p38 MAPK mediates gamma-irradiation-induced endothelial cell apoptosis, and vascular endothelial growth factor protects endothelial cells through the phosphoinositide 3-kinase-Akt-Bcl-2 pathway.

Therapeutic radiation is widely used in cancer treatments. The success of radiation therapy depends not only on the radiosensitivity of tumor cells but also on the radiosensitivity of endothelial cells lining the tumor vasculature. Vascular endothelial growth factor (VEGF) plays a critical role in protecting endothelial cells against a number of antitumor agents including ionizing radiation. Strategies designed to overcome the survival advantage afforded to endothelial cells by VEGF might aid in enhancing the efficacy of radiation therapy. In this report we examined the signaling cascade(s) involved in VEGF-mediated protection of endothelial cells against gamma-irradiation. gamma-Irradiation-induced apoptosis of human dermal microvascular endothelial cells (HDMECs) was predominantly mediated through the p38 MAPK pathway as an inhibitor of p38 MAPK (PD169316), and dominant negative mutants of p38 MAPK could significantly enhance HDMEC survival against gamma-irradiation. Inhibition of the PI3K and MAPK pathways markedly up-regulated gamma-irradiation-mediated p38 MAPK activation resulting in enhanced HDMEC apoptosis. In contrast, VEGF-treated HDMECs were protected from gamma-irradiation-induced apoptosis predominantly through the PI3K/Akt pathway. Bcl-2 expression was markedly elevated in VEGF-treated HDMECs, and it was significantly inhibited by the PI3K inhibitor LY294002. HDMECs exposed to irradiation showed a significant decrease in Bcl-2 expression. In contrast, VEGF-stimulated HDMECs, when irradiated, maintained higher levels of Bcl-2 expression. Taken together our results suggest that gamma-irradiation induces endothelial cell apoptosis predominantly via the activation of p38 MAPK, and VEGF protects endothelial cells against gamma-irradiation predominantly via the PI3K-Akt-Bcl-2 signaling pathway.

Spectrum of disease in U.S. veteran patients with hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV) infection is more prevalent in U.S. veterans attending Veterans Affairs Medical Centers than in the general population. The purpose of this study was to examine the risk factors, psychiatric and substance abuse conditions, and severity of liver disease in veterans with HCV. METHODS: The medical records and liver biopsies of 206 consecutive patients with HCV attending a multidisciplinary medical/psychiatric chronic hepatitis clinic and who met eligibility criteria for interferon alpha-2b therapy were reviewed. RESULTS: The mean age was 46.5+/-6.8 yr and 77% were Vietnam-era veterans. Risk factors included i.v. drug use (64%), blood transfusion (15%), and cocaine use (9%), and were unknown in 12%. The average estimated duration of disease was 24+/-7.6 yr. A history of alcohol abuse or dependence was identified in 80% of patients. Psychiatric illnesses were present in 60%, the most common being depression and posttraumatic stress disorder. Overall, 89% of patients had documented psychiatric and/or substance abuse diagnoses. Severe fibrosis (stages 3-4) was present in 32% and severe inflammation (grades 2-3) was present in 71% of biopsies. Psychiatric and substance abuse diagnoses did not correlate with severity of liver disease. A total of 145 patients (71%) were prescribed interferon-based treatment. The overall virological sustained response rates were 16% after interferon monotherapy and 28% after interferon/ribavirin therapy. Reasons for not receiving interferon therapy included minimal fibrosis on liver biopsy (37 patients [18%]), worsening medical conditions (nine [4%]), and worsening psychiatric and substance abuse problems (14 [7%]). CONCLUSIONS: Advanced fibrosis is common in this cohort of veteran patients with chronic hepatitis C, and the overwhelming majority of these patients have psychiatric and/or substance abuse diagnoses. Despite these comorbidities, the majority received interferon therapies in the context of a multidisciplinary clinic. These data emphasize the importance of hepatitis C care that includes linkage of medical care and psychiatric services.