The complexity of EGFR exon 19 deletion and L858R mutant cells as assessed by proteomics, transcriptomics, and metabolomics.

Most lung adenocarcinoma-associated EGFR tyrosine kinase mutations are either an exon 19 deletion (19Del) or L858R point mutation in exon 21. Although patients whose tumors contain either of these mutations exhibit increased sensitivity to tyrosine kinase inhibitors, progression-free and overall survival appear to be longer in patients with 19Del than in those with L858R. In mutant-transfected Ba/F3 cells, 19Del and L858R were compared by multi-omics analyses including proteomics, transcriptomics, and metabolomics. Proteome analysis identified increased plastin-2, TKT, PDIA5, and ENO1 expression in L858R cells, and increased EEF1G expression in 19Del cells. RNA sequencing showed significant differences between 19Del and L858R cells in 112 genes. Metabolome analysis showed that amino acids, adenylate, guanylate, NADPH, lactic acid, pyruvic acid glucose 6-phosphate, and ribose 5-phosphate were significantly different between the two mutant cells. Because GSH was increased with L858R, we combined osimertinib with the GSH inhibitor buthionine sulfoximine in L858R cells and observed synergistic effects. The complexity of EGFR 19Del and L858R mutant cells was demonstrated by proteomics, transcriptomics, and metabolomics analyses. Therapeutic strategies for lung cancer with different EGFR mutations could be considered because of their different metabolic phenotypes.

Iliac neck dilatation causes rupture of abdominal aortic aneurysm previously treated with endovascular aortic aneurysm repair.

A 78-year-old male had undergone endovascular aortic aneurysm repair (EVAR) 7 years prior to presentation. Although the sac was stable 6 months ago, the patient presented with shock at arrival, and CT showed aortic rupture with rapid expansion due to type Ib endoleak caused by iliac neck dilatation (IND). The aneurysm sac was excluded using an endovascular strategy. Bell-bottom iliac limbs can cause IND associated with type Ib endoleak. Additionally, the risk of rupture is high when re-expansion of an aneurysm occurs after sac regression after EVAR. Therefore, close follow-up is mandatory for patients with IND after EVAR.

Bral2 is indispensable for the proper localization of brevican and the structural integrity of the perineuronal net in the brainstem and cerebellum.

Perineuronal nets (PNNs) are pericellular coats of condensed matrix that enwrap the cell bodies and dendrites of many adult central nervous system (CNS) neurons. These extracellular matrices (ECMs) play a structural role as well as instructive roles in the control of CNS plasticity and the termination of critical periods. The cartilage link protein Crtl1/Hapln1 was reported to be a trigger for the formation of PNNs in the visual cortex. Bral2/Hapln4 is another link protein that is expressed in PNNs, mainly in the brainstem and cerebellum. To assess the role of Bral2 in PNN formation, we examined the expression of PNN components in targeted mouse mutants lacking Bral2. We show here that Bral2-deficient mice have attenuated PNNs, but the overall levels of chondroitin sulfate proteoglycans, lecticans, are unchanged with the exception of neurocan. Bral2 deficiency markedly affected the localization of brevican in all of the nuclei tested, and neurocan concomitant with Crtl1 in some of the nuclei, whereas no effect was seen on aggrecan even with the attenuation of Crtl1. Bral2 may have a role in the organization of the PNN, in association with brevican, that is independent of aggrecan binding. There was a heterogenous attenuation of PNN components, including glycosaminoglycans, indicating the elaborate molecular organization of the PNN components. Strikingly, a slight decrease in the number of synapses in deep cerebellar nuclei neurons was found. Taken together, these results imply that Bral2-brevican interaction may play a key role in synaptic stabilization and the structural integrity of the PNN.