Potentielle Auswirkung der Genese der Schwerhörigkeit aud die subjektiv empfundene Lebensqualität

Die Pilotstudie der Hals-Nasen und Ohrenklinik der Universität Marburg hatte das Ziel den Einfluss der Ursache der Schwerhörigkeit auf die subjektiv empfundene Lebensqualität der Patienten genauer zu beleuchten. Dazu wurden 100 Patienten anhand der objektiven klinischen Daten in vier Gruppen unterteilt ( Hörsturz, chronische Otitis media, M Menière und Otosklerose).Anhand der Königsteiner Richtlinien wurde der objektive Schweregrad bestimmt. Zusätzlich wurden die Patienten mit dem neu entwickelten Fragebogen zur Erfassung der Lebensqualität (FELAS) bezüglich der subjektiven Lebensqualität in den Rubriken Kommunikation, Aktivitätsminderung und emotionale Einbußen eruiert. In einem ersten Schritt wurden die Gruppen unterschiedlicher Genese mittels der multifaktoriellen Varianzanalsyse auf Unterschiede zwischen den Gruppen bezüglich der Lebensqualität untersucht. Dabei ließen sich keine signifikanten Unterschiede feststellen. Die Ursache der Schwerhörigkeit scheint demnach keinen Einfluss auf die Lebensqualität schwerhöriger Patienten zu haben. Zur Klärung der Frage, ob die klinischen Einteilungen mit der subjektiven Einschätzung korrelieren wurde eine Rang-Korrelation nach Spearman/Brown durchgeführt. Die dabei berechneten Korrelationen lassen eine Einschätzung der Lebensqualität auf Grund der objektiven Daten der klinischen Einteilung nicht zu

Object Oriented Finite Element Analysis for Structural Optimization using p-Elements

The optimization of continuous structures requires careful attention to discretization errors. Compared to ordinary low order formulation (h-elements) in conjunction with an adaptive mesh refinement in each optimization step, the use of high order finite elements (so called p-elements) has several advantages. However, compared to the h-method a higher order finite element analysis program poses higher demands from a software engineering point of view. In this article the basics of an object oriented higher order finite element system especially tailored to the use in structural optimization is presented. Besides the design of the system, aspects related to the employed implementation language Java are discussed

Leistungsbeurteilung und Geschlechtsdiskriminierung

In Zeiten einer zunehmenden Bedeutung betrieblicher Personalbeurteilung und leistungsabhängiger Entlohnung stellt sich die Frage, inwieweit Instrumente der Leistungsbeurteilung Geschlechtsdiskriminierungen in personal- und führungspolitischen Entscheidungen stützen oder sogar verdecken können. Der Artikel wirft einen kritischen Blick auf unser gesellschaftlich verankertes Verständnis von Leistung, bietet eine dazu differierende Beschreibung der Leistungsbeurteilung als sozialen Prozess an und skizziert auf dieser Basis Quellen der Geschlechtsdiskriminierung. Abschließend werden Gestaltungshinweise für Instrumente der Leistungsbeurteilung gegeben.The influence of performance appraisal and performance-based payment models is rising. Therefore, it should be considered if and possibly how performance appraisal instruments contain or produce sources of sex discrimination. The article undertakes a critical review of what we usually call "performance", provides a description of performance appraisal as a social process and explains some crucial sources of discrimination within. Finally, directions for the development and evaluation of performance appraisal instruments are suggested

Simultaneous coexpression of memory-related and effector-related genes by individual human CD8 T cells depends on antigen specificity and differentiation.

Phenotypic and functional cell properties are usually analyzed at the level of defined cell populations but not single cells. Yet, large differences between individual cells may have important functional consequences. It is likely that T-cell-mediated immunity depends on the polyfunctionality of individual T cells, rather than the sum of functions of responding T-cell subpopulations. We performed highly sensitive single-cell gene expression profiling, allowing the direct ex vivo characterization of individual virus-specific and tumor-specific T cells from healthy donors and melanoma patients. We have previously shown that vaccination with the natural tumor peptide Melan-A-induced T cells with superior effector functions as compared with vaccination with the analog peptide optimized for enhanced HLA-A*0201 binding. Here we found that natural peptide vaccination induced tumor-reactive CD8 T cells with frequent coexpression of both memory/homing-associated genes (CD27, IL7R, EOMES, CXCR3, and CCR5) and effector-related genes (IFNG, KLRD1, PRF1, and GZMB), comparable with protective Epstein-Barr virus-specific and cytomegalovirus-specific T cells. In contrast, memory/homing-associated and effector-associated genes were less frequently coexpressed after vaccination with the analog peptide. Remarkably, these findings reveal a previously unknown level of gene expression diversity among vaccine-specific and virus-specific T cells with the simultaneous coexpression of multiple memory/homing-related and effector-related genes by the same cell. Such broad functional gene expression signatures within antigen-specific T cells may be critical for mounting efficient responses to pathogens or tumors. In summary, direct ex vivo high-resolution molecular characterization of individual T cells provides key insights into the processes shaping the functional properties of tumor-specific and virus-specific T cells

SHP-1 phosphatase activity counteracts increased T cell receptor affinity.

Anti-self/tumor T cell function can be improved by increasing TCR-peptide MHC (pMHC) affinity within physiological limits, but paradoxically further increases (K(d) < 1 μM) lead to drastic functional declines. Using human CD8(+) T cells engineered with TCRs of incremental affinity for the tumor antigen HLA-A2/NY-ESO-1, we investigated the molecular mechanisms underlying this high-affinity-associated loss of function. As compared with cells expressing TCR affinities generating optimal function (K(d) = 5 to 1 μM), those with supraphysiological affinity (K(d) = 1 μM to 15 nM) showed impaired gene expression, signaling, and surface expression of activatory/costimulatory receptors. Preferential expression of the inhibitory receptor programmed cell death-1 (PD-1) was limited to T cells with the highest TCR affinity, correlating with full functional recovery upon PD-1 ligand 1 (PD-L1) blockade. In contrast, upregulation of the Src homology 2 domain-containing phosphatase 1 (SHP-1/PTPN6) was broad, with gradually enhanced expression in CD8(+) T cells with increasing TCR affinities. Consequently, pharmacological inhibition of SHP-1 with sodium stibogluconate augmented the function of all engineered T cells, and this correlated with the TCR affinity-dependent levels of SHP-1. These data highlight an unexpected and global role of SHP-1 in regulating CD8(+) T cell activation and responsiveness and support the development of therapies inhibiting protein tyrosine phosphatases to enhance T cell-mediated immunity

Single cell analysis reveals similar functional competence of dominant and nondominant CD8 T-cell clonotypes.

Immune protection from infectious diseases and cancer is mediated by individual T cells of different clonal origin. Their functions are tightly regulated but not yet fully characterized. Understanding the contribution of each T cell will improve the prediction of immune protection based on laboratory assessment of T-cell responses. Here we developed techniques for simultaneous molecular and functional assessment of single CD8 T cells directly ex vivo. We studied two groups of patients with melanoma after vaccination with two closely related tumor antigenic peptides. Vaccination induced T cells with strong memory and effector functions, as found in virtually all T cells of the first patient group, and fractions of T cells in the second group. Interestingly, high functionality was not restricted to dominant clonotypes. Rather, dominant and nondominant clonotypes acquired equal functional competence. In parallel, this was also found for EBV- and CMV-specific T cells. Thus, the nondominant clonotypes may contribute similarly to immunity as their dominant counterparts

MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells

Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. In this study, we report the identification of MELK as a novel oncogenic kinase from an in vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library. Analysis of clinical data reveals a high level of MELK overexpression in BBC, a feature that is largely dependent on FoxM1, a master mitotic transcription factor that is also found to be highly overexpressed in BBC. Ablation of MELK selectively impairs proliferation of basal-like, but not luminal breast cancer cells both in vitro and in vivo. Mechanistically, depletion of MELK in BBC cells induces caspase-dependent cell death, preceded by defective mitosis. Finally, we find that Melk is not required for mouse development and physiology. Together, these data indicate that MELK is a normally non-essential kinase, but is critical for BBC and thus represents a promising selective therapeutic target for the most aggressive subtype of breast cancer. DOI: http://dx.doi.org/10.7554/eLife.01763.00

Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention

SCOPE: People who carry the apolipoprotein E4 (APOE4) SNP have an increased risk of cardiovascular disease (CVD). Fish-oil supplementation may help in the prevention of CVD, though inter-individual differences in the response to n-3 PUFAs have been observed. We aimed to assess the impact of APOE genotype on peripheral blood mononuclear cell (PBMC) whole genome gene expression at baseline and following a fish-oil intervention.  METHODS AND RESULTS: Participants received 6 months of fish-oil supplementation containing 1800 mg of eicosapentaenoic acid and docosahexaenoic acid per day. APOE genotype and PBMC whole genome gene expression before and after supplementation were measured. We characterized the differences in gene expression profiles in carriers of APOE4 (N = 8) compared to non-carriers (N = 15). At baseline, 1320 genes were differentially expressed and the fish-oil supplementation differentially regulated 866 genes between APOE4 carriers and non-carriers. Gene set enrichment analysis showed that carriers had a higher gene expression of cholesterol biosynthesis and interferon (IFN) signaling pathways. Fish-oil supplementation reduced expression of IFN-related genes in carriers only.  CONCLUSION: The increased expression of IFN signaling and cholesterol biosynthesis pathways might explain part of the association between APOE4 and CVD. Fish-oil supplementation may particularly benefit APOE4 carriers by decreasing expression of IFN-related genes. This article is protected by copyright. All rights reserved