Analyzing M-CSF dependent monocyte/macrophage differentiation: Expression modes and meta-modes derived from an independent component analysis

<p>Abstract</p> <p>Background</p> <p>The analysis of high-throughput gene expression data sets derived from microarray experiments still is a field of extensive investigation. Although new approaches and algorithms are published continuously, mostly conventional methods like hierarchical clustering algorithms or variance analysis tools are used. Here we take a closer look at independent component analysis (ICA) which is already discussed widely as a new analysis approach. However, deep exploration of its applicability and relevance to concrete biological problems is still missing. In this study, we investigate the relevance of ICA in gaining new insights into well characterized regulatory mechanisms of M-CSF dependent macrophage differentiation.</p> <p>Results</p> <p>Statistically independent gene expression modes (GEM) were extracted from observed gene expression signatures (GES) through ICA of different microarray experiments. From each GEM we deduced a group of genes, henceforth called <it>sub-mode</it>. These <it>sub-modes </it>were further analyzed with different database query and literature mining tools and then combined to form so called <it>meta-modes</it>. With them we performed a knowledge-based pathway analysis and reconstructed a well known signal cascade.</p> <p>Conclusion</p> <p>We show that ICA is an appropriate tool to uncover underlying biological mechanisms from microarray data. Most of the well known pathways of M-CSF dependent monocyte to macrophage differentiation can be identified by this unsupervised microarray data analysis. Moreover, recent research results like the involvement of proliferation associated cellular mechanisms during macrophage differentiation can be corroborated.</p

Mobilisation of Hematopoietic CD34+ Precursor Cells in Patients with Acute Stroke Is Safe - Results of an Open-Labeled Non Randomized Phase I/II Trial

German Clinical Trial Register DRKS 00000723

Severe T cell hyporeactivity in ventilated COVID-19 patients correlates with prolonged virus persistence and poor outcomes

Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity.Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity

Chronic lymphocytic leukemia cells induce anti-apoptotic effects of bone marrow stroma

The prolonged life span of chronic lymphocytic leukemia (CLL) cells in vivo is assumed to depend on the surrounding microenvironment since this biologic feature is lost in vitro. We studied here the molecular interactions between CLL cells and their surrounding stroma to identify factors that help CLL cells to resist apoptosis. Sorted CLL cells from 21 patients were cultured in vitro on allogenous, normal bone marrow stromal cells (BMSCs) in the presence/absence of CD40 ligand or in culture medium alone. Surface and mRNA expression of interaction molecules, cytokine production, and apoptosis rate was measured by flow cytometric, real-time PCR and standard immunologic assays. The interaction between CLL cells and BMSCs rescued CLL cells from apoptosis. BMSCs co-cultured with CLL cells showed a strong increase in IL-8 and IL-6 secretion and up-regulated the expression of ICAM-1 and CD40 mRNA. The mRNA expression of CXCL12 and VCAM1 remained unchanged. In turn, CLL cells in interaction with BMSCs significantly up-regulated the expression of CD18 and CD49d that are ligands for the critical adhesion molecules on BMSCs. As a validation of the in vitro data, we found a significant higher expression of CD49d on CLL cells in bone marrow aspirates compared to peripheral blood CLL cells in patient samples. Up-regulation of adhesion molecules and their ligands in CLL–BMSCs interaction along with the increased cytokine production of BMSCs indicate a strong effect of CLL cells on BMSCs in favor of their apoptosis resistance

Urinary N‐terminal pro‐brain natriuretic peptide: prognostic value in patients with acute chest pain

Abstract Aims The objective of this study was to investigate the prognostic value of urinary N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with plasma NT‐proBNP in patients presenting with acute chest pain in the emergency department. Methods and results We measured simultaneously plasma and urinary NT‐proBNP at admission in 301 patients with acute chest pain. In our cohort, 174 patients suffered from acute coronary syndrome (ACS). A follow‐up (median of 55 months) was performed regarding the endpoints all‐cause mortality and major adverse cardiac events (mortality, congestive heart failure, ACS with the necessity of a coronary intervention, and stroke). Fifty‐four patients died during follow‐up; 98 suffered from the combined endpoint. A significant and positive correlation of urinary and plasma NT‐proBNP was found (r = 0.87, P < 0.05). Patients with troponin positive ACS had significantly elevated levels of plasma and urinary NT‐proBNP compared with those with unstable angina pectoris or chest wall syndrome (each P < 0.05). The highest levels of both biomarkers were found in patients with congestive heart failure (each P < 0.05). According to Kaplan–Meier analysis, plasma and urinary NT‐proBNP were significant predictors for mortality and the combined endpoint in the whole study cohort and in the subgroup of patients with ACS (each P < 0.05). Regarding Cox regression analysis, plasma and urinary NT‐proBNP were independent predictors for mortality and the combined endpoint (each P < 0.05). Conclusions Urinary NT‐proBNP seems to provide a significant predictive value regarding the endpoints all‐cause mortality and major adverse cardiac events in patients with acute chest pain and those with ACS

Urinary N‐terminal pro‐brain natriuretic peptide: prognostic value in patients with acute chest pain

Abstract Aims The objective of this study was to investigate the prognostic value of urinary N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with plasma NT‐proBNP in patients presenting with acute chest pain in the emergency department. Methods and results We measured simultaneously plasma and urinary NT‐proBNP at admission in 301 patients with acute chest pain. In our cohort, 174 patients suffered from acute coronary syndrome (ACS). A follow‐up (median of 55 months) was performed regarding the endpoints all‐cause mortality and major adverse cardiac events (mortality, congestive heart failure, ACS with the necessity of a coronary intervention, and stroke). Fifty‐four patients died during follow‐up; 98 suffered from the combined endpoint. A significant and positive correlation of urinary and plasma NT‐proBNP was found (r = 0.87, P < 0.05). Patients with troponin positive ACS had significantly elevated levels of plasma and urinary NT‐proBNP compared with those with unstable angina pectoris or chest wall syndrome (each P < 0.05). The highest levels of both biomarkers were found in patients with congestive heart failure (each P < 0.05). According to Kaplan–Meier analysis, plasma and urinary NT‐proBNP were significant predictors for mortality and the combined endpoint in the whole study cohort and in the subgroup of patients with ACS (each P < 0.05). Regarding Cox regression analysis, plasma and urinary NT‐proBNP were independent predictors for mortality and the combined endpoint (each P < 0.05). Conclusions Urinary NT‐proBNP seems to provide a significant predictive value regarding the endpoints all‐cause mortality and major adverse cardiac events in patients with acute chest pain and those with ACS

Histograms and expression profiles of an untransformed (A) and logarithmic corrected (B) microarray expression data set

<p><b>Copyright information:</b></p><p>Taken from "Analyzing M-CSF dependent monocyte/macrophage differentiation: Expression modes and meta-modes derived from an independent component analysis"</p><p>http://www.biomedcentral.com/1471-2105/9/100</p><p>BMC Bioinformatics 2008;9():100-100.</p><p>Published online 17 Feb 2008</p><p>PMCID:PMC2277398.</p><p></p

Maximum-likelihood Pearson fit of the EM-densities, for EM number 3 in (a) and number 12 in (b)

The corresponding four moments are () = 1.4, () = 1.0, skewness() = -0.95 and kurtosis() = 4.0 for (a) and () = -0.84, () = 1.0, skewness() = 0.49 and kurtosis() = 4.4 for (b).<p><b>Copyright information:</b></p><p>Taken from "Analyzing M-CSF dependent monocyte/macrophage differentiation: Expression modes and meta-modes derived from an independent component analysis"</p><p>http://www.biomedcentral.com/1471-2105/9/100</p><p>BMC Bioinformatics 2008;9():100-100.</p><p>Published online 17 Feb 2008</p><p>PMCID:PMC2277398.</p><p></p

Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy

Rationale: X-linked adrenoleukodystrophy (X-ALD) is a rare disorder caused by mutations in the ABCD1 gene, coding for peroxisomal membrane transporter adrenoleukodystrophy (ALD) protein. The disease is characterized by accumulation of very long chain fatty acids (VLCFAs) in tissues. Adult adrenomyeloneuropathy (AMN) and the cerebral inflammatory form of ALD are the main phenotypes presenting various symptoms. Patient concerns: We report a case of 37-year-old patient with diagnosis of X-ALD, confirmed based on elevated VLCFA concentrations and genetic testing of ABCD1 gene. The complete clinical picture in the patient indicates AMN phenotype with cerebral involvement. Diagnoses: The reduced synthesis of unconjugated cholic and chenodeoxycholic acids, and the reduction to 28% to 29% of peroxisomal beta-oxidation of behenic acid and normal peroxisomal metabolism of pristanic and palmitic acid were observed in the X-ALD patient. Sanger sequencing of major genes involved in primary bile acid (BA) synthesis failed to identify pathogenic mutations of the investigated set of genes. Interventions: Plasma concentrations of BAs, VLCFAs, and beta-oxidation of C22:0, C16:0, and pristanic acid were studied in primary skin fibroblasts of the patient. In addition, we performed sequencing of the ABCD1, ABCD3, CYP7A1, CYP7B1, CYP27A1, HSD3B7, AKR1D1, and SLC27A5 genes in the X-ALD family. Outcomes: In the Polish family affected with AMN a dysregulation of the primary BA synthesis pathway was found. Lessons: We have demonstrated the coincidence of the adult form of X-ALD with abnormalities in BA synthesis. We suggest that decreased synthesis of BAs may be an additional dysfunction as a consequence of the ABCD1 c.659T>C, p.(Leu220Pro) mutation and may be further evidence that disturbed cholesterol metabolism is important in the pathology of ALD

The role of the tubular biomarkers NAG, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in patients with chest pain before contrast media exposition

Aim: We evaluated the role of the tubular biomarkers N-acetyl-ss-D-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in patients with chest pain. Methods: Serum and urine samples were collected of 223 patients and 47 healthy controls. None of them was exposed to contrast media. Results: NAG showed among others significant correlation with N-terminal pro brain natriuretic peptide (NTproBNP), troponin I and creatinine. KIM-1 and NGAL showed weaker correlations. NAG was significantly elevated in all subgroups of acute coronary syndrome (ACS) compared with chest wall syndrome and controls. NAG was an independent predictor for the diagnosis of myocardial infarction. Conclusion: NAG may demonstrate the presence of acute tubular injury due to cardiac impairment already in the emergency department. NAG should be evaluated as marker of acute cardiorenal syndrome in patients with chest pain