ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke

Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2^wt) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP^wt) and its phosphorylation-deficient mutant RKIP^S153A, known inhibitors of the ERK1/2 signaling cascade. RKIP^wt and RKIP^S153A attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.     

Endometrial Cancer Stem Cells: Where Do We Stand and Where Should We Go?

Endometrial cancer is one of the most common malignant diseases in women worldwide, with an incidence of 5.9%. Thus, it is the most frequent cancer of the female genital tract, with more than 34,000 women dying, in Europe and North America alone. Endometrial Cancer Stem Cells (CSC) might be drivers of carcinogenesis as well as metastatic and recurrent disease. Therefore, targeting CSCs is of high interest to improve prognosis of patients suffering of advanced or recurrent endometrial cancer. This review describes the current evidence of molecular mechanisms in endometrial CSCs with special emphasis on MYC and NF-κB signaling as well as mitochondrial metabolism. Furthermore, the current status of immunotherapy targeting PD-1 and PD-L1 in endometrial cancer cells and CSCs is elucidated. The outlined findings encourage novel therapies that target signaling pathways in endometrial CSCs as well as immunotherapy as a promising therapeutic approach in the treatment of endometrial cancer to impede cancer progression and prevent recurrence.     

Sicherheitsanalyse der Nedap-Wahlcomputer

Zusammenfassung  Bei der Bundestagswahl 2005 waren etwa zwei Millionen Menschen in über 2.000 Wahllokalen aufgerufen, an Wahlcomputern der niederl?ndischen Firma Nedap abzustimmen. Von den etwa 80.000 Wahllokalen in Deutschland ist dies bisher nur ein geringer Anteil, jedoch entzündete sich eine breite Debatte um die Fragen der Sicherheit und Vertrauenswürdigkeit der verwendeten Rechner. Denn die Speicherung und Ausz?lung der Stimmen wird nicht auf Papier festgehalten, sondern findet direkt in den Computern statt. Frank Rieger besch?ftigt sich seit vielen Jahren im CCC und beruflich mit Mobilfunk und Informationssicherheit. Constanze Kurz ist wissenschaftliche Mitarbeiterin an der HU Berlin und Sprecherin des CCC. Ihre Forschungsschwerpunkte sind überwachungstechnologien, Biometrie und Wahlcomputer.     

Ethische Leitlinien der GI

Seit Ihrer Verabschiedung im Jahr 1994 waren die Ethischen Leitlinien der Gesellschaft für Informatik Gegenstand zuweilen kontroverser Diskussionen. Einerseits wurde begrüßt, dass sich die GI verbindlich an ein ethisches Regelwerk bindet und dadurch ihren Mitgliedern einen Leitfaden an die Hand gibt, um in Konfliktsituationen besser entscheiden zu können. Andererseits wurde bemängelt, dass die Ethischen Leitlinien Forderungen stellten, die für professionelles Handeln unabdingbar seien und deshalb keine ethischen Ansprüche darstellten. Des Weiteren wurde kritisiert, dass die Ethischen Leitlinien zu sehr im Abstrakten verharrten und deshalb keine konkrete Handlungsanweisung geben könnten. Die fachlichen und überfachlichen Anforderungen wurden zuweilen als zu anspruchsvoll empfunden. Einige dieser Kritikpunkte sind sicherlich berechtigt.Im November 2001 begann der Arbeitskreis Informatik und Verantwortung im Fachbereich Informatik und Gesellschaft (IuG) mit der Überarbeitung der Ethischen Leitlinien. Der hier vorgelegte Entwurf greift einige dieser Kritikpunkte auf. Seine Publikation soll eine breitere Diskussion innerhalb der GI ermöglichen. Die Autorinnen und Autoren dieses Entwurfs freuen sich auf diese Auseinandersetzung, die in der letzten Sitzung des Arbeitskreises durch den Vertreter der Selbständigen in der GI mit dem Hinweis begonnen wurde, dass den Leitlinien ein Berufsbild zugrunde liegt, in dem die Selbständigen nicht vorkommen.Die anlässlich der Informatik 2003 gegründete Fachgruppe Informatik und Ethik wird sich zu ihrer ersten Aufgabe machen, die Ergebnisse dieser Diskussion in die endgültige Version einfließen zu lassen. Entsprechende Diskussionsbeiträge und Anregungen sollten an Karl-Heinz Rödiger (E-Mail: roediger@informatik.uni-bremen.de), kommissarischer Sprecher der Fachgruppe, gerichtet werden.     

Novel rapid in vitro cytotoxicity test on mammalian cells based on an electrochemical measuring method

The proliferation of pharmaceuticals and chemicals and the increasing manufacture of medical goods have made an assessment of their potential toxicological risks to man and the environment indispensable. Hence, a wide range of tests has been developed in order to generate data on the harmful effects of chemicals and pharmaceuticals on organisms. Initially, toxicological data were commonly collected from tests involving animals; however, on account of ethical objections, they are gradually being replaced by in vitro cytotoxicity tests. In this work, a new in vitro screening method for the determination of cytotoxicity, based on a novel electrochemical bioactivity sensor system, was implemented. The evaluation was based on current–time curves of a potentiostatic measurement proportional to the reduction of mediator molecules by mammalian cells. Depending on the number of reduced mediator molecules used by the cells, a current signal is produced, which provides information about the viability of living cells. By adding a toxic test substance to the cell, a reduction in the current signal can be observed, depending on the cytotoxicity of the substance. It is possible to quickly create a specific cytotoxic curve and to determine the corresponding inhibitory concentrations (IC₅₀ value). First tests were performed on three mammalian cell lines and eight model compounds using this electrochemical measurement system. The IC₅₀ values obtained corresponded well with the toxicity determined with an established reference cytotoxicity assay (MTT test) and with data reported in the literature.     

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

The WWC protein family is an upstream regulator of the Hippo signalling pathway that is involved in many cellular processes. We examined the effect of an endothelium-specific WWC1 and/or WWC2 knock-out on ocular angiogenesis. Knock-outs were induced in C57BL/6 mice at the age of one day (P1) and evaluated at P6 (postnatal mice) or induced at the age of five weeks and evaluated at three months of age (adult mice). We analysed morphology of retinal vasculature in retinal flat mounts. In addition, in vivo imaging and functional testing by electroretinography were performed in adult mice. Adult WWC1/2 double knock-out mice differed neither functionally nor morphologically from the control group. In contrast, the retinas of the postnatal WWC knock-out mice showed a hyperproliferative phenotype with significantly enlarged areas of sprouting angiogenesis and a higher number of tip cells. The branching and end points in the peripheral plexus were significantly increased compared to the control group. The deletion of the WWC2 gene was decisive for these effects; while knocking out WWC1 showed no significant differences. The results hint strongly that WWC2 is an essential regulator of ocular angiogenesis in mice. As an activator of the Hippo signalling pathway, it prevents excessive proliferation during physiological angiogenesis. In adult animals, WWC proteins do not seem to be important for the maintenance of the mature vascular plexus.     

Responses of Human Neonates to Highly Diluted Odorants from Sweat

Conjugated forms of odorants contributing to sweat odor occur not only in human sweat but also in amniotic fluid, colostrum, and milk. However, it is unclear whether the released odorants are detected and hedonically discriminated by human newborns. To investigate this issue, we administered highly diluted solutions of (R)/(S)-3-methyl-3-sulfanylhexan-1-ol (MSH), (R)/(S)-3-sulfanylhexan-1-ol (SH), (E)/(Z)-3-methylhex-2-enoic acid (3M2H), and (R)/(S)-3-hydroxy-3-methylhexanoic acid (HMHA) to 3-d-old infants while their respiratory rate and oro-facial movements were recorded. Adult sensitivity to these odorants was assessed via triangle tests. Whereas no neonatal stimulus-specific response was found for respiratory rate, oro-facial reactivity indicated orthonasal detection of MSH and SH by male neonates, and of HMHA by the whole group of neonates. Dependent on the dilution of odorants, newborns evinced neutral responses or longer negative oro-facial expressions compared with the reference stimuli. Finally, newborns appeared to be more sensitive to the target odorants than did adults.