Ablation of the tumor suppressor histidine triad nucleotide binding protein 1 is protective against hepatic ischemia/reperfusion injury

The identification of cellular pathways capable of limiting ischemia/reperfusion (I/R) injury remains a frontier in medicine, and its clinical relevance is urgent. Histidine triad nucleotide binding protein 1 (HINT1) is a tumor suppressor that influences apoptosis. Because apoptotic pathways are a feature of I/R injury, we asked whether Hint1 influences hepatic I/R injury. Hint1(-/-) and C57BL/6 mice were subjected to 70% liver ischemia followed by reperfusion for 3 or 24 hours or to a sham operation. The serum aminotransferase levels, histological lesions, apoptosis, reactive oxygen species, and expression of B cell lymphoma 2-associated X protein (Bax), heme oxygenase 1 (HO-1), interleukin-6 (IL-6), IL-10, tumor necrosis factor-a, Src, nuclear factor kappa B (p65/RelA), and c-Jun were quantified. The responses to toll-like receptor ligands and nicotinamide adenine dinucleotide phosphate oxidase activity in Kupffer cells were compared in Hint1(-/-) mice and C57BL/6 mice. After I/R, the levels of serum aminotransferases, parenchymal necrosis, and hepatocellular apoptosis were significantly lower in Hint1(-/-) mice versus control mice. Furthermore, Bax expression decreased more than 2-fold in Hint1(-/-) mice, and the increases in reactive oxygen species and HO-1 expression that were evident in wild-type mice after I/R were absent in Hint1(-/-) mice. The phosphorylation of Src and the nuclear translocation of p65 were increased in Hint1(-/-) mice, whereas the nuclear expression of phosphorylated c-Jun was decreased. The levels of the protective cytokines IL-6 and IL-10 were increased in Hint1(-/-) mice. These effects increased survival after I/R in mice lacking Hint1. Hint1(-/-) Kupffer cells were less activated than control cells after stimulation with lipopolysaccharides. CONCLUSION: The Hint1 protein influences the course of I/R injury, and its ablation in Kupffer cells may limit the extent of the injury.

Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer

Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.

Effekte spezifischer Interventionen im Sportunterricht auf die exekutiven Funktionen von Primarschulkindern

Einleitung Die Annahme, dass Sport nicht nur positive Effekte auf die körperliche Gesundheit, sondern auch auf die kognitive Leistung haben kann, konnte anhand experimenteller Studien mit Erwachsenen weitgehend bestätigt werden. Ob dieselben Effekte auch bei Kindern und Jugendlichen vorzufinden sind, kann mit Blick auf die mangelnde empirische Evidenz in dieser Altersgruppe kaum zufriedenstellend beantwortet werden (Chang et al., 2012). Will man zudem der Frage nach den Wirkmechanismen nachgehen, sind Unter-suchungsdesigns angezeigt, die theoriegeleitet verschiedene Sportinterventionen mit unterschiedlichen Beanspruchungsmodalitäten kombinieren. So ist unter der Annahme der cardiovascular fitness hypothesis (Etnier et al., 2006) zur gezielten Förderung der kognitiven Leistungsfähigkeit ein systematisches Ausdauertraining sinnvoll, während theoretische Ansätze, die neurophysiologische Korrelate zur Erklärung des Zusammenhangs zwischen Sport und Kognition heranziehen (Diamond, 2000) eher kognitiv sowie koordinativ anspruchsvolle Sportangebote nahelegen würden. Daher geht der vorliegende Beitrag der Frage nach, ob spezifisch konzipierte langfristige Interventionen im Sportunterricht einen spezifischen Effekt auf die kognitive Leistungsfähigkeit von Primarschulkindern haben können. Methode Im Rahmen der quasiexperimentellen Längsschnittstudie „Sport und Kognition“ (SpuK_5.0) wurden insgesamt 250 Schülerinnen und Schüler von 16 fünften Klassen untersucht. Während knapp zwei Monaten absolvierten je vier Klassen während zwei Lektionen des obligatorischen Sportunterrichts entweder ein spielsportbezogenes EF-Training oder ein Ausdauertraining resp. ein kognitives oder kein spezifisches Training (Kontrollgruppe mit regulärem Sportunterricht). Durch die Konzeption dieser vier Experi-mentalbedingungen wurde sichergestellt, dass alle vier möglichen Kombinationen aus hoher resp. niedriger kognitiver und körperlicher Beanspruchung im Design repräsentiert waren. Ergebnisse und Diskussion Im Beitrag werden erste Ergebnisse der noch laufendenden SpuK_5.0-Studie vorgestellt und vor dem Hintergrund aktueller theoretischer Annahmen zu den zugrundeliegenden Wirkmechanismen diskutiert. Literatur Chang, Y. K., Labban, J. D., Gapin, J. I., & Etnier, J. L. (2012). The effects of acute exercise on cognitive performance: A meta-analysis. Brain Research, 1453, 87-101. Diamond, A. (2000). Close interrelation of motor development and cognitive development and of the cere-bellum and prefrontal cortex. Child Development, 71, 44-56. Etnier, J. L., Nowell, P. M., Landers, D. M., & Sibley, B. A. (2006). A meta-regression to examine the rela-tionship between aerobic fitness and cognitive performance. BRAIN RESEARCH, 52, 119-130.

Strange Relations. Cultural Translation of Noh Theatre in Ezra Pound’s Dance Poems and W. B. Yeats’s At the Hawk’s Well

Drawing on the reception of Noh drama by Ezra Pound and William Butler Yeats, the article analyses both the literary and cultural ‘translations’ of this form of Japanese theatre in their works, focusing on Yeats’s play At the Hawk’s Well (1917). I conceptualize ‘cultural translation’ as the staging of relations that mark a residual cultural difference. Referred to as ‘foreignizing’ in translation theory, this method enables what Erika Fischer-Lichte has termed a ‘liminal experience’ for the audience –– an effect Yeats intended for the performance of his play. It evokes situations in which opposites collapse and new ways of acting or new combinations of symbols can be tried out. Yeats’s play will be used to sketch how an analysis of relations could serve as a general model for the study of cultural transfer as cultural translation in general. Keywords: cultural translation, translation theory, performance, William Butler Yeats, Itō Michio, Ezra Pound, At the Hawk’s Well

Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups

Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.