Biomedical subjects

Martin Schiller

Publications and source records attributed to Martin Schiller.

8 recordsLinked to original sources

PubMed2006

Interleukin-4 supports interleukin-12-induced proliferation and interferon-gamma secretion in human activated lymphoblasts and T helper type 1 cells.

Interleukin-12 (IL-12) and IL-4 are known to differentially promote T helper (Th) cell differentiation. While IL-12 induces interferon-gamma (IFN-gamma) production and maturation of Th1 cells, IL-4 is thought to antagonize IL-12 and to favour Th2 development. Here we studied the combined action of various concentrations of common gamma-chain (gamma(c)-chain) cytokines, including IL-4 and the Th1 cytokine IL-12, in human activated lymphoblasts and Th1 cells. IL-4 and IL-7 potentiated IL-12-induced proliferation at every concentration tested (1-10 ng/ml) without increasing rescue from apoptosis, indicating that proliferation was directly affected by these cytokine combinations. With regards to cytokine secretion, IL-2 together with IL-12 initiated tumour necrosis factor-alpha synthesis, enhanced IFN-gamma production, and shedding of soluble IL-2 receptor alpha as expected. Importantly, combining IL-4 with IL-12 also enhanced IFN-gamma secretion in lymphoblasts and a Th1 cell line. Investigating signal transduction in lymphoblasts induced by these cytokines, we found that not only IL-2 but also IL-4 enhances signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation by IL-12. Tyrosine phosphorylations of janus kinase 2 (JAK-2), tyrosine kinase 2 (TYK2), extracellular signal-regulated kinase (ERK) and STAT4, STAT5 and STAT6 were not potentiated by combinations of these cytokines, suggesting specificity for increased STAT3 phosphorylation. In conclusion, two otherwise antagonizing cytokines co-operate in activated human lymphoblasts and Th1 cells, possibly via STAT3 as a converging signal. These data demonstrate that IL-4 can directly enhance human Th1 cell function independently of its known actions on antigen-presenting cells. These findings should be of importance for the design of cytokine-targeted therapies of human Th-cell-driven diseases.

Apoptosis↗

PubMed2005

Inhibition of sphingolipid synthesis impairs cellular activation, cytokine production and proliferation in human lymphocytes.

The localisation of the T cell receptor and other signalling molecules in membrane microdomains (MM) is essential for the activation of T lymphocytes. These MM are stabilized by sphingolipids and cholesterol. It was recently shown that the activation of T lymphocytes leads to the confluence of small MM and the formation of an immunological synapse which is thought to be essential for a persistent activation and proliferation. We studied the effects of an inhibition of sphingolipid synthesis on T lymphocyte function. Both sphingolipid inhibitors, PDMP and myriocin, inhibited glucosphingolipids in whole cell lipid extracts and in MM. Both compounds inhibited the proliferation of superantigen-stimulated PBMC without inducing cell death. However, only the ceramide-like compound PDMP inhibited the expression of activation markers and the secretion of IFN-gamma which was not seen with myriocin treatment. The MM localisation of Lck and LAT was not significantly reduced in PDMP-treated cells. In conclusion, our results show that glucosphingolipids are necessary for cell growth of human T lymphocytes. However, inhibition of glucosphingolipid synthesis itself did not inhibit cellular activation. Our data show that glucosphingolipids - in contrast to cholesterol - are not essential for the stabilisation of MM.

Cell Division↗

PubMed2005

High-performance exact algorithms for motif search.

OBJECTIVE: The human genome project has resulted in the generation of voluminous biological data. Novel computational techniques are called for to extract useful information from this data. One such technique is that of finding patterns that are repeated over many sequences (and possibly over many species). In this paper we study the problem of identifying meaningful patterns (i.e., motifs) from biological data, the motif search problem. METHODS: The general version of the motif search problem is NP-hard. Numerous algorithms have been proposed in the literature to solve this problem. Many of these algorithms fall under the category of heuristics. We concentrate on exact algorithms in this paper. In particular, we concentrate on two different versions of the motif search problem and offer exact algorithms for them. RESULTS: In this paper we present algorithms for two versions of the motif search problem. All of our algorithms are elegant and use only such simple data structures as arrays. For the first version of the problem described as Problem 1 in the paper, we present a simple sorting based algorithm, SMS (Simple Motif Search). This algorithm has been coded and experimental results have been obtained. For the second version of the problem (described in the paper as Problem 2), we present two different algorithms--a deterministic algorithm (called DMS) and a randomized algorithm (Monte Carlo algorithm). We also show how these algorithms can be parallelized. CONCLUSIONS: All the algorithms proposed in this paper are improvements over existing algorithms for these versions of motif search in biological sequence data. The algorithms presented have the potential of performing well in practice.

Algorithms↗

PubMed2003

[Burnout in Residential Drug- and Alcohol Treatment]

OBJECTIVE: The study aimed at comparing burnout in staff members at residential drug and alcohol detoxification wards with and without teamsupervision. METHOD: 4 times in a period of 18 month all staff members (n = 44) were assessed for burnout using a german version (Checkliste Burnoutmerkmale) of the Maslach Burnout Inventory (MBI, Maslach u. Jackson 1986) to asses the severity and the CBE (Checkliste Burnoutentstehungsmerkmale) for associated burnout risc-factors. RESULT: There was no statistical differences between the mean scores of the 3 different wards due to extreme SDs. The interpersonal differences among staff on the 4 occasions were remarkably. On repeated measurements the intraindividual changes were high. Higher scores were correlated with high workload (seen as frequent admissions). CONCLUSION: Work-related variables (admissions) turned out to be of more importance than supervision in times of chronic staff-shortage.

Journal Article↗

PubMed2003

[Burnout in alcohol and drug withdrawal treatment. Comparison of 2 different departments over the course of 18 months].

Adult↗

PubMed2002

A fast, simple and sensitive method for the detection and quantification of detergent-resistant membranes.

The aggregation of the T cell receptor and other signaling molecules leads to the formation of large molecular activation clusters in the cell membrane. These molecular clusters are associated with a high concentration of cholesterol, sphingomyelin and gangliosides and were referred to as lipid microdomains. Electron microscopy studies of viable cells indicate that distinct subgroups of lipid microdomains exist and they contain different types of signaling molecules. Lipid microdomains are insoluble in ice-cold solutions containing detergent and are also referred to as detergent-resistant membranes (DRM). Currently, sucrose density centrifugation is the standard method for DRM isolation. Cholera toxin B subunit (CTB) is a specific ligand for ganglioside GM1 and can be used for the detection of GM1 containing DRM. In this paper, we describe a new and simple method for quantification of GM1 associated with DRM. We used a CTB-horseradish peroxidase (HRP) conjugate and 2,2'-azino-di-3-ethyl-benzthiazoline-6-sulfonic acid (ABTS) for the detection of DRM in floating fractions of a sucrose density gradient. Absorbance values (A(405)) were determined using a microtiter plate and an ELISA plate reader. The linear range for the HRP-ABTS reaction was determined in the presence of lysis buffer and sucrose concentrations up to 40%. Linearity of the assay was determined over a wide range (5-1000 microU peroxidase activity per well) in a single experiment and the limit of detection of this method was approximately 10 ng of CTB per gradient fraction. The method is nonradioactive, rapid and easy and can be used for the analysis of DRM resident proteins. We applied this method to Jurkat T cells and after centrifugation observed the existence of DRM floating to 5%/30% sucrose interface. After separation of the sucrose gradient, we identified a large GM1 content in the corresponding fractions 4 to 6. The presence of protein in these fractions was confirmed by silver-stained polyacrylamide gels. We confirmed the presence of adaptor molecules (LAT) and Src kinases (Lck) in the DRM containing fractions 4 to 6.

Benzothiazoles↗

PubMed2002

Enhanced killing of B lymphoma cells by granulocyte colony-stimulating factor-primed effector cells and Hu1D10--a humanized human leucocyte antigen DR antibody.

Antibody-based approaches have become a novel treatment modality for lymphoma patients. Humanized 1D10 (Hu1D10; Remitogen) is among the antibodies that are currently under evaluation in phase II clinical trials in lymphoma patients. The 1D10 antibody is directed against a polymorphic epitope on the beta-chain of human leucocyte antigen (HLA) class II. We found expression of the 1D10 epitope on B cells and monocytes from approximately 50% of healthy donors. Analyses of 1D10 expression on malignant cells revealed that approximately half of the HLA class II-positive haematological malignancies expressed the 1D10 epitope. In whole blood antibody-dependent cellular cytotoxicity (ADCC) assays, Hu1D10 was more effective than rituxan in killing malignant ARH-77 B cells. Interestingly, Hu1D10-mediated lymphoma cell lysis was significantly enhanced when blood from granulocyte colony-stimulating factor (G-CSF)-treated patients was compared with blood from healthy controls. Analyses of the relevant effector cell populations revealed that FcgammaRI (CD64)-positive polymorphonuclear cells were critical for enhanced Hu1D10-mediated lymphoma killing during G-CSF therapy, while the same effector cell population induced only marginal lysis with rituxan. Furthermore, Hu1D10 was highly effective in inducing apoptosis in primary lymphoma cells from B chronic lymphocytic leukaemia patients. These preclinical results form the basis for a phase I/II clinical trial of Hu1D10 in combination with G-CSF.

Adoptive Transfer↗

PubMed2002

[Death by illegal drugs in Bavaria-data from 1990 up to 2000].

Abstract. Mortality has often been regarded as a measure for overall outcome and both treatment and drug policy effectiveness. The number of deaths by illegal drugs from the years 1990 - 2000 in Bavaria were analysed using statistical trend tests (Spearman rho and Kendall tau). In Bavaria in general (p = 0.014) as well as in 5 out of seven counties a significant increase in drug related mortality was found.

Cause of Death↗