Protein engineered variants of hepatocyte growth factor/scatter factor promote proliferation of primary human hepatocytes and in rodent liver.

BACKGROUND & AIMS: Hepatocyte growth factor/scatter factor (HGF/SF) stimulates hepatocyte DNA synthesis and protects against apoptosis; in vivo it promotes liver regeneration and reduces fibrosis. However, its therapeutic value is limited by its complex domain structure, high cost of production, instability, and poor tissue penetration due to sequestration by heparin sulfate proteoglycans (HSPGs). METHODS: Using protein engineering techniques, we created a full-length form of HGF/SF (called HP21) and a form of the small, naturally occurring HGF/SF fragment, NK1 (called 1K1), which have reduced affinity for HSPG. We characterized the stability and proliferative and anti-apoptotic effects of these variants in primary human hepatocytes and in rodents. RESULTS: Analytical ultracentrifugation showed that 1K1 and NK1 were more stable than the native, full-length protein. All 4 forms of HGF/SF induced similar levels of DNA synthesis in human hepatocytes; 1K1 and NK1 required heparin, an HSPG analogue, for full agonistic activity. All the proteins reduced levels of Fas ligand-mediated apoptosis, reducing the activity of caspase-3/7 and cleavage of poly(adenosine diphosphate-ribose) polymerase. 1K1 was more active than NK1 in rodents; in healthy mice, 1K1 significantly increased hepatocyte DNA synthesis, and in mice receiving carbon tetrachloride, it reduced fibrosis. In rats, after 70% partial hepatectomy, daily administration of 1K1 for 5 days significantly increased liver mass and the bromodeoxyuridine labeling index compared with mice given NK1. CONCLUSIONS: 1K1, an engineered form of the small, naturally occurring HGF/SF fragment NK1, has reduced affinity for HSPG and exerts proliferative and antiapoptotic effects in cultured hepatocytes. In rodents, 1K1 has antifibrotic effects and promotes liver regeneration. The protein has better stability and is easier to produce than HGF/SF and might be developed as a therapeutic for acute and chronic liver disease.

A review of factors predicting perioperative death and early outcome in hepatopancreaticobiliary cancer surgery.

OBJECTIVES: In the context of comparisons of surgical outcomes, risk adjustment is the retrospective adjustment of a provider's or a surgeon's results for case mix and/or hospital volume. It allows accurate, meaningful inter-provider comparison. It is therefore an essential component of any audit and quality improvement process. The aim of this study was to review the literature to identify those factors known to affect prognosis in hepatobiliary and pancreatic cancer surgery. METHODS: PubMed was used to identify studies assessing risk in patients undergoing resection surgery, rather than bypass surgery, for hepatobiliary and pancreatic cancer. RESULTS: In total, 63 and 68 papers, pertaining to 24 609 and 63 654 patients who underwent hepatic or pancreatic resection for malignancy, respectively, were identified. Overall, 22 generic preoperative factors predicting outcome on multivariate analysis, including demographics, blood results, preoperative biliary drainage and co-morbidities, were identified, with tumour characteristics proving disease-specific factors. Operative duration, transfusion, operative extent, vascular resection and additional intra-abdominal procedures were also found to be predictive of early outcome. CONCLUSIONS: The development of a risk adjustment model will allow for the identification of those factors with most influence on early outcome and will thus identify potential targets for preoperative optimization and allow for the development of a multicentre risk prediction model.