Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis

Objective: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. Design: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). Setting: Research laboratories of Hannover Medical School and Harvard Medical School. Patients: Septic patients/C57Bl/6 mice and human endothelial cells. Interventions: Food and Drug Administration-approved library screening. Measurements and Main Results: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. Conclusions: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.

A számviteli érdekhordozói elméletek evolúciója és a szabályozás – klasszikus tézisek és új irányok a pénzügyi beszámolásban (Evolution of the financial accounting stakeholder theories and the regulation – classic theses and new ways in the financial report)

A modernkori számvitel egyik alapvető kérdése, hogy a pénzügyi beszámolás címzettjét – az érdekhordozókat – miként lehet azonosítani. Ez a törekvés már a klasszikus, azóta meghaladottá vált elméletekben is központi szerepet töltött be és modern, posztmodern elméletekben kulcsfontosságúvá vált. A tapasztalatok alapján az azonosított érdekhordozók köre módosult, bővült. Ennek a fejlődésnek a vizsgálata során a számvitel számos olyan ismérvét sikerült azonosítani, amely segítségével a vonatkozó szabályok tökéletesíthetők. Emellett az evolúció vizsgálata segítségével közvetlenül is megfigyelhetővé vált az, hogy a számvitelt extern módon szabályozó hatalom szükségessége milyen feltételek teljesítése mellett igazolható. A vizsgálat során azonosíthatóvá váltak olyan helyzetek, amikor a számviteli szabályozó és „kívülről irányított” pénzügyi beszámolás szuboptimális helyzethez vezet. A cikk az érdekhordozói elméletek fejlődését a klasszikus felfogásoktól indulva mutatja be. Feltárja, hogy a modern – jelenleg elfogadott – koalíciós vállalatfelfogás miben hozott újat, elsősorban miként hívta életre az extern szabályozót. _____ One of the key problems of the modern financial accounting is how to define the stakeholders. This problem was already a key issue in the already outdated classical stakeholder theories. Research and experience noted that the group of stakeholders has widened and has been modified. Through this evolution researchers identified many characteristics of financial reporting through which the regulation could have been improved. This advance pointed out which are the situations when the existence of an extern accounting regulator may be justified, since under given circumstances this existence led to suboptimal scenario. This paper deals with the stakeholder theories, starting with the classical ones. The article points out how did the currently accepted theory changed the assertions of the previous one and how was the external regulator created as an inevitable consequence. The paper also highlights the main issues raised by the post-modern theories; those, which try to fit the current questions into the current stakeholder models. The article also produces a Hungarian evidence for the previously mentioned suboptimal scenario, where the not tax-driven regulation proves to be suboptimal.

Self-determination theory and student motivation in social studies in an urban Broward County public high school

This study investigated how students perceived their motivation in high school social studies classes in school and to determine if a correlation exists between students’ grade level, race, gender, and their motivation. The sample included 337 high school students in Broward County, Florida. To assess students’ perceptions on their motivation the academic self-regulation questionnaire was utilized. Results indicate that social studies students show high levels of external regulation, with a mean score at 22.31 on a scale of 36 points. The results show a mean score of 24 on a scale of 28 points for identified regulation among social studies students. Findings revealed that student motivation could be gauged. No statistical significance was found between high school students’ grade level, race, gender, and their motivation in social studies classes. The findings of this study have shown that students at Boyd H. Anderson High School want to learn social studies.

Improving Student Mathematics Achievement through Self Regulation and Goal Setting

As middle school students’ mathematic scores decline in comparison to other countries, researchers have found self-regulation to be a tool to improve students’ mathematics achievement. The following is an action research project conducted in a middle school where result showed an increase in students’ mathematics achievement.

The role of emotion regulation on social participation following stroke

© 2014 The British Psychological Society.