Inhibition of Human Urokinase-Type Plasminogen Activator (uPA) Enzyme Activity and Receptor Binding by DNA Aptamers as Potential Therapeutics through Binding to the Different Forms of uPA.

Urokinase-type plasminogen activator is widely discussed as a marker for cancer prognosis and diagnosis and as a target for cancer therapies. Together with its receptor, uPA plays an important role in tumorigenesis, tumor progression and metastasis. In the present study, systematic evolution of ligands by exponential enrichment (SELEX) was used to select single-stranded DNA aptamers targeting different forms of human uPA.

ICOS Costimulation Differentially Affects T Cells in Secondary Lymphoid Organs and Inflamed Tissues.

B-cell interaction with follicular helper T cells and subsequent differentiation of B cells into high-affinity APCs normally takes place in secondary lymphoid organs. The costimulator ICOS plays a key role in this process and is therefore considered as an attractive target to modulate exaggerated B-cell responses in autoimmune or allergic diseases. Inflamed tissues were recently recognized as additional sites of active T-cell/B-cell interaction.

Quantification of MicroRNAs in Urine-Derived Specimens.

MicroRNAs are small noncoding RNAs which regulate the expression of genes involved in a multitude of cellular processes. Dysregulation of microRNAs and-in consequence-of the affected pathways is frequently observed in numerous pathologies including cancers. Therefore, tumor-related alterations in microRNA expression and function can reflect molecular processes of tumor onset and progression qualifying microRNAs as potential diagnostic and prognostic biomarkers.

Validation of the diagnostic utility of urinary midkine for the detection of bladder cancer.

As it has been demonstrated previously that midkine (also known as neurite growth-promoting factor 2) protein levels in urine of bladder cancer (BCa) patients are increased compared to healthy controls, the present study validated the diagnostic utility of midkine in an independent patient cohort and compared the observed values with voided urine cytology (VUC), which is the current reference standard for non-invasive diagnosis of BCa. Voided urine samples were prospectively collected from 92 BCa patients and 70 control subjects. Protein levels of midkine were assessed using a commercially available enzyme-linked immunosorbent assay and normalized to urinary creatinine.

Local T/B cooperation in inflamed tissues is supported by T follicular helper-like cells.

Autoimmune diseases and other inflammatory conditions are characterized by large lymphocytic tissue infiltrates in which T and B cells can be found in close contact. Here, using a murine airway inflammation model, we compare antigen-specific T and B cells in lung tissue versus lung-draining lymph node. In the lung we identify a B-cell population exhibiting a classical germinal centre phenotype without being organized into ectopic lymphoid tissue.

ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2.

The co-stimulators ICOS (inducible T cell co-stimulator) and CD28 are both important for T follicular helper (TFH) cells, yet their individual contributions are unclear. Here, we show that each molecule plays an exclusive role at different stages of TFH cell development. While CD28 regulated early expression of the master transcription factor Bcl-6, ICOS co-stimulation was essential to maintain the phenotype by regulating the novel TFH transcription factor Klf2 via Foxo1.

Comprehensive analysis of CD4+ T cells in the decision between tolerance and immunity in vivo reveals a pivotal role for ICOS.

We have established a comprehensive in vivo mouse model for the CD4(+) T cell response to an "innocuous" versus "dangerous" exogenous Ag and developed an in vivo test for tolerance. In this model, specific gene-expression signatures, distinctive upregulation of early T cell-communication molecules, and differential expansion of effector T cells (Teff) and regulatory T cells (Treg) were identified as central correlates of T cell tolerance and T cell immunity. Different from essentially all other T cell-activation molecules, ICOS was found to be induced in the immunity response and not by T cells activated under tolerogenic conditions.

Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs.

Background: Under inflammatory conditions, T cell-dependent (TD) protein antigens induce proinflammatory T- and B-cell responses. In contrast, tolerance induction by TD antigens without costimulation triggers the development of regulatory T cells. Under both conditions, IgG antibodies are generated, but whether they have different immunoregulatory functions remains elusive.