New Insight into Intrachromosomal Deletions Induced by Chrysotile in the gpt delta Transgenic Mutation Assay

BACKGROUND: Genotoxicity is often a prerequisite to the development of malignancy. Considerable evidence has shown that exposure to asbestos fibers results in the generation of chromosomal aberrations and multilocus mutations using various in vitro approaches. However, there is less evidence to demonstrate the contribution of deletions to the mutagenicity of asbestos fibers in vivo. OBJECTIVES: In the present study, we investigated the mutant fractions and the patterns induced by chrysotile fibers in gpt delta transgenic mouse primary embryo fibroblasts (MEFs) and compared the results obtained with hydrogen peroxide (H(2)O(2)) in an attempt to illustrate the role of oxyradicals in fiber mutagenesis. RESULTS: Chrysotile fibers induced a dose-dependent increase in mutation yield at the redBA/gam loci in transgenic MEF cells. The number of λ mutants losing both redBA and gam loci induced by chrysotiles at a dose of 1 μg/cm(2) increased by > 5-fold relative to nontreated controls (p < 0.005). Mutation spectra analyses showed that the ratio of λ mutants losing the redBA/gam region induced by chrysotiles was similar to those induced by equitoxic doses of H(2)O(2). Moreover, treatment with catalase abrogated the accumulation of γ-H2AX, a biomarker of DNA double-strand breaks, induced by chrysotile fibers. CONCLUSIONS: Our results provide novel information on the frequencies and types of mutations induced by asbestos fibers in the gpt delta transgenic mouse mutagenic assay, which shows great promise for evaluating fiber/particle mutagenicity in vivo

Utility of Ki67 labeling index, cyclin D1 expression, and ER-activity level in postmenopausal ER-positive and HER2-negative breast cancer with neoadjuvant chemo-endocrine therapy.

In this study, we investigated the relationships of pathological response after neoadjuvant chemo-endocrine therapy with alterations in the Ki67 labeling index (LI), expression of cyclin D1 (CCND1) and progesterone receptor (PgR), and estrogen receptor (ER) activity in breast cancer. A total of 43 Japanese post-menopausal ER-positive and human epidermal growth factor receptor 2-negative invasive breast cancer patients with tumors >2 cm or positive lymph nodes were enrolled. Exemestane alone was administered for 2 months. Neoadjuvant chemo-endocrine therapy included four cycles of doxorubicin plus paclitaxel followed by weekly paclitaxel. The immunohistochemical expression of Ki67 LI, CCND1, and PgR, and ER activity were evaluated using core needle biopsy samples at the pretreatment and post-exemestane alone stages. ER activity was evaluated through transfection of an adenovirus vector carrying an estrogen-response element-green fluorescent protein gene. In current study, marked pathological responses (including 4.7% with pathological complete response) were obtained in 34.9% of patients. Ki67 LI and PgR expression were significantly decreased after treatment. High Ki67 LI at pretreatment was a significant predictive factor of marked pathological response. At the stage of post-exemestane alone, Ki67 LI was not significantly associated with pathological response; however, high CCND1 expression was significantly correlated with high Ki67 LI. Moreover, low-level ER activity at the post-exemestane alone stage was significantly associated with marked pathological response. In conclusions, pretreatment Ki67 LI was a predictor of response to neoadjuvant chemo-endocrine therapy. CCND1 expression and ER activity at the post-endocrine therapy alone stage may be useful in determining further treatments

Heterotopic ossification in primary rectal cancer with squamous cell carcinoma-like differentiation

OBJECTIVES: Heterotopic ossification (HO), which occurs when bone tissue forms outside the skeleton, is extremely rare in rectal cancer. Adenocarcinoma is the histological type of all reported primary colorectal cancers with HO. However, in the present case, we observed areas of adenocarcinoma with squamous cell carcinoma-like differentiation. Here we conducted histopathological and immunohistochemical analyses to identify the mechanisms of HO development, to differentiate between adenocarcinoma and squamous cell carcinoma-like phenotypes, and to understand the associated prognostic implications. CASE REPORT: A 62-year-old woman was admitted to our hospital with symptoms of intermittent hematochezia without abdominal pain. Colonoscopy revealed stenosis with a protuberant mass in the rectum. Abdominopelvic contrast-enhanced computed tomography showed irregular wall thickness of the rectum, multiple lymph node metastases, and liver metastases. The rectal tumor exhibited calcified deposits with marked hyperintensity. We then performed Hartmann’s operation and D3 lymph node resection. The biopsy specimen revealed tubular and solid adenocarcinoma nests and squamous carcinoma-like components over a necrotic extent without secreted mucin. She received chemotherapy (mFOLFOX6 with bevacizumab) as the first option and is alive 5 months after surgery. CONCLUSION: To the best of our knowledge, this is the first case of heterotopic ossification in a primary rectal cancer with squamous cell carcinoma-like differentiation that was surgically resected. This case suggests that BMP-2 transformed fibroblasts and pluripotent stem cells into osteocytes. We conclude that the squamous cell carcinoma-like lesion was squamous metaplasia of adenocarcinoma