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Abstract David D. Derse, Ph.D., Head of the Retrovirus Gene Expression Section in the HIV Drug Resistance Program at the National Cancer Institute-Frederick (NCI-Frederick), passed away on October 9, 2009, a scant six weeks after being diagnosed with liver cancer. It was with great sadness that family, friends, and colleagues gathered together for his memorial service on Saturday, October 17, 2009, at the Middletown United Methodist Church in Maryland. As a NCI scientist since 1986, Dave studied the molecular mechanisms of infection and replication of a number of different types of retroviruses. Dave became an internationally known expert on human T cell lymphotrophic viruses type 1 and 2 (HTLV-1 and HTLV-2) and served on the editorial boards of Virology and Retrovirology. His most recent studies focused on the mechanisms of HTLV-1 virion morphogenesis, transmission, and replication.

Presents abstracts related to leukemia. 'Activation of Cyclin Dependent Kinases and Overexpression of an Anti-Apoptotic Chemokine in HTLV-Infected Lymphocytes,' by Ralph Grassmann, Tobias Ruckes, Iris Schmitt, Domenica Saul, Elisabeth Derow and Kerstin Haller; 'Tax Expressing Cells Display an Impaired DNA-Damage Response,' by Abdelali Haoudi, Molly Burton, Tony Nguyen and O. John Semmes.

Background: Hepatic oval cells proliferate to replace hepatocytes and restore liver function when hepatocyte proliferation is compromised or inadequate. Exposure to chemical carcinogens, severe liver steatosis, and partial hepatectomy has been used in animal models to demonstrate the role of oval cells in liver regeneration. Ischemia-reperfusion injury (IRI) causes hepatocellular damage and death in the absence of confounding chemical toxicity; however, oval cell induction by IRI has not been demonstrated in vivo. We examine oval cell induction following partial IRI., Methods: Wistar rats were subjected to 2 IRI protocols: 70% warm liver ischemia for 30 minutes followed by reperfusion or 70% warm liver ischemia for 30 minutes with partial hepatectomy of the nonischemic lobes followed by reperfusion. Liver injury was monitored by serum alanine aminotransferase (ALT) at 1 day and 7 days of reperfusion. Oval cell proliferation was monitored by indirect immunofluorescence staining using the surface markers BD.2 and Thy-1. Cellular proliferation was quantified by 5-ethynyl-2'-deoxyuridine (EdU) incorporation in vivo., Results: Serum ALT elevation was only observed at the 1-day time point in the IRI with partial hepatectomy model. Oval cell marker expression was restricted to the biliary structures in both the ischemic and the nonischemic control lobes. Oval cell induction, measured by changes in the frequency of BD.2 and Thy-1 expression and EdU incorporation, was not significantly altered by IRI., Conclusion: In both mild and moderate IRI models, we did not find evidence of oval cell induction or proliferation. EdU staining was restricted to hepatocytes, suggesting that liver regeneration following IRI is mediated by hepatocyte proliferation.

Background: Tumor necrosis factor-α (TNF-α) is a potent proinflammatory cytokine involved in a variety of disease pathologies, including ischemia/reperfusion (I/R) injuries in transplantation. The interaction of TNF-α with its cognate receptor TNF receptor I (TNFRI) results in the activation of signal transduction pathways that regulate either cell survival or cell death. Hepatocytes express TNFRI and respond to TNF-α released by resident Kupffer cells as well as leukocytes that migrate to the liver during I/R injury. Upon binding TNF-α, the hepatocyte proliferates or undergoes apoptosis or necroptosis. The decision by the cell to commit to one path or the other is not understood. The damaged tissue exhibits cell death and hemorrhaging from the influx of immune mediators. TNF-α inhibitors ameliorate the injury in animal models, suggesting that lowering (but not eliminating) TNF-α levels shifts the balance of TNF-α toward its beneficial functions., Methods: We review TNF-α signal transduction pathways and the role of TNF-α in liver I/R injury., Conclusions: Because TNF-α plays an important role in hepatocyte proliferation, complete inhibition of TNF-α is not desirable in treating liver I/R injury. The strategy for developing pharmacological therapies may be the identification of specific intermediates in the TNF-α/TNFR1 signal transduction pathway and directed targeting of proapoptotic and pronecroptotic events.