Cerium oxide nanoparticles are potent antioxidants, based on their ability to either donate or receive electrons as they alternate between the +3 and +4 valence states. The dual oxidation state of ceria has made it an ideal catalyst in industrial applications, and more recently, nanoceria's efficacy in neutralizing biologically generated free radicals has been explored in biological applications. Here, we report the in vivo characteristics of custom-synthesized cerium oxide nanoparticles (CeNPs) in an animal model of immunological and free-radical mediated oxidative injury leading to neurodegenerative disease. The CeNPs are 2.9 nm in diameter, monodispersed and have a -23.5 mV zeta potential when stabilized with citrate/EDTA. This stabilizer coating resists being 'washed' off in physiological salt solutions, and the CeNPs remain monodispersed for long durations in high ionic strength saline. The plasma half-life of the CeNPs is ∼4.0 h, far longer than previously described, stabilized ceria nanoparticles. When administered intravenously to mice, the CeNPs were well tolerated and taken up by the liver and spleen much less than previous nanoceria formulations. The CeNPs were also able to penetrate the brain, reduce reactive oxygen species levels, and alleviate clinical symptoms and motor deficits in mice with a murine model of multiple sclerosis. Thus, CeNPs may be useful in mitigating tissue damage arising from free radical accumulation in biological systems.

Purpose: Gastrointestinal stromal tumors (GIST) are characterized by expressing a gainof-function mutation in KIT, and to a lesser extent, PDGFR. Imatinib mesylate, a tyrosine kinase inhibitor, has activity against GISTs that contain oncogenic mutations of KIT. In this study, KIT and PDGFRa mutation status was analyzed and protein modeling approaches were used to assess the potential effect of KIT mutations in response to imatinib therapy. Experimental Design: Genomic DNA was isolated from GIST tumors. Exons 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRa were evaluated for oncogenic mutations. Protein modeling was used to assess mutations within the juxtamembrane region and the kinase domain of KIT. Results: Mutations in KITexons 9,11, and 13 were identified in GISTs with the majority of changes involving the juxtamembrane region of KIT. Molecular modeling indicates that mutations in this region result in disruption of the KITautoinhibited conformation, and lead to gain-of-function activation of the kinase. Furthermore, a novel germ-line mutation in KIT was identified that is associated with an autosomal dominant predisposition to the development of GIST. Conclusions: We have used protein modeling and structural analyses to elucidate why patients with GIST tumors containing exon11mutations are the most responsive to imatinib mesylate treatment. Importantly, mutations detected in this exon and others displayed constitutive activation of KIT. Furthermore, we have found tumors that are both KITand PDGFRa mutation negative, suggesting that additional, yet unidentified, abnormalities may contribute to GIST tumorigenesis.

Background. Mammography has led to earlier detection of subclinical ductal carcinoma in situ (DCIS) of the breast either as nonpalpable calcifications or as an incidental finding in a biopsy performed for another reason. Many women in whom DCIS was detected early may not be destined to have an invasive carcinoma. How should subclinical DCIS be treated if that is the case? What is the role of excision and surveillance only as an alternative to mastectomy or irradiation?. Methods. All patients with DCIS detected as non‐palpable calcifications or as an incidental finding were eligible for this study. Diagnosis was confirmed, and the histologic subtype was determined. Results of postbiopsy mammography confirmed excision of calcifications; wide local reexcision and assessment of margins was also performed in most patients. The maximum diameter of calcifications considered suitable for this treatment was 25 mm. Results. Between 1978 and 1990, 70 women (72 breasts) were entered into this study (mean follow‐up time, 49 months; median follow‐up time, 47 months). Of this group, 66% were detected as calcifications and 33% were detected as incidental findings. The recurrence rate was 15.3%. All but one of the patients who experienced a recurrence had the comedo type of DCIS as the initial lesion. Each of the recurrences was of the comedo type. All but one recurrence was at the same site as the primary lesion. None of the patients with DCIS as an incidental finding experienced a recurrence. Conclusions. Excision and surveillance is a reasonable alternative to mastectomy or irradiation for selected women with DCIS that presents as nonpalpable calcifications or as an incidental finding.

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