In vivo mapping of notch pathway activity in normal and stress hematopoiesis.

Accumulating evidence suggests that Notch signaling is active at multiple points during hematopoiesis. Until recently, the majority of such studies focused on Notch signaling in lymphocyte differentiation and knowledge of individual Notch receptor roles has been limited due to a paucity of genetic tools available. In this manuscript we generate and describe animal models to identify and fate-map stem and progenitor cells expressing each Notch receptor, delineate Notch pathway activation, and perform in vivo gain- and loss-of-function studies dissecting Notch signaling in early hematopoiesis.

Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice.

The conserved role of Notch signaling in controlling intestinal cell fate specification and homeostasis has been extensively studied. Nevertheless, the precise identity of the cells in which Notch signaling is active and the role of different Notch receptor paralogues in the intestine remain ambiguous, due to the lack of reliable tools to investigate Notch expression and function in vivo. We generated a new series of transgenic mice that allowed us, by lineage analysis, to formally prove that Notch1 and Notch2 are specifically expressed in crypt stem cells.

Genome wide expression profiling of human peripheral blood mononuclear cells stimulated with BAY 50-4798, a novel T cell selective interleukin-2 analog.

BAY 50-4798, a novel, engineered form of interleukin (IL)-2, is a selective agonist for the high-affinity IL-2 receptor and induces the proliferation of activated human T cells with potency similar to recombinant IL-2 (rIL-2), but has reduced proliferative activity on natural killer cells and is associated with a diminished secondary cytokine cascade. In the current study, the transcriptional profiles of human peripheral blood mononuclear cells (PBMCs) stimulated in vitro with BAY 50-4798 and rIL-2 were compared using Affymetrix microarray technology in combination with Ingenuity Pathway Analysis (IPA) to determine whether there are quantitative or qualitative differences in the molecular networks activated by these IL-2 analogs. A total of 299 genes were differentially expressed in response to the two IL-2 analogs, with an increase in the number of differences over time.

Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog.

Recombinant interleukin-2 (IL-2) (aldesleukin, Proleukin, Chiron, Emeryville, CA) is approved for treatment of cancer patients and under investigation in HIV-infected individuals. However, treatment with aldesleukin is associated with toxicity, which may be due to its elicitation of inflammatory mediators from cells that express the intermediate-affinity IL-2 receptor. BAY 50-4798, a novel IL-2 analog, is a selective agonist for the high-affinity receptor.