DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Direct Measurement of the 4He(12C, 16O)γ Total Cross Section Near Stellar Energies

A cross section measurement employing a direct 16O detection method for the reaction energies from Ecm = 2.4 to 0.7 MeV is planned at Kyushu University Tandem Laboratory (KUTL). To perform this experiment and to obtain quantitative information about the cross section to within an error of 10%, we have developed several instruments, including a blow-in type windowless gas target, a recoil mass separator and a RF-deflector. The measurements at Ecm = 2.4 and 1.5 MeV have been performed with these instruments. For measuring at Ecm < 1.2 MeV, a hybrid detector employing both, an ionization chamber and a silicon detector was developed to reduce the carbon backgrounds more efficiently. The oxygen ions were clearly separated from carbon background by using the energy deposit in the ionization chamber. Experiment of Ecm = 1.2 MeV was performed and the cross section was obtained

Direct Measurement of the

A cross section measurement employing a direct 16O detection method for the reaction energies from Ecm = 2.4 to 0.7 MeV is planned at Kyushu University Tandem Laboratory (KUTL). To perform this experiment and to obtain quantitative information about the cross section to within an error of 10%, we have developed several instruments, including a blow-in type windowless gas target, a recoil mass separator and a RF-deflector. The measurements at Ecm = 2.4 and 1.5 MeV have been performed with these instruments. For measuring at Ecm < 1.2 MeV, a hybrid detector employing both, an ionization chamber and a silicon detector was developed to reduce the carbon backgrounds more efficiently. The oxygen ions were clearly separated from carbon background by using the energy deposit in the ionization chamber. Experiment of Ecm = 1.2 MeV was performed and the cross section was obtained

Eosinophil may be a predictor of immune‐related adverse events induced by different immune checkpoint inhibitor types: A retrospective multidisciplinary study

Abstract Background Immune checkpoint inhibitors (ICIs) can cause severe immune‐related adverse events (irAEs). However, biomarkers for irAEs common to different types of ICIs and cancers have not been reported. This study examined whether eosinophils can be used as a predictor of irAEs. Methods Six hundred fourteen patients with cancer (esophageal, gastric, head and neck, lung, melanoma, renal cell, urothelial, and other cancer) received anti‐PD‐1, anti‐PD‐L1, or anti‐CTLA‐4 plus anti‐PD‐1 therapy. The patients were divided into two groups depending on whether they experienced irAEs (irAE group) or not (non‐irAE group). Eosinophils were examined before the two‐course treatment. Results Patients in the irAE group who received anti‐PD‐1 or anti‐CTLA‐4 plus anti‐PD‐1 therapy had higher eosinophils before the two‐course treatment than those in the non‐irAE group (p < 0.05). The eosinophils in the anti‐PD‐L1 therapy group tended to increase in the irAE group. Furthermore, eosinophils in gastric, head and neck, lung, melanoma, renal, and urothelial cancers were significantly higher in the irAE group than in the non‐irAE group (p < 0.05). The optimal cutoff value for eosinophils against irAEs was 3.0% (area under the curve = 0.668). In multivariate analyses, eosinophils of ≥3.0% were an independent factor for irAEs (odds ratio: 2.57, 95% CI: 1.79–3.67). Conclusion An increased eosinophil before the two‐course treatment may be a predictor of irAEs in various cancers treated with different ICIs