DMEK may provide quick visual rehabilitation in the treatment of corneal endothelial disorders by transplantation of an organ-cultured DM transplanted through a clear corneal tunnel incision. DMEK may be a highly accessible procedure to corneal surgeons, because donor DM sheets can be prepared from preserved corneo-scleral rims.

Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis. Among the genes that were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family, because its contribution to hepatocarcinogenesis remains unknown. Moreover, the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA prompted us to clone it from the cDNA library constructed from a human hepatoma cell line, Key words: protein serine-threonine kinases; pre-malignant lesions; hepatocellular carcinoma; RNA interference; apoptosis Hepatocellular carcinoma (HCC) is the 8th highest cause of death among human cancers and is endemic in Asia, Africa and southern Europe. Most cases of HCC arise from persistent chronic infection with human hepatitis B virus (HBV) or hepatitis C virus (HCV). 1 Host responses are presumed to be involved in the development of HCC among patients harboring HBV or HCV, because these viruses lack apparent oncogenes and the infected patients develop HCC after suffering from chronic hepatitis-related pathology. 2,3 Hepatitis virus infection induces the generation of virus antigenspecific cytotoxic T lymphocytes, which have been implicated in both the eradication of viruses and liver injury. 4 Cycles of cytotoxic T lymphocyte-mediated liver cell destruction and regeneration are thought to prepare the mitogenic environment. 4,5 To elucidate the molecular and cellular mechanism of HCC initiation and development, Nakamoto et al. 6 has established a mouse model of HCC by using HBV surface antigen (HBsAg) transgenic mice (HBsTg). In this model, bone marrow cells and splenocytes were obtained from syngeneic wild-type mice, which were immunized with HBsAg and were transplanted into HBsTg mice, which were irradiated beforehand. At 15 months after the transplantation, the transgenic mice developed multiple foci of HCC surrounded by non-malignant areas consisting of hepatocytes with atypical nuclear configuration. 6,7 To obtain the molecular insights on hepatocarcinogenesis, we compared the gene expression pattern between non-tumor portion of this model as a pre-malignant lesion and normal tissues by using a fluorescent differential display (FDD) analysis. We observed that several genes are expressed differentially in this pre-malignant lesion, compared to normal liver tissues. Of interest is that the gene expression of Pim-3, originally identified as depolarization-induced gene in a rat pheochromocytoma cell line,...

No abstract

Acetaminophen (APAP) causes a massive production of intrahepatic tumor necrosis factor alpha (TNF-alpha). However, it still remains elusive regarding the roles of TNF-alpha in APAP-induced liver injury. Hence, we examined pathogenic roles of the TNF-alpha-TNF receptor with a molecular weight of 55 kDa (TNF-Rp55) axis in APAP-induced hepatotoxicity using TNF-Rp55-deficient [TNF-Rp55-knockout (KO)] mice. When wild-type (WT) BALB/c and TNF-Rp55-KO mice were intraperitoneally injected with a lethal dose of APAP (750 mg/kg), the mortality of TNF-Rp55-KO mice was marginally but significantly reduced compared with WT mice. Upon treatment with a nonlethal dose (600 mg/kg), WT mice exhibited an increase in serum transaminase levels. Histopathologically, centrilobular hepatic necrosis with leukocyte infiltration was evident at 10 and 24 h after APAP challenge. Moreover, mRNA expression of adhesion molecules, several chemokines, interferon-gamma (IFN-gamma), and inducible nitric oxide synthase (iNOS) was enhanced in the liver. On the contrary, serum transaminase elevation and histopathological changes were attenuated in TNF-Rp55-KO mice injected with APAP (600 mg/kg). The gene expression of all molecules except for IFN-gamma and iNOS was significantly attenuated in TNF-Rp55-KO mice. Moreover, anti-TNF-alpha neutralizing antibodies alleviated liver injury when administered at 2 or 8 h after but not at 1 h before APAP challenge to WT mice. Collectively, the TNF-alpha-TNF-Rp55 axis has pathogenic roles in APAP-induced liver failure.

Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.DOI: http://dx.doi.org/10.7554/eLife.21032.001