Activated growth factor receptor tyrosine kinases (RTK) play pivotal roles in a variety of human cancers, including breast cancer. Ron, a member of the Met RTK proto-oncogene family, is overexpressed or constitutively active in 50% of human breast cancers. To define the significance of Ron overexpression and activation in vivo, we generated transgenic mice that overexpress a wild-type or constitutively active Ron receptor in the mammary epithelium. In these animals, Ron expression is significantly elevated in mammary glands and leads to a hyperplastic phenotype by 12 weeks of age. Ron overexpression is sufficient to induce mammary transformation in all transgenic animals and is associated with a high degree of metastasis, with metastatic foci detected in liver and lungs of >86% of all transgenic animals. Furthermore, we show that Ron overexpression leads to receptor phosphorylation and is associated with elevated levels of tyrosine phosphorylated B-catenin and the up-regulation of genes, including cyclin D1 and c-myc, which are associated with poor prognosis in patients with human breast cancers. These studies suggest that Ron overexpression may be a causative factor in breast tumorigenesis and provides a model to dissect the mechanism by which the Ron induces transformation and metastasis.

In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Previous studies demonstrated that targeted deletion of the Ron receptor tyrosine kinase (TK) domain in mice leads to marked hepatocyte protection in a well-characterized model of lipopolysaccharide (LPS)-induced acute liver failure in D-galactosamine (GalN)-sensitized mice. Hepatocyte protection in TK2/2 mice was observed despite paradoxically elevated serum levels of tumor necrosis factor alpha (TNF-a). To understand the role of Ron in the liver, purified populations of Kupffer cells and hepatocytes from wildtype (TK1/1) and TK2/2 mice were studied. Utilizing quantitative reverse-transcription polymerase chain reaction (RT-PCR), we demonstrated that Ron is expressed in these cell types. Moreover, we also recapitulated the protected hepatocyte phenotype and exaggerated cytokine production observed in the TK2/2 mice in vivo through the use of purified cultured cells ex vivo. We show that isolated TK2/2 Kupffer cells produce increased levels of TNF-a and select cytokines compared to TK1/1 cells following LPS stimulation. We also show that conditioned media from LPS-treated TK2/2 Kupffer cells was more toxic to hepatocytes than control media, suggesting the exaggerated levels of cytokines produced from the TK2/2 Kupffer cells are detrimental to wildtype hepatocytes. In addition, we observed that TK2/2 hepatocytes were more resistant to cell death compared to TK1/1 hepatocytes, suggesting that Ron functions in both the epithelial and inflammatory cell compartments to regulate acute liver injury. These findings were confirmed in vivo in mice with hepatocyte and macrophage cell-type-specific conditional Ron deletions. Mice with Ron loss selectively in hepatocytes exhibited less liver damage and increased survival compared to mice with Ron loss in macrophages. Conclusion: We dissected cell-type-specific roles for Ron such that this receptor modulates cytokine production from Kupffer cells and inhibits hepatocyte survival in response to injury. (HEPATOLOGY 2011;53:1618-1628

SummaryThe Ron receptor tyrosine kinase has been increasingly recognized for its tumorigenic potential in the last decade. Ron receptor activation leads to the activation of common receptor tyrosine kinase downstream signaling pathways, and most prominently in tumor models, activation of MAPK, PI3K and β-catenin. Numerous experimental models of mammalian tumorigenesis have demonstrated that increased Ron receptor activity correlates with increased tumorigenesis in a variety of organs of epithelial origin. The evidence for Ron as an oncogene in human tumor biology is growing. The Ron receptor is overexpressed and over-activated in a large number of human tumors, and overexpression of Ron correlates with a worse clinical outcome for patients in at least two human cancer states, namely breast and bladder cancer. Several experimental approaches have been taken to successfully block Ron activity and function, and given this convincing data, approaches to block Ron receptor activity in targeted human cancers should prove to be fruitful in the setting of future clinical research trials.

p ‐ tert ‐Butylcalix[6]arene reactant: p ‐ tert ‐Butylphenol from Aldrich Chemical Company, Inc. product: p ‐ tert ‐Butylcalix[6]arene

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T he Ron receptor tyrosine kinase (TK), also known as stem cell-derived TK, is a heterodimeric single-span transmembrane glycoprotein involved in a wide range of biologic processes, including modulation of inflammatory responses. [1][2][3][4] The intracellular signaling responses of Ron and its only known ligand, the kringle-containing hepatocyte growth factor-like protein, also known as macrophage-stimulating protein, have been studied largely in vitro in resident peritoneal macrophages. To explore the role of the Ron receptor in vivo, our laboratory generated mice with the deletion of the TK domain of the Ron receptor (Ron TK Ϫ/Ϫ mice). 1 Ron TK Ϫ/Ϫ mice have no overt phenotypic abnormalities; however, the responses of Ron TK Ϫ/Ϫ and other Ron receptor mutant mice in several experimental murine models of inflammation, including injection of endotoxin, are markedly exaggerated compared with Ron TK ϩ/ϩ mice. 1,2,5 Very little is known about the biology of the Ron receptor in the liver, either in vitro or in vivo. Ron messenger RNA and protein have been detected in liver tissue, 6,7 and Ron protein has been localized by immunohistochemistry to the hepatocyte and Kupffer cell populations. 8 Given the observations previously noted with Ron TK Ϫ/Ϫ mice, we hypothesized that mice lacking functional Ron receptor would have exaggerated responses in experimental murine models of lipopolysaccharide (LPS)-and Kupffer cell-mediated liver injury.We tested our hypothesis using a well-characterized LPS-induced murine model of acute liver failure (ALF) in galactosamine (GalN)-sensitized mice. 9-11 LPS-induced

Objective Hepatic encephalopathy (HE) is challenging to identify in children with acute liver failure (ALF), and was not a requirement for enrollment into the Pediatric ALF Study Group (PALFSG). The outcomes of PALFSG participants presenting with and without HE are presented. Methods PALFSG participants were classified based on daily assessment of HE during the first 7 days following study enrollment: Group1 - never developed HE; Group2 - no HE at enrollment with subsequent HE development; and Group 3 - HE at study enrollment. Clinical and biochemical parameters and outcomes of death, spontaneous recovery (SR), or liver transplantation (LT) were compared between groups. Results Data from 769PALFSG (54% male; median age 4.2 years; range 0–17.9 years) participants were analyzed, with 277 in Group 1 (36%), 83 in Group 2 (11%) and 409 in Group 3 (53%). Mortality occurred in 11% of all participants and was highest among Group 3 participants who demonstrated persistent grade III–IV HE (55%) or showed progression of HE (26%). Eleven (4%) Group 1 participants died within 21 days of enrollment. SR was highest in Group 1 (79%) and lowest in Group 2 (25%; p<.001). Conclusion Mortality21 days following enrollment was highest in participants enrolled with severe HE (grades III or IV) or demonstrating HE progression. However, 4% of participants without recorded clinical HE in the 7 days following enrollment died within 21 days. Improved assessment of neurological injury and PALF prognostication schema are needed.