Cyclopenta[ b]indole Derivative Inhibits Aurora B in Primary Cells

The Aurora family of kinases is closely involved in regulating cell division. Inhibition of Aurora A and B with small molecules is currently being investigated in clinical trials for the treatment of different cancers. It has also been evaluated as a treatment option against different autoimmune diseases in preclinical studies. Here, we present a cyclopenta[b]indole derivative capable of inhibiting Aurora B selectively in kinase assays. To evaluate the Aurora B inhibition capacity of the compound, we used a kinase IC50 assay as well as a suppression assay of proliferating primary cells. In addition, we examined if the cells had gained a phenotype characteristic for Aurora B inhibition after treatment with the compound. We found that the compound selectively inhibited Aurora B (IC50 = 1.4 μM) over Aurora A (IC50 > 30 μM). Moreover, the compound inhibited proliferating PBMCs with an IC50 = 4.2 μM, and the cells displayed reduced phosphorylation of histone H3 as well as tetraploidy, consistent with Aurora B inhibition

Cultivation of the causative agent of human neoehrlichiosis from clinical isolates identifies vascular endothelium as a target of infection

ABSTRACTCandidatus (Ca.) Neoehrlichia mikurensis is the cause of neoehrlichiosis, an emerging tick-borne infectious disease characterized by fever and vascular events. The bacterium belongs to the Anaplasmataceae, a family of obligate intracellular pathogens, but has not previously been cultivated, and it is uncertain which cell types it infects. The goals of this study were to cultivate Ca. N. mikurensis in cell lines and to identify possible target cells for human infection. Blood components derived from infected patients were inoculated into cell lines of both tick and human origin. Bacterial growth in the cell cultures was monitored by real-time PCR and imaging flow cytometry. Ca. N. mikurensis was successfully propagated from the blood of immunocompromised neoehrlichiosis patients in two Ixodes spp. tick cell lines following incubation periods of 7–20 weeks. Human primary endothelial cells derived from skin microvasculature as well as pulmonary artery were also susceptible to infection with tick cell-derived bacteria. Finally, Ca. N. mikurensis was visualized within circulating endothelial cells of two neoehrlichiosis patients. To conclude, we report the first successful isolation and propagation of Ca. N. mikurensis from clinical isolates and identify human vascular endothelial cells as a target of infection

Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology

The Role of Eosinophils in Bullous Pemphigoid: A Developing Model of Eosinophil Pathogenicity in Mucocutaneous Disease

Bullous pemphigoid (BP) is an autoimmune blistering disease which carries a significant mortality and morbidity. While historically BP has been characterized as an IgG driven disease mediated by anti-BP180 and BP230 IgG autoantibodies, developments in recent years have further elucidated the role of eosinophils and IgE autoantibodies. In fact, eosinophil infiltration and eosinophilic spongiosis are prominent features in BP. Several observations support a pathogenic role of eosinophils in BP: IL-5, eotaxin, and eosinophil-colony stimulating factor are present in blister fluid; eosinophils line the dermo-epidermal junction (DEJ) in the presence of BP serum, metalloprotease-9 is released by eosinophils at the site of blisters; eosinophil degranulation proteins are found on the affected basement membrane zone as well as in serum corresponding with clinical disease; eosinophil extracellular DNA traps directed against the basement membrane zone are present, IL-5 activated eosinophils cause separation of the DEJ in the presence of BP serum; and eosinophils are the necessary cell required to drive anti-BP180 IgE mediated skin blistering. Still, it is likely that eosinophils contribute to the pathogenesis of BP in numerous other ways that have yet to be explored based on the known biology of eosinophils. We herein will review the role of eosinophils in BP and provide a framework for understanding eosinophil pathogenic mechanisms in mucocutaneous disease

Functional and Phenotypic Studies of Eosinophilic Granulocytes in Patients with Eosinophilic Esophagitis

Eosinophilic Esophagitis (EoE) is a chronic inflammatory disorder of unknown etiology, in which the esophagus is infiltrated by eosinophils and T cells. Topical corticosteroids are one of the treatment options for patients with EoE. The function of eosinophils in EoE is unknown, here we hypothesize that eosinophils serve as immunoregulatory cells. The eosinophils in the blood of untreated adult patients with EoE have a distinct phenotype. The aims of this thesis were to explore whether the eosinophilic phenotype of untreated patients with EoE can be reverted to the healthy phenotype by topical corticosteroid treatment, and to examine whether blood eosinophils from children with EoE have a distinct phenotype, different from that of healthy children. Moreover, we tested the hypothesis that eosinophils, similar to regulatory T cells, can diminish T cell proliferation and express FOXP3. The role of the eosinophilic protein galectin-10 in mediating immunosuppression was also investigated. This thesis demonstrates that the EoE phenotype of blood eosinophils is not restored by topical corticosteroid treatment, except with respect to CD18. We also show that eosinophils from patients with EoE have an immunoregulatory phenotype, i.e., increased levels of FOXP3 and galectin-10. Moreover, eosinophils from healthy subjects and patients with EoE are able to suppress T cell proliferation in vitro, in part via galectin-10. We show that eosinophils exposed to activated T cells release galectin-10 via DNA nets and appear to transfer this protein to T cells through synapses. Two subsets of eosinophils emerge after co-culturing. Finally, we demonstrate that the blood eosinophils of children with EoE have a distinct phenotype, different from that of healthy children and that of adults with EoE. Importantly, we reveal marked age-related differences regarding the molecular patterns displayed by the blood eosinophils of healthy donors. Our finding that eosinophils from patients with EoE have upregulated immunoregulatory molecules could indicate that the function of eosinophils in EoE is to reduce a T cell-mediated inflammation in the esophagus

Functional and Phenotypic Studies of Eosinophilic Granulocytes in Patients with Eosinophilic Esophagitis

Eosinophilic Esophagitis (EoE) is a chronic inflammatory disorder of unknown etiology, in which the esophagus is infiltrated by eosinophils and T cells. Topical corticosteroids are one of the treatment options for patients with EoE. The function of eosinophils in EoE is unknown, here we hypothesize that eosinophils serve as immunoregulatory cells. The eosinophils in the blood of untreated adult patients with EoE have a distinct phenotype. The aims of this thesis were to explore whether the eosinophilic phenotype of untreated patients with EoE can be reverted to the healthy phenotype by topical corticosteroid treatment, and to examine whether blood eosinophils from children with EoE have a distinct phenotype, different from that of healthy children. Moreover, we tested the hypothesis that eosinophils, similar to regulatory T cells, can diminish T cell proliferation and express FOXP3. The role of the eosinophilic protein galectin-10 in mediating immunosuppression was also investigated. This thesis demonstrates that the EoE phenotype of blood eosinophils is not restored by topical corticosteroid treatment, except with respect to CD18. We also show that eosinophils from patients with EoE have an immunoregulatory phenotype, i.e., increased levels of FOXP3 and galectin-10. Moreover, eosinophils from healthy subjects and patients with EoE are able to suppress T cell proliferation in vitro, in part via galectin-10. We show that eosinophils exposed to activated T cells release galectin-10 via DNA nets and appear to transfer this protein to T cells through synapses. Two subsets of eosinophils emerge after co-culturing. Finally, we demonstrate that the blood eosinophils of children with EoE have a distinct phenotype, different from that of healthy children and that of adults with EoE. Importantly, we reveal marked age-related differences regarding the molecular patterns displayed by the blood eosinophils of healthy donors. Our finding that eosinophils from patients with EoE have upregulated immunoregulatory molecules could indicate that the function of eosinophils in EoE is to reduce a T cell-mediated inflammation in the esophagus

IFRS 3 Business Combinations - Internationells skillnader i implementeringen

Bakgrund och Problem: Redovisningen världen över har i huvidsak förgrenats i två redovisningstraditioner, anglosaxisk och kontinental. I och med ökad globalisering har behovet av harmonisering ökat varför alla noterad företag inom EU idag måste tillämpa IFRS. En stor skillnad gentemot de gamla regelveret är hänförligt till IFRS 3 Business Combinations och goodwill. Intresse finns därmed att undersöka huruvida länder tillhörande den anglosaxiska respektive kontinentala redovisningstraditionen identifierar olika stor andel immateriella tillgångar vid företagsförvärv. Syfte: Syftet med uppsatsen är att undersöka huruvida det finns skillnader i redovisningen av goodwill enligt IFRS 3 Business Combinations mellan länder som historiskt sett anses ha tillhört den kontinentala traditionen respektive den anglosaxiska traditionen. Vidare är syftet att undersöka ifall det finns andra företagsspecifika attribut som påverkar redovisningen av goodwill vid företagsförvärv och ifall dessa kan tänkas påverka studiens utfall. Metod: Studien antog en kvantitativ ansats där sekundärdata i form av årsredovisningar låg som grund. Data inhämtades ifrån 20 årsredovisningar från respektive land åren 2007 och 2008. För att besvara frågeställningen sattes hypoteser upp som testades med för materialet lämpliga statistiska test. Relationen mellan andelen identifierade immateriella tillgångar testades emot; redovisningstradition, nationstillhörighet, förvärvarens storlek, förvärvens soliditet samt förvärvarens industritillhörighet. Resultat och slutsatser: Inget av de statistiska testerna hänförliga till redovisningstradition eller nationstillhörighet visade på något statistisk samband gällande andelen identifierade immateriella tillgångar. Dock kunde ett statiskt samband skönjas mellan andelen identifierade immateriella tillgångar och både förvärvarens storlek och soliditet. En svag signifikans kunde även påvisas mellan andelen identifierade immateriella tillgångar och förvärvarens industritillhörighet, något som kan ha påverkat de övriga resultatet på grund av ett skevt urval. Förslag till fortsatt forskning: Författarna föreslår fortsatt forskning i frågan huruvida den anglosaxiska och kontinentala klassificeringen fortfarande är relevant, framförallt gällande övriga IFRS standarder studien inte hanterat. Vidare ges förslag till fortsatt forskning om liknande studier med ett större och mer homogent urval. Slutligen anser författarna det av intresse att studera skillnader i tillämpningen mellan de företag som följer US GAAP och IFRS