Liver cancers, the majority of which are hepatocellular carcinomas (HCCs), rank as the fourth in cancer mortality worldwide and are the most rapidly increasing type of cancer in the United States. However, the molecular mechanisms underlying HCC development are not well understood. Activation of the hedgehog pathway is shown to be involved in several types of gastrointestinal cancers. Here, we provide evidence to indicate that hedgehog signaling activation occurs frequently in HCC. We detect expression of Shh, PTCH1 and Gli1 in 115 cases of HCC and in 44 liver tissues adjacent to the tumor. Expression of Shh is detectable in about 60% of HCCs examined. Consistent with this, hedgehog target genes PTCH1 and Gli1 are expressed in over 50% of the tumors, suggesting that the hedgehog pathway is frequently activated in HCCs. Of five cell lines screened, we found Hep3B, Huh7 and PLC/PRF/5 cells with detectable hedgehog target genes. Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis. In contrast, no effects are observed after these treatments in HCC36 and HepG2 cells, which do not have detectable hedgehog signaling. Thus, our data indicate that hedgehog signaling activation is an important event for development of human HCCs.

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Solid pseudopapillary tumor of pancreas (SPT) is a rare neoplasm that occurs most often in young females with the two distinct features, the 'solid-cystic' gross appearance, and the 'solid-pseudopapillary' microscopic pattern. It has been reported that almost all SPT tumors contain a mutation in the b-catenin gene; however, the histogenetic origin of this tumor remains largely a mystery. E-cadherin is a cell adhesion molecule that links to catenins to form cell adhesion junctions, which is associated with the cytoskeleton formation. In this study, we examined the expression of E-cadherin and b-catenin from SPT in an attempt to determine the molecular basis for the unusual morphology of this tumor. Nine cases of SPT were retrieved from Surgical Pathologic Archives of three institutions, including one male and eight females. H&E slides of each case were reviewed to confirm the diagnosis. The b-catenin gene was sequenced in one case. E-cadherin and b-catenin immunostains, were performed on all nine cases. Sequencing analysis on one case showed a point mutation of the b-catenin gene, confirming previous findings that almost all SPT tumors contain mutation in the b-catenin gene. Immunostains showed that, in both solid and pseudopapillary areas, all the tumor cells lost expression of E-cadherin, and bcatenin nuclear expression was observed in all cases. Our findings suggest that loss of cytoplasmic b-catenin protein in the cell adhesion complex due to b-catenin gene mutation, results in instability of the complex, loss of E-cadherin in cell membrane, and eventually dissociation of the tumor cells to form the pseudopapillary pattern. Modern Pathology (2007) 20, 509-513.

The detection of VZV DNA in the serum and peripheral blood mononuclear cells of all 25 zoster patients documents that viremia is a common manifestation of herpes zoster. Sorivudine cream appears to be a safe and well-tolerated adjuvant therapy; however, further phase 2 studies are needed to determine its clinical efficacy for the treatment of herpes zoster. Trials registration. ClinicalTrials.gov identifier: NCT00652184.

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