Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism.

Small heat shock proteins (sHsps) are molecular chaperones that protect cells from cytotoxic effects of protein misfolding and aggregation. HspB1, an sHsp commonly associated with senile plaques in Alzheimer's disease (AD), prevents the toxic effects of Aß aggregates in vitro. However, the mechanism of this chaperone activity is poorly understood. Here, we observed that in two distinct transgenic mouse models of AD, mouse HspB1 (Hsp25) localized to the penumbral areas of plaques. We have demonstrated that substoichiometric amounts of human HspB1 (Hsp27) abolish the toxicity of Aß oligomers on N2a (mouse neuroblastoma) cells. Using biochemical methods, spectroscopy, light scattering, and microscopy methods, we found that HspB1 sequesters toxic Aß oligomers and converts them into large nontoxic aggregates. HspB1 was overexpressed in N2a cells in response to treatment with Aß oligomers. Cultured neurons from HspB1-deficient mice were more sensitive to oligomer-mediated toxicity than were those from wild-type mice. Our results suggest that sequestration of oligomers by HspB1 constitutes a novel cytoprotective mechanism of proteostasis. Whether chaperone-mediated cytoprotective sequestration of toxic aggregates may bear clues to plaque deposition and may have potential therapeutic implications must be investigated in the future.

Primary surgery for oropharyngeal cancer.

OBJECTIVE: The development of new techniques for transoral resection has led to a renewed interest in primary surgical treatment of oropharyngeal squamous cell cancer (SCCA). We reviewed our experience with primary surgery for oropharyngeal SCCA to identify factors associated with survival. STUDY DESIGN: Case series with chart review. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Patients who underwent primary surgical treatment of oropharyngeal SCCA from 1985 to 2002 were analyzed. Patients who failed nonoperative treatment or had distant metastases at presentation were excluded. RESULTS: A total of 105 patients met study criteria. The majority of patients (91%) had advanced stage disease (III/IV). All patients received postoperative radiation; chemotherapy was used in eight patients. Five-year disease-free survival was 83 percent for stage I, 67 percent for stage II, 56 percent for stage III, and 43 percent for stage IV disease. Crude local control rates were 94 percent for T1 disease, 90 percent for T2 disease, 81 percent for T3 disease, and 80 percent for T4 disease; crude regional control rates were 100 percent for N0 disease, 90 percent for N1 disease, 84 percent for N2 disease, and 82 percent for N3 disease. Cox proportional hazards models revealed that nodal stage (hazard ratio [HR] 2.3, P = 0.02) and black race (HR 2.6, P = 0.004) were the only significant predictors of disease-free survival. CONCLUSION: Primary surgical treatment of oropharyngeal SCCA is effective in achieving excellent locoregional control and permits deintensification of adjuvant therapy, even in patients with advanced stage disease. Nodal status and race are the primary determinants of disease-free survival. These data provide useful information for counseling and treatment planning.