👤 Masahide Oki

The development of resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and a poor response to immune checkpoint inhibitors (ICIs) remain challenges in ALK-rearranged non-small cell lung cancer (NSCLC). We performed immune-related gene expression profiling (irGEP) for ALK-rearranged NSCLC to assess the characteristics of the tumor microenvironment and explore potential therapeutic avenues. This study analyzed tumor samples from the ALCURE trial, a prospective observational study examining the efficacy of and mechanisms of resistance to alectinib in patients with ALK-rearranged NSCLC. The irGEP analysis was performed with a panel encompassing 750 immune-related genes. Tumor samples from 52 of the 249 ALCURE trial patients were analyzed. Tumors with high CD8A expression showed upregulation of SNAI1 and downregulation of CDH1, with these genes encoding an epithelial-mesenchymal transition (EMT)-related transcription factor and E-cadherin, respectively, suggestive of EMT progression in these tumors. Tumors with high CD8A expression also manifested downregulation of genes related to tumor angiogenesis, including ANGPT2 (angiopoietin-2) and FLT1 (VEGF receptor 1), suggestive of a quiescent angiogenic state that may facilitate the recruitment of CD8 CD8 Show less

Cataracts are opacifications of the lens that cause loss of visual acuity and ultimately of eyesight. Age-related cataract develops in most elderly people, but the mechanisms of cataract onset are incompletely understood. The Ihara Cataract Rat (ICR) is an animal model of hereditary cataracts showing cortical opacity that commonly develops prematurely. We identified putative mechanisms of cataract onset in the ICR rat model by measuring gene expression changes before and after cortical cataract development and conducting point mutation analysis. Genes differentially expressed between 4-week-old animals without cortical cataracts and 8-10-week-old animals with cortical cataracts were selected from microarray analysis. Three connections were identified by STRING analysis: (i) Epithelial-Mesenchymal Transition (EMT), including Col1a2, and Pik3r1. (ii) Lens homeostasis, including Aqp5, and Cpm. (iii) Lipid metabolism, including Scd1, Srebf1, and Pnpla3. Subsequently, mutation points were selected by comparing ICR rats with 12 different rats that do not develop cataracts. The apolipoprotein Apoc3 was mutated in ICR rats. Analyses of gene expression changes and point and mutations suggested that abnormalities in EMT or lipid metabolism could contribute to cataract development in ICR rats. Show less

Cataract causes vision loss and blindness due to formation of opacities of the lens. The regulatory mechanisms of cataract formation and progression remain unclear, and no effective drug treatments are clinically available. In the present study, we tested the effect of ataxia telangiectasia mutated (Atm) inhibitors using an ex vivo model in which rat lenses were cultured in galactose-containing medium to induce opacity formation. After lens opacities were induced by galactose, the lenses were further incubated with the Atm inhibitors AZD0156 or KU55933, which decreased lens opacity. Subsequently, we used microarray analysis to investigate the underlying molecular mechanisms of action, and extracted genes that were upregulated by galactose-induced opacity, but not by inhibitor treatment. Quantitative measurement of mRNA levels and subsequent STRING analysis revealed that a functional network consisting primarily of actin family and actin-binding proteins was upregulated by galactose treatment and downregulated by both Atm inhibitors. In particular, Acta2 is a known marker of epithelial-mesenchymal transition (EMT) in epithelial cells, and other genes connected in this functional network (Actn1, Tagln, Thbs1, and Angptl4) also suggested involvement of EMT. Abnormal differentiation of lens epithelial cells via EMT could contribute to formation of opacities; therefore, suppression of these genes by Atm inhibition is a potential therapeutic target for reducing opacities and alleviating cataract-related visual impairment. Show less