ABSTRACT
An 11-year-old boy presented with Staphylococcus aureus infective endarteritis and mycotic pseudoaneurysms within the context of a previously undiagnosed aortic coarctation. He had an urgent resection of the pseudoaneurysm and coarctation repair. Nuances to his initial diagnosis and key learning points related to the complication of pseudoaneurysm are discussed.
Subject(s)
Aneurysm, False/etiology , Aneurysm, Infected/etiology , Aortic Aneurysm, Thoracic/etiology , Aortic Coarctation/complications , Endarteritis/etiology , Staphylococcal Infections/etiology , Staphylococcus aureus/isolation & purification , Aneurysm, False/diagnosis , Aneurysm, False/microbiology , Aneurysm, Infected/diagnosis , Aneurysm, Infected/microbiology , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/microbiology , Aortic Coarctation/diagnosis , Child , Diagnosis, Differential , Endarteritis/diagnosis , Endarteritis/microbiology , Humans , Imaging, Three-Dimensional , Male , Staphylococcal Infections/diagnosis , Staphylococcal Infections/microbiology , Tomography, X-Ray ComputedABSTRACT
Epidermal growth factor (EGF)-induced EGFR tyrosine kinase receptor activation in cancer cell survival responses has become a strategic molecular-targeting clinical therapeutic intent, but the failures of these targeted approaches in the clinical setting demand alternate strategies. Here, we uncover a novel neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with GPCR neuromedin B, which is essential for EGF-induced receptor activation and cellular signaling. Neu1 and MMP-9 form a complex with EGFR on the cell surface. Tamiflu (oseltamivir phosphate), anti-Neu1 antibodies, broad range MMP inhibitor galardin (GM6001), neuromedin B GPCR specific antagonist BIM-23127, the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 and MMP-9 specific inhibitor dose-dependently inhibited Neu1 activity associated with EGF stimulated 3T3-hEGFR cells. Tamiflu, anti-Neu1 antibodies and MMP9i attenuated EGFR phosphorylation associated with EGF-stimulated cells. Preclinical data provide the proof-of-evidence for a therapeutic targeting of Neu1 with Tamiflu in impeding human pancreatic cancer growth and metastatic spread in heterotopic xenografts of eGFP-MiaPaCa-2 tumors growing in RAGxCγ double mutant mice. Tamiflu-treated cohort exhibited a reduction of phosphorylation of EGFR-Tyr1173, Stat1-Tyr701, Akt-Thr308, PDGFRα-Tyr754 and NFκBp65-Ser311 but an increase in phospho-Smad2-Ser465/467 and -VEGFR2-Tyr1175 in the tumor lysates from the xenografts of human eGFP-MiaPaCa-2 tumor-bearing mice. The findings identify a novel promising alternate therapeutic treatment of human pancreatic cancer.