No abstract

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes (SGMS1 and 2) encoding human SM synthases 1 and 2. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane (DRM) fraction in which HCV replicates. SGMS1 expression had a correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase (SPT) inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle.

SummaryWe conducted a phase I pharmacokinetic dose escalation study of a recombinant humanized anti-p185 HER2 monoclonal antibody (MKC-454) in 18 patients with metastatic breast cancer refractory to chemotherapy. Three or six patients at each dose level received 1, 2, 4 and 8 mg kg -1 of MKC-454 as 90-min intravenous infusions. The first dose was followed in 3 weeks by nine weekly doses. Target trough serum concentration has been set at 10 µg ml -1 based on in vitro observations. The mean value of minimum trough serum concentrations at each dose level were 3.58 ± 0.63, 6.53 ± 5.26, 40.2 ± 7.12 and 87.9 ± 23.5 µg ml -1 respectively. At 2 mg kg -1 , although minimum trough serum concentrations were lower than the target trough concentration with a wide range of variation, trough concentrations increased and exceeded the target concentration, as administrations were repeated weekly. Finally 2 mg kg -1 was considered to be sufficient to achieve the target trough concentration by the weekly dosing regimen. One patient receiving 1 mg kg -1 had grade 3 fever, one at the 1 mg kg -1 level had severe fatigue defined as grade 3, and one at 8 mg kg -1 had severe bone pain of grade 3. No antibodies against MKC-454 were detected in any patients. Objective tumour responses were observed in two patients; one receiving 4 mg kg -1 had a partial response in lung metastases and the other receiving 8 mg kg -1 had a complete response in soft tissue metastases. These results indicate that MKC-454 is well tolerated and effective in patients with refractory metastatic breast cancers overexpressing the HER2 proto-oncogene. Further evaluation of this agent with 2-4 mg kg -1 weekly intravenous infusion is warranted.

A 14-year-old girl presented at the hospital after discovering an abdominal tumor. CT scan and ultrasonography indicated a hepatic tumor and also revealed the absence of the portal vein. The patient was admitted to excise the hepatic tumor. It was found that the venous blood from the small intestines flowed into the left renal vein and then emptied directly into the inferior vena cava. A tumor extending from the right lobe through the middle portion of the liver was excised. The postoperative course was satisfactory and marked regeneration of the residual hepatic tissue was observed. Also the blood level of ammonia in the superior mesenteric vein was low, approximately 120 micrograms/dl, compared to the normal value of 350 micrograms/dl in the portal vein. This low blood level may indicate the presence of some homeostatic control mechanism.

No abstract