Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K+ channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.

Background and purpose Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (FLAIR-rSI) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial, intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of DWI-FLAIR mismatch, i.e., in those with no marked FLAIR hyperintensity in the region of the acute DWI lesion. In this post-hoc analysis, we investigated if quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analysed by binary logistic regression using different endpoints, i.e., favourable outcome defined as mRS 0-1, independent outcome defined as mRS 0-2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for NIHSS at symptom onset and stroke lesion volume. Results FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS 0-1 (p=0.169) and shift analysis (p=0.086), but 2 reached significance for mRS 0-2 (p=0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical endpoints with increasing FLAIR-rSI. Conclusion In patients in whom no marked parenchymal FLAIR hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of DWI lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.

Background: Decompressive hemicraniectomy (DHC) is life-saving in patients with malignant middle cerebral artery infarction (MMI), but outcome, perspectives and complications after DHC in daily practice are largely unknown. Methods: From 2008 until 2014, we extracted patient's characteristics as well as complications from our database for patients with MMI who underwent DHC. Additionally, we analysed medical records from the different rehabilitation steps. Results: We identified 48 consecutive patients (mean 57 years, 21 male, 41.7% >60 years) with MMI who underwent DHC. The decision for DHC was made on an individual basis, including patients without impaired consciousness or stroke onset >48 h. In-hospital patients achieved only marginal clinical improvement. Seventy-five percent attended an early-rehabilitation, 44% achieved post-stroke rehabilitation and 6% carried on late-stage rehabilitation. In all, 45.5% returned home after rehabilitation. In-hospital mortality was 14.6%, overall mortality was 16.7%. Surviving patients (78.9%) had a modified Rankin Scale of 4-5. Frequent neurologic complications were symptomatic epilepsy and delirium. Following DHC/bone-flap-reimplantation, wound-healing disorders, epidural hematoma and wound infections were major surgery-related complications. Pulmonary infections were frequent in the acute-phase and urinary tract infections were predominant in the late-phase. Conclusions: DHC is a life-saving technique in patients with MMI, but complications are frequent, were underestimated in randomized clinical trials and may worsen the functional outcome.