<div>Abstract<p>The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5′-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant <i>in vivo</i> efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in <i>in vivo</i> xenograft models. Mutation of PTEN is associated with reduced apoptosis <i>in vitro</i> and diminished efficacy <i>in vivo</i> in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.</p></div>
Packaging high power radio frequency integrated circuits (RFICs) in low temperature cofired ceramic (LTCC) presents many challenges. Within the constraints of LTCC fabrication, the design must provide the usual electrical isolation and interconnections required to package the IC, with additional consideration given to RF isolation and thermal management. While iterative design and prototyping is an option for developing RFIC packaging, it would be expensive and most likely unsuccessful due to the complexity of the problem. To facilitate and optimize package design, thermal and mechanical simulations were used to understand and control the critical parameters in LTCC package design. The models were validated through comparisons to experimental results. This paper summarizes an experimentally-validated modeling approach to RFIC package design, and presents some results and key findings.
Packaging a high power radio frequency integrated circuit (RFIC) in low temperature cofired ceramic (LTCC) presents many challenges. Within the constraints of LTCC fabrication, the design must provide the usual electrical isolation and interconnections required to package the IC, with additional consideration given to RF isolation and the structural integrity issues. While iterative design and prototyping is an option for RFIC packaging development, it is a tedious and expensive process that would most likely be unsuccessful due to the complexity of the problem. To facilitate package design and optimization, thermo-mechanical assembly simulations were used to identify and manage the critical process parameters to control solder failures in the LTCC package assembly. The modeling results were confirmed through comparisons to prototype testing. This paper summarizes an assembly-based modeling approach to RFIC package design and solder failure analysis, and presents some results and key findings to date.
Sandia is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin company, for the United States Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000
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