In search of the origins and enduring impact of agile software development

The Agile Manifesto is a philosophical touchpoint for all agile software development (ASD) methods. We examine the manifesto and some of its associated agile methods in an effort to identify the major impacts of ASD. We have encountered some difficulty in delineating agile and non-agile software processes, which is partially the result of terminological confusion. It is clear from the volume of published research that ASD has made a significant contribution, and we have identified two lasting and important impacts. Firstly, the reduction in iteration durations and secondly, the push for reduced levels of documentation (especially in relation to software requirements). Other aspects of the Agile Manifesto may not have exerted a significant impact; for example, the use of tooling to automate processes has become central to continuous software engineering (CSE) and may not be wholly congruent with the manifesto. Furthermore, many organisations may still rely on business contracts despite calls in the manifesto for greater levels of informal customer collaboration

Critical Roles of the WASP N-Terminal Domain and Btk in LPS-Induced Inflammatory Response in Macrophages

While Wiskott-Aldrich syndrome protein (WASP) plays critical roles in TCR signaling as an adaptor molecule, how it transduces innate immune signals remains to be elucidated. To investigate the roles of WASP in innate immune cells, we established bone marrow-derived macrophage (BMDM) cell lines from WASP15 transgenic (Tg) mice overexpressing the WASP N-terminal region (exons 1–5). Upon LPS stimulation, WASP15 Tg BMDM cell lines produce lower levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-12p40 than the wild-type BMDM cell line. In addition, the production of nitric oxide by WASP15 Tg BMDM cells in response to LPS and IFN-γ was significantly impaired. Furthermore, we uncovered that the WASP N-terminal domain associates with the Src homology (SH) 3 domain of Bruton's tyrosine kinase (Btk). Overexpression of the WASP N-terminal domain diminishes the extent of tyrosine phosphorylation of endogenous WASP in WASP15 Tg BMDM cells, possibly by interfering with the specific binding between endogenous WASP and Btk during LPS signaling. These observations strongly suggest that the interaction between WASP N-terminal domain and Btk plays important roles in the LPS signaling cascade in innate immunity

Structure Guided Optimization, In Vitro Activity and In Vivo Activity of Pan-PIM Kinase Inhibitors

Proviral Insertion of Moloney virus (PIM) 1, 2 and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. High expression of PIM1, 2 & 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias. As such, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts towards this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000 fold to yield compounds with pan PIM Ki’s < 10 picoM is described. During the optimization, a focus was initially placed on increasing potency while simultaneously reducing the liphophilicity and then, from a low logP space, a hydrophobic interaction was optimized. From these efforts, compound 5d was identified with suitable PK properties and kinase selectivity to establish a PK/PD-efficacy relationship in multiple myeloma and acute myeloid leukemia Pim dependent tumor models