Sung W. Cho

High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity

The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1.

Transcatheter Arterial Chemoembolization Is a Feasible Palliative Locoregional Therapy for Breast Cancer Liver Metastases

Background. Liver metastases are common in advanced breast cancer. We sought to evaluate the role of transcatheter arterial chemoembolization (TACE) in breast cancer patients with hepatic metastases. Methods. A retrospective review of ten patients with breast cancer who were treated with TACE for unresectable liver metastases (1998–2008). Results. All patients, median age 46.5, had received prior systemic chemotherapies. Adriamycin was administered for 6, cisplatin/gemcitabine for 2, cisplatin for one and oxaliplatin for one patient. Median number of TACE cycles was 4. Kaplan Meier survival analysis showed an increase in median survival for patients who responded to treatment when compared to those who did not respond (24 vs 7 months, P = .02). Conclusions. This is one of the largest series of breast cancer patients with liver metastases treated with TACE. It suggests that TACE is a feasible palliative option and warrants further investigations.