Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a ...cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits. Cross-ancestry genome-wide association analyses in individuals of European and East Asian ancestry identify 11 new risk loci for intracranial aneurysms and highlight a polygenic architecture explaining a substantial fraction of disease heritability.
Background Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal ...studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. Aims (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD;(2) to assess to which extent these lesions explain progression of SVD imaging markers;(3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance;and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. Design/methods The RUN DMC - InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. Discussion Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.
The cytotoxic effect of doxorubicin on human breast cancer cells (MCF-7) appeared to be correlated with drug concentration, exposure time and cellular uptake of doxorubicin. The effects of short-term ...stimulation of the growth of MCF-7 cells with 30 pM oestradiol was investigated with respect to the uptake of doxorubicin and cell kill. Culture of MCF-7 cells in steroid hormone-deprived medium resulted in an approx. 90% arrest of the cells in the G0G1-phase of the cell cycle. Growth stimulation with 30 pM oestradiol caused a 3-5-fold increase in the number of cells in S-G2M phase at between 18 and 24 h after administration of oestradiol to the medium. Incubation of oestradiol-stimulated cells with 0.37 microM doxorubicin during both 1 and 6 h resulted in an augmented inhibition of cell growth compared to unstimulated controls. An enhanced cellular uptake of doxorubicin after administration of oestradiol was observed only after an incubation period of 6 h and not of 1 h. These observations suggest that both an increased sensitivity to doxorubicin and an augmented cellular uptake of the drug may underlie the cytotoxic effects of doxorubicin after pretreatment with oestradiol.
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