Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.

Metatropic dysplasia is a clinical heterogeneous skeletal dysplasia characterized by short extremities, a short trunk with progressive kyphoscoliosis, and craniofacial abnormalities that include a prominent forehead, midface hypoplasia, and a squared-off jaw. Dominant mutations in the gene encoding TRPV4, a calcium permeable ion channel, were identified all 10 of a series of metatropic dysplasia cases, ranging in severity from mild to perinatal lethal. These data demonstrate that the lethal form of the disorder is dominantly inherited and suggest locus homogeneity in the disease. Electrophysiological studies demonstrated that the mutations activate the channel, indicating that the mechanism of disease may result from increased calcium in chondrocytes. Histological studies in two cases of lethal metatropic dysplasia revealed markedly disrupted endochondral ossification, with reduced numbers of hypertrophic chondrocytes and presence of islands of cartilage within the zone of primary mineralization. These data suggest that altered chondrocyte differentiation in the growth plate leads to the clinical findings in metatropic dysplasia.

Reduced expression of tocopherol-associated protein (TAP/Sec14L2) in human breast cancer.

We show that TAP/Sec14L2 had a high expression in normal/benign breast, prostate, and liver tissues as compared to lung, colon, and kidney. Its expression was downregulated in breast cancer cell lines shown by quantitative-PCR. Further, 57% of 141 human invasive breast carcinomas had no or markedly reduced TAP/Sec14L2 expression by immunohistochemical staining, and the rate increased to 80% in high grade invasive carcinomas (p < .01). This downregulation of TAP/Sec14L2 was also present in ductal carcinoma in situ (DCIS) associated with invasive carcinomas. These findings raise the possibility that TAP/Sec14L2 may serve as a tumor suppressor in breast carcinogenesis.

Fine-needle aspiration of dedifferentiated acinic cell carcinoma: Report of a case with cyto-histological correlation.

Dedifferentiated Acinic Cell Carcinoma (DAcCC) is a rare salivary gland malignancy. It has a high tendency to recur and metastasize and thus has a poor prognosis. So far, to our knowledge, only one case of DAcCC has been reported in the cytology literature. Herein, we describe a second case of DAcCC from a fine-needle aspiration (FNA) along with its subsequent histological correlation.

Dual expression of alpha-tocopherol-associated protein and estrogen receptor in normal/benign human breast luminal cells and the downregulation of alpha-tocopherol-associated protein in estrogen-receptor-positive breast carcinomas.

The hormonal carcinogenesis of breast cancer involves hormone-driven cell proliferation and genetic alterations, including oncogene activation and suppressor gene inactivation. However, the predominant genes involved in these processes are currently unknown. Our previous studies identified a gene, namely alpha-tocopherol-associated protein, which is preferentially expressed in normal/benign breast and prostate tissue, but its expression is downregulated in breast and prostate carcinomas. To further examine its function in hormone-induced carcinogenesis, we examined if there is an association between alpha-tocopherol-associated protein and estrogen-receptor expression in normal/benign breast tissue and in human breast carcinomas. We found that alpha-tocopherol-associated protein is coexpressed with estrogen receptor in the luminal cells of normal/benign breast tissue in a scattered manner by immunohistochemical staining of consecutive tissue sections of 20 cases, whereas alpha-tocopherol-associated protein expression is downregulated in 46% (45 of 98) of estrogen-receptor/progesterone-receptor-positive, so-called luminal type A or B human breast carcinoma. This is similar to the association of alpha-tocopherol-associated protein and androgen receptor expression in normal/benign prostate and prostate carcinomas. In contrast,alpha-tocopherol-associated protein expression is mostly negative in basal, Her2 and triple-negative nonbasal subtypes of high-grade breast carcinomas. These findings are consistent with alpha-tocopherol-associated protein acting as an antiproliferative factor in estrogen-receptor-positive luminal cells in normal/benign breast tissue. alpha-Tocopherol-associated protein downregulation may have triggered hormonal carcinogenesis in at least some of the breast carcinomas, providing further, albeit indirect evidence to support a role for vitamin E in breast cancer prevention.