Our findings contradict previous studies on ascending thoracic and abdominal aortic aneurysms, suggesting that the former might not cause weakening but rather only stiffening and reduction in tissue extensibility and elastin content. Marked heterogeneity was evident in healthy and aneurysmal aortas. The present data offer insight into the pathogenesis of aneurysm dissection. Information on directional and regional variations is pertinent because dissections develop circumferentially and bulging preferentially occurs in the anterior region.
Purpose: Cetuximab, an antibody directed against the EGF receptor, is an effective clinical therapy for patients with head and neck squamous cell cancer (HNSCC). Despite great clinical promise, intrinsic or acquired cetuximab resistance hinders successful treatment outcomes but little is known about the underlying mechanism.Experimental Design: To study the role of oncogenic HRAS in cetuximab resistance in HNSCC, the frequency of oncogenic HRAS mutations was determined in a cohort of 180 genomic DNAs from head and neck cancer specimens. We also used a combination of cetuximab-resistant cell lines and a transgenic mouse model of RAS-driven oral cancer to identify an oncogenic RAS-specific gene expression signature that promotes cetuximab resistance.Results: Here, we show that activation of RAS signaling leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. HRAS depletion in cells containing oncogenic HRAS or PIK3CA restored cetuximab sensitivity. In our study, the gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC. Finally, a subset of patients with head and neck cancer with oncogenic HRAS mutations was found to exhibit de novo resistance to cetuximab-based therapy.Conclusions: Collectively, these findings identify a distinct cetuximab resistance mechanism. Oncogenic HRAS in HNSCC promotes activation of ERK signaling, which in turn mediates cetuximab resistance through a specific gene expression signature.
Ascending thoracic aortic aneurysms (ATAA) were resected from patients during graft replacement and non-aneurysmal vessels during autopsy. Tissues were histomechanically tested according to region and orientation, and the experimental recordings reduced with a Fung-type strain--energy function, affording faithful biomechanical characterisation of the vessel response. The material and rupture properties disclosed that ATAA and non-aneurysmal aorta were stiffer and stronger circumferentially, accounted by preferential collagen reinforcement. The deviation of microstructure in the right lateral region, with a longitudinal extracellular matrix and smooth muscle element sub-intimally, reflects the regional differences in material properties identified. ATAA had no effect on strength, but caused stiffening and extensibility reduction, corroborating our histological observation of deficient elastin but not collagen content. Our findings may serve as input data for the implementation of finite element models, to be used as improved surgical intervention criteria, and may further our understanding of the pathophysiology of ATAA and aortic dissection.
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