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  • Author: Daniel Kaufmann x
  • Life Sciences x
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Abstract

The histone variant 2AX (H2AX) is phosphorylated at Serine 139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress, such as tumor radio- and chemotherapy, is considered to be the main inducer of phosphorylated H2AX (γH2AX), which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γH2AX accumulation under severe hypoxic/anoxic (0.02% oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF-dependent accumulation of γH2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2% oxygen), which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of γH2AX was delayed by the RNAi-mediated knockdown of HIF-1α or HIF-2α and further decreased when both HIF-αs were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2α. These results suggest that both HIF-1 and HIF-2 are involved in γH2AX accumulation by tumor hypoxia, which might increase a cancer cell’s capacity to repair DNA damage, contributing to tumor therapy resistance.

Abstract

Background: Severe traumatic brain injury (TBI) is associated with a 30%–70% mortality rate. S100B has been proposed as a biomarker for indicating outcome after TBI. Nevertheless, controversy has arisen concerning the predictive value of S100B for severe TBI in the context of multitrauma. Therefore, our aim was to determine whether S100B serum levels correlate with primary outcome following isolated severe TBI or multitrauma in males.

Methods: Twenty-three consecutive male patients (age 18–65years), victims of severe TBI [Glasgow Coma Scale (GCS) 3–8] (10 isolated TBI and 13 multitrauma with TBI) and a control group consisting of eight healthy volunteers were enrolled in this prospective study. Clinical outcome variables of severe TBI comprised: survival, time to intensive care unit (ICU) discharge, and neurological assessment [Glasgow Outcome Scale (GOS) at ICU discharge]. Venous blood samples were taken at admission in the ICU (study entry), 24h later, and 7days later. Serum S100B concentration was measured by an immunoluminometric assay.

Results: At study entry (mean time 10.9h after injury), mean S100B concentrations were significantly increased in the patient with TBI (1.448μg/L) compared with the control group (0.037μg/L) and patients with fatal outcome had higher mean S100B (2.10μg/L) concentrations when compared with survivors (0.85μg/L). In fact, there was a significant correlation between higher initial S100B concentrations and fatal outcome (Spearman's =0.485, p=0.019). However, there was no correlation between higher S100B concentrations and the presence of multitrauma. The specificity of S100B in predicting mortality according to the cut-off of 0.79μg/L was 73% at study entry.

Conclusions: Increased serum S100B levels constitute a valid predictor of unfavourable outcome in severe TBI, regardless of the presence of associated multitrauma.

Clin Chem Lab Med 2006;44:1234–42.