Blood levels of Glial Fibrillary Acidic Protein (GFAP) in patients with neurological diseases

Background and Purpose: The brain-specific astroglial protein GFAP is a blood biomarker candidate indicative of intracerebral hemorrhage in patients with symptoms suspicious of acute stroke. Comparably little, however, is known about GFAP release in other neurological disorders. In order to identify potential “specificity gaps” of a future GFAP test used to diagnose intracerebral hemorrhage, we measured GFAP in the blood of a large and rather unselected collective of patients with neurological diseases. Methods: Within a one-year period, we randomly selected in-patients of our university hospital for study inclusion. Patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage were excluded. Primary endpoint was the ICD-10 coded diagnosis reached at discharge. During hospital stay, blood was collected, and GFAP plasma levels were determined using an advanced prototype immunoassay at Roche Diagnostics. Results: A total of 331 patients were included, covering a broad spectrum of neurological diseases. GFAP levels were low in the vast majority of patients, with 98.5% of cases lying below the cut-off that was previously defined for the differentiation of intracerebral hemorrhage and ischemic stroke. No diagnosis or group of diagnoses was identified that showed consistently increased GFAP values. No association with age and sex was found. Conclusion: Most acute and chronic neurological diseases, including typical stroke mimics, are not associated with detectable GFAP levels in the bloodstream. Our findings underline the hypothesis that rapid astroglial destruction as in acute intracerebral hemorrhage is mandatory for GFAP increase. A future GFAP blood test applied to identify patients with intracerebral hemorrhage is likely to have a high specificity

An advanced decision support system for European disaster management : the feature of the skills taxonomy

Mankind has faced a huge increase in severe natural and man-made disasters worldwide in the last few years. Emergency responders on a strategic, tactical, and operational level can be assisted by decision support systems (DSS) to enhance disaster preparedness, response, and recovery. Policy makers are in need of an advanced, resilient and integrated incident command and control systems for emergency responders that incorporates health care-related features. To address this need, a DSS was developed in the European Union (EU) project named Securing Health.Emergency.Learning.Planning (S-HELP). Improving the health care delivery process through health care-related DSS features, the identification of key emergency responders and their associated tasks performed in preparedness, response, and recovery-related interventions is absolutely necessary. Thus, we establish a skills taxonomy for the S-HELP DSS Toolset “Decision Making Module” to interlink key emergency interventions/tasks with main national emergency responders supported by international emergency responders with a special focus on the EU. Furthermore, we provide an overview of which key emergency interventions/tasks can be covered by EU Civil Protection Modules by incorporating availability, start of operation, self-sufficiency, and operation time. This skills taxonomy for the S-HELP DSS Toolset “Decision Making Module” improves the interoperability of emergency responders when they cope with major disasters such as mass flooding, chemical spills, and biological-hazards policy scenarios that impact on health care. In the future, operation research models related to fields such as humanitarian logistics or disease control could be incorporated into or benefit from the S-HELP DSS

Patients are grouped according to discharge diagnosis (“ICD” = International Classification of Diseases).

<p>“n” depicts the number of patients per diagnosis. “n<0.05” displays the number of patients per diagnosis with GFAP values below the lower detection limit of the used immunoassay. The remaining values (those above the lower detection limit) are displayed as individual values in the graph. Individual patients with increased GFAP values are easy to recognize. Mean GFAP values and standard deviation (SD) are also provided for each diagnosis. The diagnoses with the three highest mean GFAP values are labelled in red. * = GFAP value of one sample is missing. ** = Results of the BE FAST study for comparison <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062101#pone.0062101-Foerch2" target="_blank">[4]</a>.</p

Inhibition of p90 ribosomal S6 kinases disrupts melanoma cell growth and immune evasion

Abstract Background The mitogen-activated protein kinase (MAPK) signaling pathway is frequently hyperactivated in malignant melanoma and its inhibition has proved to be an efficient treatment option for cases harboring BRAFV600 mutations (BRAFMut). However, there is still a significant need for effective targeted therapies for patients with other melanoma subgroups characterized by constitutive MAPK activation, such as tumors with NRAS or NF-1 alterations (NRASMut, NF-1LOF), as well as for patients with MAPK pathway inhibitor-resistant BRAFMut melanomas, which commonly exhibit a reactivation of this pathway. p90 ribosomal S6 kinases (RSKs) represent central effectors of MAPK signaling, regulating cell cycle progression and survival. Methods RSK activity and the functional effects of its inhibition by specific small molecule inhibitors were investigated in established melanoma cell lines and patient-derived short-term cultures from different MAPK pathway-hyperactivated genomic subgroups (NRASMut, BRAFMut, NF-1LOF). Real-time qPCR, immunoblots and flow cytometric cell surface staining were used to explore the molecular changes following RSK inhibition. The effect on melanoma cell growth was evaluated by various two- and three-dimensional in vitro assays as well as with melanoma xenograft mouse models. Co-cultures with gp100- or Melan-A-specific cytotoxic T cells were used to assess immunogenicity of melanoma cells and associated T-cell responses. Results In line with elevated activity of the MAPK/RSK signaling axis, growth and survival of not only BRAFMut but also NRASMut and NF-1LOF melanoma cells were significantly impaired by RSK inhibitors. Intriguingly, RSK inhibition was particularly effective in three-dimensional growth settings with long-term chronic drug exposure and suppressed tumor cell growth of in vivo melanoma models. Additionally, our study revealed that RSK inhibition simultaneously promoted differentiation and immunogenicity of the tumor cells leading to enhanced T-cell activation and melanoma cell killing. Conclusions Collectively, RSK inhibitors exhibited both multi-layered anti-tumor efficacy and broad applicability across different genomic melanoma subgroups. RSK inhibition may therefore represent a promising novel therapeutic strategy for malignant melanoma with hyperactivated MAPK signaling

Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke

Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach

Additional file 9 of Inhibition of p90 ribosomal S6 kinases disrupts melanoma cell growth and immune evasion

Additional file 9: Supplementary Figure Legends

Additional file 4 of Inhibition of p90 ribosomal S6 kinases disrupts melanoma cell growth and immune evasion

Additional file 4: Suppl. Figure S4. Anchorage-independent growth and colony formation of melanoma cell lines is suppressed by RSK inhibitors