Primary brain tumors including anaplastic astrocytomas and glioblastoma multiforme are difficult to treat because of their locally invasive nature and chemoradioresistance. Novel therapies are needed. One class of therapeutics is fusion proteins consisting of peptide toxins fused to brain tumor selective ligands. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). DAB389EGF is selectively toxic to EGF receptor (EGFR) overexpressing cells. Close to half of all high-grade primary brain tumors have EGFR gene amplification and EGFR overexpression. With the use of convection-enhanced delivery (CED), DAB389EGF may be delivered locally at high concentrations to the brain tumor. CED would avoid many of the pharmacologic and toxicologic barriers which have limited effective use of this agent including rapid clearance from the circulation, high anti-diphtheria toxin antibody titers in the blood and toxicities to the liver and kidney. Both cell lines and animal models are available to assess the potential of this agent for brain tumor therapy. Since significant amounts of clinical grade DAB389EGF are available, some careful additional preclinical efficacy work should lead to testing of this agent in patients within the next few years.
Purpose A number of NEMO mutations in the shared sequences of NEMO isoform A and B have been associated with NF-κB-linked diseases. Here, we first report an exclusive NEMO B mutation as the genetic etiology of a male case with recurrent bacterial pneumonia and explore the underlying mechanism. Methods The genomic protein-coding regions of genes were analyzed using the whole exome sequencing (WES) technique, and the rare gene variant was confirmed by Sanger sequence analysis; activation of NF-kB signaling pathway was assessed by co-immunoprecipitation, western blotting, and single-cell RNA-seq analysis; glycolytic changes of peripheral immune cells were evaluated by extracellular acidification rate assay; protein-protein binding affinity and stability were estimated by structure modeling and molecular docking analysis. Results A c.20T > C mutation in exon 1 of the IKBKG germline sequence (NM_001099856.2) resulted in a Val7Ala replacement in the exclusive N-terminal sequence of NEMO B. This mutation significantly decreased the binding affinity and stability of NEMO B with IKKα/β, leading to the failure to form functional NEMO/IKK complex and the subsequent inhibition of RelA phosphorylation and nuclear translocation to initiate pro-inflammatory TNF-α and IL-1β gene transcription and metabolic support by glycolysis in response to the TLR4 agonist LPS. Single-cell sequencing analysis revealed abnormalities in monocyte and T-lymphocyte function and B-cell hyperplasia. Conclusions The exclusive N-terminal sequence of NEMO B is essential for a functional NEMO/IKKa/IKKb complex to activate NF-κB-dependent antibacterial immunity.
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