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The Werner syndrome helicase/3′-exonuclease (WRN) is a major component of the DNA repair and replication machinery. To analyze whether WRN is involved in the repair of topoisomerase-induced DNA damage we utilized U2-OS cells, in which WRN is stably down-regulated (wrn-kd), and the corresponding wild-type cells (wrn-wt). We show that cells not expressing WRN are hypersensitive to the toxic effect of the topoisomerase I inhibitor topotecan, but not to the topoisomerase II inhibitor etoposide. This was shown by mass survival assays, colony formation and induction of apoptosis. Upon topotecan treatment WRN deficient cells showed enhanced DNA replication inhibition and Sphase arrest, whereas after treatment with etoposide they showed the same cell cycle response as the wild-type. A considerable difference between WRN and wild-type cells was also observed for DNA single-and double-strand break formation in response to topotecan. Topotecan induced most DNA single-strand breaks 6 h after treatment. In both wrn-wt and wrn-kd cells these breaks were repaired at similar kinetics. However, in wrn-kd but not wrn-wt cells they were converted into DNA doublestrand breaks (DSBs) at high frequency, as shown by neutral comet assay and phosphorylation of H2AX. Our data provide evidence that WRN is involved in the repair of topoisomerase I, but not topoisomerase II-induced DNA damage, most likely via preventing the conversion of DNA singlestrand breaks into DSBs during the resolution of stalled replication forks at topo I-DNA complexes. We suggest that the WRN status of tumor cells impacts anticancer therapy with topoisomerase I, but not topoisomerase II inhibitors.

Introduction Acute aortic dissection type A (AADA) is a severe and complex disease that is often linked to diverse, possible complications. Without appropriate surgical treatment approximately 75% of all patients die within 14 days after the onset of symptoms. 1 Because of advances in surgery, anesthesia and medical therapy postoperative outcome is steadily improving. 2-4 Most published literature concerns about surgical outcome, survival of patients, and complications leading to disability. Postoperative QoL comparing physical and psychological status is rarely considered in this view. The following article concerns about long-term outcome and quality of life (QoL) after AADA, and focuses on the changes of QoL concerning physical and mental status. Methods Patient Selection From January 1, 1999, until December 31, 2006, 120 patients received an emergency operation for Stanford type A aortic dissection. All patients were recorded and were asked to answer an SF-36 questionnaire during routine follow-up (FU). Four patients refused FU and seven were lost to FU resulting in 109 patients for this study group. Data Collection Dataset was acquired using SF-36 QoL questionnaire. The first SF-36 questionnaire (FU I) was obtained within 45 AE 32 months after surgery, the second (FU II), 46 AE 10 months thereafter. Some of the patients could not show up for their Keywords ► aortic dissection ► SF-36 ► quality of life ► long-term outcome

Research on cardiac hypertrophy and heart failure is frequently based on pressure overload mouse models induced by TAC. The standard procedure is to perform a partial thoracotomy to visualize the transverse aortic arch. However, the surgical trauma caused by the thoracotomy in open-chest models changes the respiratory physiology as the ribs are dissected and left unattached after chest closure. To prevent this, we established a minimally invasive, closed chest approach via lateral thoracotomy. Herein we approach the aortic arch via the 2 intercostal space without entering the chest cavities, leaving the mouse with a less traumatic injury to recover from. We perform this operation using standard laboratory settings for open chest TAC procedures with equal survival rates. Apart from maintaining physiological breathing patterns due to the closed chest approach, the mice seem to benefit by showing rapid recovery, as the less invasive technique appears to facilitate a fast healing process and to reduce immune response after trauma.

Background Aortic arch repair for aortic dissection is still associated with a high mortality rate. Providing adequate means of neuromonitoring to guide cerebral hemodynamics is advantageous, especially during selective anterior cerebral perfusion (SACP). Objective We aimed to investigate an easy multimodal neuromonitoring set-up consisting of processed electroencephalography (EEG), near infrared spectroscopy (NIRS), and transcranial doppler sonography (TCD). Material and methods We collected intraoperative data from six patients undergoing surgery for aortic dissection. In addition to standard hemodynamic monitoring, patients underwent continuous bilateral NIRS, processed EEG with bispectral index (BIS), and intermittent transcranial doppler sonography of the medial cerebral artery (MCA) with a standard B‑mode ultrasound device. Doppler measurements were taken bilaterally before cardiopulmonary bypass (CPB), during CPB, and during SACP at regular intervals. Results Of the patients four survived without neurological deficits while two suffered fatal outcomes. Of the survivors two suffered from transient postoperative delirium. Multimodal monitoring led to a change in CPB flow or cannula repositioning in three patients. Left-sided mean flow velocities of the MCA decreased during SACP, as did BIS values. Conclusion Monitoring consisting of BIS, NIRS, and TCD may have an impact on hemodynamic management in aortic arch operations.

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Human aortic aneurysms have been associated with inflammation and vascular remodeling. Since the endocannabinoid system modulates inflammation and tissue remodeling, we investigated its components in human aortic aneurysms. We obtained anterior aortic wall samples from patients undergoing elective surgery for aortic aneurysm or coronary artery disease as controls. Histological and molecular analysis (RT-qPCR) was performed, and endocannabinoid concentration was determined using LC-MRM. Patient characteristics were comparable between the groups except for a higher incidence of arterial hypertension and diabetes in the control group. mRNA level of cannabinoid receptors was significantly higher in aneurysms than in controls. Concentration of the endocannabinoid 2-arachidonoylglycerol was significantly higher, while the second endocannabinoid anandamide and its metabolite arachidonic acid and palmitoylethanolamide were significantly lower in aneurysms. Histology revealed persistent infiltration of newly recruited leukocytes and significantly higher mononuclear cell density in adventitia of the aneurysms. Proinflammatory environment in aneurysms was shown by significant upregulation of M-CSF and PPAR but associated with downregulation of chemokines. We found comparable collagen-stained area between the groups, significantly decreased mRNA level of CTGF, osteopontin-1, and MMP-2, and increased TIMP-4 expression in aneurysms. Our data provides evidence for endocannabinoid system activation in human aortic aneurysms, associated with persistent low-level inflammation and vascular remodeling.

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