The Hic-5 protein is encoded by a transforming growth factor-β1- and hydrogen peroxide-inducible gene,hic-5, and has striking similarity to paxillin, especially in their C-terminal LIM domains. Like paxillin, Hic-5 is localized in focal adhesion plaques in association with focal adhesion kinase in cultured fibroblasts. We carried out yeast two-hybrid screening to identify cellular factors that form a complex with Hic-5 using its LIM domains as a bait, and we identified a cytoplasmic tyrosine phosphatase (PTP-PEST) as one of the partners of Hic-5. These two proteins are associated in mammalian cells. From in vitro binding experiments using deletion and point mutations, it was demonstrated that the essential domain in Hic-5 for the binding was LIM 3. As for PTP-PEST, one of the five proline-rich sequences found on PTP-PEST, Pro-2, was identified as the binding site for Hic-5 in in vitro binding assays. Paxillin also binds to the Pro-2 domain of PTP-PEST. In conclusion, Hic-5 may participate in the regulation of signaling cascade through its interaction with distinct tyrosine kinases and phosphatases.

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third‐generation EGFR‐tyrosine kinase inhibitor (EGFR‐TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR‐TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor‐like biological activity of lamellarin N into kinase inhibitor‐like activity. Ba/F3 and PC‐9 cells expressing the EGFR in‐frame deletion within exon 19 (del ex19)/T790M/C797S triple‐mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple‐mutant EGFR PC‐9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple‐mutant EGFR PC‐9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR‐TKI that prevents the development of cross‐resistance against known drugs in this class.

The aim of this study was to investigate the effect of the COVID-19 pandemic on regular clinic visits among people with diabetes and to elucidate the factors related to visit patterns among these patients during the pandemic. This was a longitudinal study using anonymized insurance claims data from the Joint Health Insurance Society in Tokyo from October 2017 to September 2020. First, we identified patients with diabetes who were fully enrolled in the health plan from fiscal year 2017 until September 2020 and who were regularly receiving glucose-lowering medications (every 1–3 months) from October 2017 to September 2018. We divided follow-up into the pre-pandemic period (October 2018 to March 2020) and the pandemic period (April 2020 to September 2020). A multilevel logistic regression model was used to determine the risks of delayed clinic visits/medication prescriptions (i.e., >3 months after a previous visit/prescription) during the pandemic period. We identified 1118 study participants. The number of delayed clinic visits/medication prescriptions during the pre-pandemic and pandemic periods was 188/3354 (5.6%) and 125/1118 (11.2%), respectively. There was a significant increase in delayed clinic visits during the pandemic (adjusted odds ratio 3.68 (95% confidence interval 2.24 to 6.04, P < .001), even after controlling for confounding factors. We also found a significant interaction between sex and delayed visits; women had significantly fewer clinic visits during the COVID-19 pandemic than men. We clarified the relationship of the COVID-19 pandemic with delays in regular clinic visits and medication prescriptions among people with diabetes. The response to the COVID-19 pandemic differed between men and women.

JAK3 inhibitor VI is a mutant specific inhibitor for epidermal growth factor receptor with the gatekeeper mutation T790M

Ivermectin (IVM), an avermectin-derivative anthelmintic, specifically binds to glutamate-gated chloride ion channels (GluCls), causing paralysis in invertebrates. IVM also exhibits other biological activities such as Wnt/β-catenin pathway inhibition in vertebrates that do not possess GluCls. This study showed that affinity purification using immobilized IVM B1a isolated TELO2, a cofactor of phosphatidylinositol 3-kinase-related kinases (PIKKs), as a specific IVM B1a-binding protein. TELO2 knockdown reduced cytoplasmic β-catenin and the transcriptional activation of β-catenin/TCF. IVM B1a bound to TELO2 through the C-terminal α-helix, in which mutations conferred IVM resistance. IVM reduced the TELO2 and PIKK protein levels and the AKT and S6 kinase phosphorylation levels. The inhibition of mTOR kinase reduced the cytoplasmic β-catenin level. Therefore, IVM binds to TELO2, inhibiting PIKKs and reducing the cytoplasmic β-catenin level. In conclusion, our data indicate TELO2 as a druggable target for human diseases involving abnormalities of the Wnt/β-catenin pathway and PIKKs, including mTOR.