CD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their recruitment to the inflammatory site.

Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response.

Activation of the Wnt/ß-catenin pathway is common in wilms tumor, but rarely through ß-catenin mutation and APC promoter methylation.

PURPOSE: The Wnt/ß-catenin pathway is known to be crucial for the regulation of embryogenesis and cell differentiation, and its constitutive activation is associated with a wide range of malignancies. There are two major principles for an activated Wnt/ß-catenin pathway. The first is caused by the failure of the destruction complex, mainly due to the decreased expression of the tumor suppressor gene adenomatous polyposis coli (APC); the second is the mutation of the ß-catenin (CTNNB1) protein itself. Wilms tumors (WTs) are also thought to be malignancies with a high rate of Wnt/ß-catenin pathway activation. The aim of this study was to analyze a large cohort of WT for activated Wnt/ß-catenin pathway. METHODS: The transcription of axis inhibition protein 2 (AXIN2) and APC was analyzed by real-time PCR. Expression was compared with those in healthy renal tissues as a control. Methylation status of the APC promoter was measured by pyrosequencing and correlated with APC expression. Finally, the mutations of CTNNB1 itself were detected by Sanger sequencing. RESULTS: The analysis was done in a cohort of 103 WTs, treated in our institution. There was a significant overexpression of AXIN2 in WTs (P < 0.0001), with 33 (32 %) tumors showing higher expression (median + 3× SD) than normal kidney tissue. In contrast, the expression of APC as well as its promoter methylation did not differ from control (P = 0.78; P = 0.82). Finally, there were only seven (6.8 %) mutations detectable in CTNNB1, and five out of seven were seen in WTs with AXIN2 overexpression. CONCLUSION: The finding that AXIN2, one of the major Wnt target genes, is overexpressed in our cohort of WTs, is indicative for the activation of the Wnt/ß-catenin pathway. However, neither the alteration of APC nor frequent CTNNB1 mutations were seen in our analyses. Therefore, other mechanisms might be responsible for the common activation of the Wnt/ß-catenin pathway.

Quality assessment of patient information on orthognathic surgery on the internet.

OBJECTIVE: The aim of this study was to assess the quality of online information for patients on orthognathic surgery. MATERIALS AND METHODS: A selection of search terms specific for orthognathic surgery was chosen and 150 websites were identified using the Internet search engines Google, Yahoo and Bing. Irrelevant websites were excluded. The remaining websites were assessed with a modified Ensuring Quality Information for Patients (EQIP) tool. EQIP evaluates the quality of medical patient information by measuring the three key aspects of content, structure, and identification data. RESULTS: 48 relevant websites were identified. EQIP values ranged between 2 and 28 (median 13.65). While 37 of the 48 websites described details of the surgical procedures, only 13 mentioned possible risks and complications of the surgery. No differences were found between the websites of private practices, dentists and public hospitals, universities, or others (p = 0.66). Websites found by Google had a significantly lower EQIP score compared with Yahoo and Bing (11.12 vs. 16.60 for Yahoo and 16.23 for Bing; p = 0.012). The better the rank of the website, the higher the EQIP score (r = -0.411, p = 0.004). CONCLUSIONS: The results of this study reflected a large variation of quality of information on orthognathic surgery on the Internet. Therefore, surgeons must be aware that they might be confronted with unrealistic expectations of patients, who may underestimate the potential risks and drawbacks of orthognathic surgery.

The Influence of Intrinsic Motivation and Synergistic Extrinsic Motivators on Creativity and Innovation.

Despite the vast amount of research focusing on intrinsic and extrinsic motivation, the effects of extrinsic motivators on creativity and innovation have been scarcely investigated. Extrinsic factors can be seen as synergistic extrinsic motivators when they have a positive effect on the outcome. The present study investigates synergistic extrinsic motivators that organizations can use to foster creativity and innovation of their intrinsically motivated knowledge workers. The analysis is based on Amabile and Pratt's dynamic componential model of creativity and innovation in organizations combined with elements from Ryan and Deci's self-determination theory. The quantitative data stemmed from 90 knowledge workers of an international consulting company who participated in an online self-assessment. In exploratory factor analyses, extrinsic motivation items consolidated two factors "relational rewards" and "transactional rewards", while creativity and innovation items resulted in a one-factor solution, called "creativity/innovation performance". The results of hierarchical regression analyses confirmed the widely found positive effects of intrinsic motivation on creative and innovative performance. Moreover, the results supported the hypothesis that the extrinsic motivator, relational rewards, moderated the relationship between intrinsic motivation and creativity/innovation performance significantly and positively. The findings showed the higher the perceived probability of receiving relational rewards and the higher the intrinsic motivation, the greater the positive effect on creative/innovative outcomes. At the same time, the results did not confirm the hypothesis, that the moderator transactional rewards had a statistically significant effect on the relationship between intrinsic motivation and creative/innovative performance. Finally, the empirical evidence provided practical implications on how to stimulate the creativity/innovation performance of knowledge workers within organizations.

Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis.

Apoptosis in response to the ligand CD95L (also known as Fas ligand) is initiated by caspase-8, which is activated by dimerization and self-cleavage at death-inducing signaling complexes (DISCs). Previous work indicated that the degree of substrate cleavage by caspase-8 determines whether a cell dies or survives in response to a death stimulus. To determine how a death ligand stimulus is effectively translated into caspase-8 activity, we assessed this activity over time in single cells with compartmentalized probes that are cleaved by caspase-8 and used multiscale modeling to simultaneously describe single-cell and population data with an ensemble of single-cell models. We derived and experimentally validated a minimal model in which cleavage of caspase-8 in the enzymatic domain occurs in an interdimeric manner through interaction between DISCs, whereas prodomain cleavage sites are cleaved in an intradimeric manner within DISCs. Modeling indicated that sustained membrane-bound caspase-8 activity is followed by transient cytosolic activity, which can be interpreted as a molecular timer mechanism reflected by a limited lifetime of active caspase-8. The activation of caspase-8 by combined intra- and interdimeric cleavage ensures weak signaling at low concentrations of CD95L and strongly accelerated activation at higher ligand concentrations, thereby contributing to precise control of apoptosis.

APG350 induces superior clustering of TRAIL receptors and shows therapeutic antitumor efficacy independent of cross-linking via Fcγ receptors.

Cancer cells can be specifically driven into apoptosis by activating Death-receptor-4 (DR4; TRAIL-R1) and/or Death-receptor-5 (DR5; TRAIL-R2). Albeit showing promising preclinical efficacy, first-generation protein therapeutics addressing this pathway, especially agonistic anti-DR4/DR5-monoclonal antibodies, have not been clinically successful to date. Due to their bivalent binding mode, effective apoptosis induction by agonistic TRAIL-R antibodies is achieved only upon additional events leading to antibody-multimer formation. The binding of these multimers to their target subsequently leads to effective receptor-clustering on cancer cells. The research results presented here report on a new class of TRAIL-receptor agonists overcoming this intrinsic limitation observed for antibodies in general. The main feature of these agonists is a TRAIL-mimic consisting of three TRAIL-protomer subsequences combined in one polypeptide chain, termed the single-chain TRAIL-receptor-binding domain (scTRAIL-RBD). In the active compounds, two scTRAIL-RBDs with three receptor binding sites each are brought molecularly in close proximity resulting in a fusion protein with a hexavalent binding mode. In the case of APG350-the prototype of this engineering concept-this is achieved by fusing the Fc-part of a human immunoglobulin G1 (IgG1)-mutein C-terminally to the scTRAIL-RBD polypeptide, thereby creating six receptor binding sites per drug molecule. In vitro, APG350 is a potent inducer of apoptosis on human tumor cell lines and primary tumor cells. In vivo, treatment of mice bearing Colo205-xenograft tumors with APG350 showed a dose-dependent antitumor efficacy. By dedicated muteins, we confirmed that the observed in vivo efficacy of the hexavalent scTRAIL-RBD fusion proteins is-in contrast to agonistic antibodies-independent of FcγR-based cross-linking events.