To identify critical events associated with heat-induced cell killing, we examined foci formation of ␥H2AX (histone H2AX phosphorylated at serine 139) in heat-treated cells. This assay is known to be quite sensitive and a specific indicator for the presence of double-strand breaks. We found that the number of ␥H2AX foci increased rapidly and reached a maximum 30 minutes after heat treatment, as well as after X-ray irradiation. When cells were heated at 41.5°C to 45.5°C, we observed a linear increase with time in the number of ␥H2AX foci. An inflection point at 42.5°C and the thermal activation energies above and below the inflection point were almost the same for cell killing and foci formation according to Arrhenius plot analysis. From these results, it is suggested that the number of ␥H2AX foci is correlated with the temperature dependence of cell killing. During periods when cells were exposed to heat, the cell cycledependent pattern of cell killing was the same as the cell cycle pattern of ␥H2AX foci formation. We also found that thermotolerance was due to a depression in the number of ␥H2AX foci formed after heating when the cells were pre-treated by heat. These findings suggest that cell killing might be associated with double-strand break formation via protein denaturation.
Background and Objectives Some patients with early‐stage oral cancer have a poor prognosis owing to the delayed neck metastasis (DNM). Tumor budding is reportedly a promising prognostic marker in many cancers. Moreover, the tissue surrounding a tumor is also considered to play a prognostic role. In this study, we evaluated whether tumor budding and adjacent tissue at the invasive front can be potential novel predictors of DNM in early tongue cancer. Methods In total, 337 patients with early‐stage tongue squamous cell carcinoma were retrospectively reviewed. The patient characteristics and histopathological factors were evaluated for association with DNM. DNM rates were calculated; items which were significant in the univariate analysis were used as explanatory variables, and independent factors for DNM were identified by the multivariate analysis. Results The univariate analysis identified T classification, depth of invasion, tumor budding, vascular invasion, and adjacent tissue at the invasive front as significant predictors of DNM; the multivariate analysis using these factors revealed all the above variables except vascular invasion, which are independent predictors of DNM. Conclusion In addition to conventional predictors, high grade tumor budding and adjacent tissue at the invasive front can serve as useful predictors of DNM in early tongue cancer.
A multi‐institutional study was undertaken to determine whether mandibular canal (MC) invasion and mandibular medullary bone invasion are independent factors in lower gingival squamous cell carcinoma (SCC). A total of 345 patients with lower gingival SCC were retrospectively reviewed. Mandibular bone invasion was categorized into three types; no bone invasion; invasion through cortical bone (medullary); and MC invasion. The overall survival rate and factors affecting local, regional, and distant failures were assessed by Cox proportional hazards regression analysis and Kaplan–Meier estimates. Bone invasion was present in 201 (58%) patients, of whom 107 (31%) had medullary invasion and 94 (27%) had MC invasion. Using the International Union Against Cancer (UICC) staging system and American Joint Committee on Cancer (AJCC) system, 171 (50%) patients were classified as T4a. When the bone invasion criteria were excluded from the UICC/AJCC system definition, 152 T4a tumors were downstaged and reclassified to T1 in 12 (3%), to T2 in 98 (28%), and to T3 in 42 (12%). In Cox multivariate analysis, MC invasion was an independent predictor of overall survival but medullary bone invasion was not. Medullary bone invasion was an independent variable for distant control. The current T staging system has restricted prognostic utility. The authors recommend a modified T staging system, whereby tumors with MC invasion instead of medullary bone invasion are classified as T4a, and tumors are first classified as T1 to T3 based on size and then upstaged by one T classification in the presence of medullary invasion.
Conventional clinical treatments with X-rays provide an effective modality for widely various human cancers, however, therapeutic results are sometimes poor. Many mutations have been reported to be in the p53 gene in advanced human cancers. The p53 plays a pivotal role in the pathway which controls apoptosis, cell growth and cell proliferation, and mutations or deletions in the p53 gene lead to resistance to cancer therapy. The involvement of the p53 gene in determining the sensitivity of many cell types toward low linear energy transfer (LET) radiation is now well established. In contrast to low LET radiation, high LET radiation has several potential advantages over X-rays, one of which is the fact that its effects may be independent of cellular p53 gene status. It is conceivable that effective future therapeutic strategies may be designed on the basis of genetic and biochemical events involved in cell death. Therefore, the accurate characterization and quantification of the mode of cell death, such as apoptosis and necrosis, has become increasingly important for the further understanding of the biological effectiveness of high LET radiation. This review discusses the mechanisms of p53-independent apoptosis by high LET radiation.
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