also found that the number of small diameter myelinated axons was significantly increased in rhGas6treated mice. Thus, remyelination of small axons was an important index of corpus callosum recovery. As OPCs mature, they synthesize myelin proteins that contribute to remyelination. We used Olig1 immunostaining as a marker of OPC maturation to determine if direct administration of rhGas6 affected OPC development. Olig1, a closely related homolog to Olig2, is co-expressed with Olig2 in many cells of the oligodendrocyte lineage. As OPCs mature, there is a shift in Olig1 immunostaining from a nuclear to a cytoplasmic localization. Analysis of the corpus callosum showed that the number of cells with Olig1-positive cytoplasmic localization was increased in rhGas6-treated mice but only the dose of 4 mg/ml was statistically significant. Further, the percentage of cells with Olig1-positive cells with cytoplasmic localization relative to total number of Olig1positive cells was increased in mice treated with 4 mg/ml of rhGas6. Taken together, these data provide compelling support for rhGas6 having a beneficial effect on corpus callosum recovery following cuprizone toxicity. Although 400 ng/ml rhGas6 was a therapeutic dose for the clearance of cellular debris, maintenance of cell survival and axonal integrity, 4 mg/ml of rhGas6 was more effective for remyelinationy. To our knowledge this is the first report of a beneficial effect of rhGas6 administration in vivo. These results open new avenues for rhGas6 as a treatment modality, in addition to the study of mechanisms by which rhGas6 exerts this effect. Conventional prognostic markers of breast cancer, such as age, tumor-node-metastasis stage, and hormone receptor status are lacking in their ability to predict the recurrence or diseasespecific death in later periods of the disease, which is one of the greatest problems during the postoperative clinical follow-up. Clinical assays for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 are useful for choosing the best postoperative adjuvant therapy. Thereafter, the difference between these two groups decreases year by year up to 10 years. Therefore, the development of other diagnostic parameters for the risk of death from cancer in later periods.

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