PKCβ facilitates leukemogenesis in chronic lymphocytic leukaemia by promoting constitutive BCR-mediated signalling

B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model

Towards a Test Definition Language for Integrated Circuits

The Standard Test Interface Language (STIL) is the de-facto standard for transferring test data between the test generation environment and the test equipment. STIL's flexibility and extensibility facilitates its use as the sole input language for automatic test-pattern generation (ATPG). However, STIL format is complex and does not provide support for algorithmic interactive testing which necessitate the use of additional programming languages to do that. In this paper, we propose a new Test Definition Language for Integrated Circuits (TDLIC) based on the Extensible Markup Language (XML). TDLIC is a description language for defining tests of digital ICs in a precise and reusable form. The proposed TDLIC provides a common platform for specifying test data as well as complex test procedures. A case study that includes a validation platform is used to show the full capabilities of TDLIC. The validation platform is an FPGA-based system that emulates the automatic test equipment and a prototype IC with four circuits to be tested. </jats:p