Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis.

Dissecting the Helicobacter pylori-regulated transcriptome of B cells.

Persistent infections with the bacterial group-I carcinogen Helicobacter pylori (H. pylori) have been associated with a broad range of gastric disorders, including gastritis, ulceration, gastric cancer or mucosa-associated lymphoid tissue (MALT) lymphoma. Pathogenesis of H.

Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells.

Background: Aberrant hedgehog (HH) signaling is implicated in the development of various cancer entities such as medulloblastoma. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Increased phosphorylation of essential effectors such as Smoothened (SMO) and GLI proteins by kinases including Protein Kinase A, Casein Kinase 1, and Glycogen Synthase Kinase 3 β controls effector activity, stability and processing.

Platform independent protein-based cell-of-origin subtyping of diffuse large B-cell lymphoma in formalin-fixed paraffin-embedded tissue.

Diffuse large B-cell lymphoma (DLBCL) is commonly classified by gene expression profiling according to its cell of origin (COO) into activated B-cell (ABC)-like and germinal center B-cell (GCB)-like subgroups. Here we report the application of label-free nano-liquid chromatography - Sequential Window Acquisition of all THeoretical fragment-ion spectra - mass spectrometry (nanoLC-SWATH-MS) to the COO classification of DLBCL in formalin-fixed paraffin-embedded (FFPE) tissue. To generate a protein signature capable of predicting Affymetrix-based GCB scores, the summed log-transformed fragment ion intensities of 780 proteins quantified in a training set of 42 DLBCL cases were used as independent variables in a penalized zero-sum elastic net regression model with variable selection.

Multiple roles of Bet v 1 ligands in allergen stabilization and modulation of endosomal protease activity.

Background: Over 100 million people worldwide suffer from birch pollen allergy. Bet v 1 has been identified as the major birch pollen allergen. However, the molecular mechanisms of birch allergic sensitization, including the roles of Bet v 1 and other components of the birch pollen extract, remain incompletely understood.

Understanding cell signaling in cancer stem cells for targeted therapy - can phosphoproteomics help to reveal the secrets?

Background: Cancer represents heterogeneous and aberrantly proliferative manifestations composed of (epi)genetically and phenotypically distinct cells with a common clonal origin. Cancer stem cells (CSC) make up a rare subpopulation with the remarkable capacity to initiate, propagate and spread a malignant disease. Furthermore, CSC show increased therapy resistance, thereby contributing to disease relapse.

Limiting the Number of Potential Binding Modes by Introducing Symmetry into Ligands: Structure-Based Design of Inhibitors for Trypsin-Like Serine Proteases.

In the absence of X-ray data, the exploration of compound binding modes continues to be a challenging task. For structure-based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin-like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties.

A Bisbenzamidine Phosphonate as a Janus-faced Inhibitor for Trypsin-like Serine Proteases.

A hybrid approach was applied for the design of an inhibitor of trypsin-like serine proteases. Compound 16 [(R,R)- and (R,S)-diphenyl (4-(1-(4-amidinobenzylamino)-1-oxo-3-phenylpropan-2-ylcarbamoyl)phenylamino)(4-amidinophenyl)methylphosphonate hydrochloride], prepared in a convergent synthetic procedure, possesses a phosphonate warhead prone to react with the active site serine residue in a covalent, irreversible manner. Each of the two benzamidine moieties of 16 can potentially be accommodated in the S1 pocket of the target enzyme, but only the benzamidine close to the phosphonate group would then promote an irreversible interaction.