The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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

Readiness fields to human tongue protrusion

Sophisticated tongue movements are coordinated finely via cortical control. We elucidated the cortical processes associated with voluntary tongue movement. Movement-related cortical fields were investigated during self-paced repetitive tongue protrusion. Surface tongue electromyograms were recorded to determine movement onset. To identify the location of the primary somatosensory cortex (S1), tongue somatosensory evoked fields were measured. The readiness fields (RFs) over both hemispheres began prior to movement onset and culminated in the motor fields (MFs) around movement onset. These signals were followed by transient movement evoked fields (MEFs) after movement onset. The MF and MEF peak latencies and magnitudes were not different between the hemispheres. The MF current sources were located in the precentral gyrus, suggesting they were located in the primary motor cortex (M1); this was contrary to the MEF sources, which were located in S1. We conclude that the RFs and MFs mainly reflect the cortical processes for the preparation and execution of tongue movement in the bilateral M1, without hemispheric dominance. Moreover, the MEFs may represent proprioceptive feedback from the tongue to bilateral S1. Such cortical processing related to the efferent and afferent information may aid in the coordination of sophisticated tongue movements

胃癌リンパ節転移初期像の検討 : 見張りリンパ節を指標とした胃癌手術は有効か

胃癌外科治療におけるリンパ節廓清術は,術後QOLを考慮して,拡大廓清から縮小廓清の方向へ転化している.さらに近年では症例個々の癌病巣からのリンパ流を確認し,流れの最上流に位置するリンパ節をsentinel nodeとし,このリンパ節を術中病理検索して転移のない場合は,転移なしと考え縮小手術を行うsentinel node navigation surgeryが広く行われ始めている.しかし,本法はほとんどの症例で癌局在部位からのリンパ流が単一流でないと多数のリンパ節を術中に検索する必要性があり,また転移リンパ節を見落とす可能性がある.そこで今回我々は,胃癌においてリンパ節転移の初期症例として少数個リンパ節転移例を対象に,そのリンパ流が単一かを検討した. [対象]標準的2群リンパ節までの廓清が行われ治癒切除となった深達度ssまでの胃癌症例で,転移リンパ節個数が2個から4個までの145症例を対象とした. [結果]全症例の30～40%に複数のリンパ流によるリンパ節転移が存在し,早期癌においても30%, mp癌では38%, ss癌では41%に複数リンパ流による転移が存在した. [考察]胃癌はリンパの流れが多方向にあるため,すべてのsentinel nodeを同定することは困難と考えられた.In consideration of the quality of life of patients, there is a trend in gastric cancer surgery to perform limited rather than extended lymph node dissection. If a sentinel node dissected during surgery is negative for cancer cells pathologically, there is believed to be almost no chance of lymph node metastasis. In this study we focused on gastric cancer cases with lymph node metastasis in order to reveal whether the lymphatic flow is a single stream from the cancerous lesion. Of 145 gastric cancer cases, about 30-40% had lymph node metastasis by multiple routes, and 30% of m, sm cancer, 38% of mp cancer, and 41% of ss cancer cases had multiple routes. Multiple sentinel nodes were involved in gastric cancer, and thus we conclude that it is difficult to identify the sentinel node in gastric cancer

根治切除不能再発胃malignant GISTに対しSTI571が著効した1例

症例は40歳男性.胃malignant GIST原発巣切除術後再発をきたし,約2年6ヵ月の間に5回の再発巣切除を行った.しかし,再度再発し,骨盤から胸腔内まで多発転移巣を認め,腹部大動脈周囲を取り巻くように再発巣があることから根治切除不能と診断した.原発巣および切除転移巣の免疫染色においてc-kit陽性であったことからイマニチブの投与を開始した.6週間後の腹部CT検査において大動脈周囲転移巣の消失,肝転移巣,腹腔内転移巣の縮小,壊死化を認め,4ヵ月後の肝転移巣超音波下穿刺組織診において腫瘍細胞を認めなかった.これまでGISTに対する有効な化学療法はなかったがイマニチブの投与は再発GISTの治療において第一選択となる可能性があると考えられた.Gastrointestinal stromal tumors (GIST) have been considered chemoresistant, but recent reports have demonstrated the efficacy of STI571 (imatinib), a tyrosine kinase inhibitor, for c-kit positive GIST. We describe our experience with a patient with radically unresectable recurrent gastric GIST which significantly responded to STI571. A 40-year-old man underwent cardiectomy due to cardial submucosal tumor, which was diagnosed as malignant GIST by histopathology. However, this tumor relapsed in the abdominal cavity 15 months after the first surgery and the recurrent tumor was resected again. The patient experienced five relapses in the abdominal cavity and liver in about 30 months, and every time surgical resection was performed. Finally this patient was admitted for the seventh time due to tumors developing in the mesenterium and remnant liver in October 2001. Encouraged by recent successful clinical reports of STI571 against GIST, STI571 twice daily at 400 mg/day was administered orally, and CT scan at week 6 showed disappearance of the tumor surrounding the aorta, regression of the metastatic liver tumor and the tumor beside the spleen. Abdominal CT scan after 4 months showed further regression of the tumors. Aspiration cytology of metastatic liver tumor did not show any distinctive tumor cells. STI571 is thought to be a possible standard treatment for patients with GIST

Prevention of Root Caries Using Oxalic Acid

Certain dentin hypersensitivity treatment materials include oxalic acid to coat dentin surfaces with minerals, while certain organic acids possess a remineralization effect. Herein, an organic acid that inhibits the demineralization and coating of root surfaces was evaluated. Specimens were produced using five non-carious extracted bovines. Four different acids were used: oxalic acid (OA), malonic acid (MA), polyacrylic acid (PA), and succinic acid (SA). Each acid was applied to the root surface and washed using distilled water or a remineralization solution, and the surface was observed using scanning electron microscopy (SEM). All the surfaces of each specimen, barring the polished surface, were covered with wax and immersed in an automatic pH cycling system for two weeks. Dentin demineralization was analyzed using transverse microradiography (TMR) before and after pH cycling. SEM analysis demonstrated that the three acid groups demineralized the dentin surface, whereas the OA group generated crystals covering the dentin surface, even in a distilled water environment. TMR analysis revealed that the OA groups showed significantly lower integrated mineral loss compared with the other groups, even in the distilled water environment. The results suggest that OA generates insoluble calcium oxalate crystals on the dentin and suppresses demineralization even under low saliva conditions

Prevention of Root Caries Using Oxalic Acid

Certain dentin hypersensitivity treatment materials include oxalic acid to coat dentin surfaces with minerals, while certain organic acids possess a remineralization effect. Herein, an organic acid that inhibits the demineralization and coating of root surfaces was evaluated. Specimens were produced using five non-carious extracted bovines. Four different acids were used: oxalic acid (OA), malonic acid (MA), polyacrylic acid (PA), and succinic acid (SA). Each acid was applied to the root surface and washed using distilled water or a remineralization solution, and the surface was observed using scanning electron microscopy (SEM). All the surfaces of each specimen, barring the polished surface, were covered with wax and immersed in an automatic pH cycling system for two weeks. Dentin demineralization was analyzed using transverse microradiography (TMR) before and after pH cycling. SEM analysis demonstrated that the three acid groups demineralized the dentin surface, whereas the OA group generated crystals covering the dentin surface, even in a distilled water environment. TMR analysis revealed that the OA groups showed significantly lower integrated mineral loss compared with the other groups, even in the distilled water environment. The results suggest that OA generates insoluble calcium oxalate crystals on the dentin and suppresses demineralization even under low saliva conditions