Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [I]I-osimertinib and [Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required

The 17,18-epoxyeicosatetraenoic acid–G protein–coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques

Background: Metabolites of eicosapentaenoic acid exert various physiologic actions. 17, 18-Epoxyeicosatetraenoic acid (17, 18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.Objective: We evaluated the effectiveness of 17, 18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17, 18-EpETE.Methods: Contact hypersensitivity was induced by topical application of 2, 4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17, 18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17, 18-EpETE was examined by using KO mice and specific inhibitor treatment.Results: We found that preventive or therapeutic treatment with 17, 18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17, 18-EpETE was recognized by G protein–coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17, 18-EpETE was abolished in the absence or inhibition of GPR40.Conclusion: 17, 18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases

Reconnaissance report on the 2000 Tottori-ken Seibu Earthquake

金沢大学理工研究域地球社会基盤学系Damage done to civil structures by the 2000 Tottori-ken Seibu Earthquake was investigated. Field surveys were made from October 8-10 by eight members dispatched by the JSCE in cooperation with other researchers. Descriptions are given of the earthquake, seismic ground motion; the damage done to such civil structures as roads, road bridges, lifelines, dams, port facilities; slope failures; and public risk management. Although peak ground accelerations were extremely intensive, structural damage was not as severe as compared with the average damage caused by past earthquakes in Japan. Such disaster responses as search and rescue activities, emergency responses, disaster information communication, and victim supports are discussed

A Refined Culture System for Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids

Summary: Gut epithelial organoids are routinely used to investigate intestinal biology; however, current culture methods are not amenable to genetic manipulation, and it is difficult to generate sufficient numbers for high-throughput studies. Here, we present an improved culture system of human induced pluripotent stem cell (iPSC)-derived intestinal organoids involving four methodological advances. (1) We adopted a lentiviral vector to readily establish and optimize conditioned medium for human intestinal organoid culture. (2) We obtained intestinal organoids from human iPSCs more efficiently by supplementing WNT3A and fibroblast growth factor 2 to induce differentiation into definitive endoderm. (3) Using 2D culture, followed by re-establishment of organoids, we achieved an efficient transduction of exogenous genes in organoids. (4) We investigated suspension organoid culture without scaffolds for easier harvesting and assays. These techniques enable us to develop, maintain, and expand intestinal organoids readily and quickly at low cost, facilitating high-throughput screening of pathogenic factors and candidate treatments for gastrointestinal diseases

The gut microbiota induces Peyer’s-patch-dependent secretion of maternal IgA into milk

The evolutionary strategy of transferring maternal antibodies via milk profoundly impacts the survival, lifelong health, and wellbeing of all neonates, including a pronounced impact on human breastfeeding success and infant development. While there has been increased recognition that interorgan connectivity influences the quality of a mother’s milk, potentially to personalize it for her offspring, the underlying bases for these processes are incompletely resolved. Here, we define an essential role of Peyer’s patches (PPs) for the generation of plasma cells that secrete maternal immunoglobulin A (IgA) into milk. Our metagenomic analysis reveals that the presence of certain residential microorganisms in the gastrointestinal (GI) tract, such as Bacteroides acidifaciens and Prevotella buccalis, is indispensable for the programming of maternal IgA synthesis prior to lactational transfer. Our data provide important insights into how the microbiome of the maternal GI environment, specifically through PPs, can be communicated to the next generation via milk