Myeloperoxidase interacts with endothelial cell-surface cytokeratin 1 and modulates bradykinin production by the plasma Kallikrein-Kinin system. (1/12)

During an inflammatory state, functional myeloperoxidase (MPO) is released into the vessel as a result of intravascular neutrophil degradation. One mechanism of resulting cellular injury involves endothelial internalization of MPO, which causes oxidative damage and impairs endothelial signaling. We report the discovery of a protein that facilitates MPO internalization, cytokeratin 1 (CK1), identified using affinity chromatography and mass spectrometry. CK1 interacts with MPO in vitro, even in the presence of 100% human plasma, thus substantiating biological relevance. Immunofluorescent microscopy confirmed that MPO added to endothelial cells can co-localize with endogenously expressed CK1. CK1 acts as a scaffolding protein for the assembly of the vasoregulatory plasma kallikrein-kinin system; thus we explored whether MPO and high molecular weight kininogen (HK) reside on CK1 together or whether they compete for binding. The data support cooperative binding of MPO and HK on cells such that MPO masked the plasma kallikrein cleavage site on HK, and MPO-generated oxidants caused inactivation of both HK and kallikrein. Collectively, interactions between MPO and the components of the plasma kallikrein-kinin system resulted in decreased bradykinin production. This study identifies CK1 as a facilitator of MPO-mediated vascular responses and thus provides a new paradigm by which MPO affects vasoregulatory systems.  (+info)

Lymphoepithelioma-like hepatocellular carcinoma. (2/12)

Lymphoepithelioma-like carcinomas (LELC) of the liver are rare. Only nine cases have been reported. All of them were considered to be cholangiocarcinoma and the majority were positive for Epstein-Barr virus (EBV) on EBER in situ hybridization. Here we report a case of hepatocellular carcinoma (HCC) mainly composed of LELC. The patient was a 56-year-old man with chronic hepatitis C virus (HCV) infection and cirrhosis. A right-side hepatectomy was performed to remove a 3-cm diameter tumor. Microscopically, the tumor was mainly composed of undifferentiated carcinoma with heavy lymphocytic infiltration, consistent with LELC. The tumor cells of the LELC component were focally positive for HePar 1, CK19 and CK7 and more diffusely positive (50% of tumor cells) for AE1/AE3 on immuno-histochemical study. EBER in situ hybridization was negative. This is the first confirmed case of HCC with an LELC component. In the available literature, all three cases of LELC of the liver that were negative for EBV were associated with chronic viral hepatitis and cirrhosis, suggesting a different carcinogenesis of EBV-positive LELC of the liver.  (+info)

Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/beta-catenin signaling in keratinocytes. (3/12)

The epidermis (containing primarily keratinocytes and melanocytes) overlies the dermis (containing primarily fibroblasts) of human skin. We previously reported that dickkopf 1 (DKK1) secreted by fibroblasts in the dermis elicits the hypopigmented phenotype of palmoplantar skin due to suppression of melanocyte function and growth via the regulation of two important signaling factors, microphthalmia-associated transcription factor (MITF) and beta-catenin. We now report that treatment of keratinocytes with DKK1 increases their proliferation and decreases their uptake of melanin and that treatment of reconstructed skin with DKK1 induces a thicker and less pigmented epidermis. DNA microarray analysis revealed many genes regulated by DKK1, and several with critical expression patterns were validated by reverse transcriptase-polymerase chain reaction and Western blotting. DKK1 induced the expression of keratin 9 and alpha-Kelch-like ECT2 interacting protein (alphaKLEIP) but down-regulated the expression of beta-catenin, glycogen synthase kinase 3beta, protein kinase C, and proteinase-activated receptor-2 (PAR-2), which is consistent with the expression patterns of those proteins in human palmoplantar skin. Treatment of reconstructed skin with DKK1 reproduced the expression patterns of those key proteins observed in palmoplantar skin. These findings further elucidate why human skin is thicker and paler on the palms and soles than on the trunk through topographical and site-specific differences in the secretion of DKK1 by dermal fibroblasts that affects the overlying epidermis.  (+info)

Lentivirus-mediated oncogene introduction into mammary cells in vivo induces tumors. (4/12)

We recently reported the introduction of oncogene-expressing avian retroviruses into somatic mammary cells in mice susceptible to infection by transgenic expression of tva, encoding the receptor for subgroup A avian leukosis-sarcoma virus (ALSV). Because ALSV-based vectors poorly infect nondividing cells, they are inadequate for studying carcinogenesis initiated from nonproliferative cells (e.g., stem cells). Lentivirus pseudotyped with the envelope protein of ALSV infects nondividing TVA-producing cells in culture but has not previously been tested for introducing genes in vivo. Here, we demonstrate that these vectors infected mammary cells in vivo when injected into the mammary ductal lumen of mice expressing tva under the control of the keratin 19 promoter. Furthermore, intraductal injection of this lentiviral vector carrying the polyoma middle T antigen gene induced atypical ductal hyperplasia and ductal carcinoma in situ-like premalignant lesions in 30 days and palpable invasive tumors at a median latency of 3.3 months. Induced tumors were a mixed epithelial/myoepithelial histologic diagnosis, occasionally displayed squamous metaplasia, and were estrogen receptor-negative. This work demonstrates the first use of a lentiviral vector to introduce oncogenes for modeling cancer in mice, and this vector system may be especially suitable for introducing genetic alterations into quiescent cells in vivo.  (+info)

Mutations in the keratin 9 gene in Pakistani families with epidermolytic palmoplantar keratoderma. (5/12)

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mRNA-based skin identification for forensic applications. (6/12)

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Interaction of oral bacteria with gingival epithelial cell multilayers. (7/12)

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The most common mutation of KRT9, c.C487T (p.R163W), in epidermolytic palmoplantar keratoderma in two large Chinese pedigrees. (8/12)

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