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

B(C6F5)(3)-catalyzed group transfer polymerization of alkyl methacrylates with dimethylphenylsilane through in situ formation of silyl ketene acetal by B(C6F5)(3)-catalyzed 1,4-hydrosilylation of methacrylate monomer

The group transfer polymerization (GTP) of alkyl methacrylates has been studied using hydrosilane and tris(pentafluorophenyl) borane (B(C6F5)(3)) as the new initiation system. For the B(C6F5)(3)-catalyzed polymerization of methyl methacrylate (MMA) using triethylsilane, tri-n-butylsilane (nBu(3)SiH), dimethylphenylsilane (Me2PhSiH), triphenylsilane, and triisopropylsilane, nBu(3)SiH and Me2PhSiH were suitable for producing well-defined polymers with predicted molar masses and a low polydispersity. The livingness of the GTP of MMA using Me2PhSiH/B(C6F5)(3) was verified by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) measurement of the resulting polymers, kinetic analyses, and chain extension experiments. The B(C6F5)(3)-catalyzed GTP using Me2PhSiH was also applicable for other alkyl methacrylates, such as the n-propyl, n-hexyl, n-decyl, 2-ethylhexyl, iso-butyl, and cyclohexyl methacrylates. The in situ formation of the silyl ketene acetal by the 1,4-hydrosilylation of MMA was proved by the MALDI-TOF MS and H-2 NMR measurements of the polymers obtained from the B(C6F5)(3)-catalyzed GTPs of MMA with Me2PhSiH or Me2PhSiD, which was terminated using CH3OH or CD3OD

A case of complete remission of Hodgkin lymphoma confirmed histopathologically by neck dissection

Abstract Background Hodgkin lymphoma (HL) is diagnosed definitively by biopsy, and treatment is based on stage. Owing to the nature of the disease, post‐treatment efficacy is determined mainly by fluorodeoxyglucose‐positron emission tomography/computed tomography, and the efficacy of treatment is not confirmed by histopathology. We report a case of tongue cancer after treatment for HL, in which a post‐treatment lymph node with complete remission was histopathologically confirmed by neck dissection. Case The patient was a 74‐year‐old man who was referred to our hospital for cancer on the right side of his tongue. He had previously undergone chemotherapy for HL involving the right side of his neck and achieved complete remission. Because he had cT3N2cM0 tongue cancer, glossectomy and bilateral neck dissection were performed. Surprisingly, histopathological examination revealed that there was neither metastatic lymph nodes nor lymphoma cells in his right neck. Moreover, there was no lymphatic structure in his remnant lymph nodes. Conclusion This was a rare case in which complete remission of HL was confirmed by histopathological analysis. The absence of lymph node structure and lymphatic flow led to contralateral neck lymph node metastases of tongue cancer

A case report of angiosarcoma originating from the tongue

Key Clinical Message Angiosarcoma is a rare malignant disease with an extremely poor prognosis, showing rapid progression of the local tumor and/or distant metastases. Although multidisciplinary approach including systemic chemotherapy and radiation therapy is ideal for this disease, surgical resection have a role in disease control and should be performed as soon as possible. Abstract Angiosarcomas originating from the tongue are rare and have extremely malignant features, leading to a poor prognosis. Herein, we report the case of a patient with angiosarcoma arising from the tongue who was successfully treated surgically. A 71‐year‐old man was diagnosed with a mass on the right side of his tongue and visited the Department of Oral and Maxillofacial Surgery at our hospital. The patient was referred to our department for further examination and treatment after a biopsy of the right edge of the tongue. An irregularly raised tumor 50 mm in length was noted on the right lingual border. The preoperative diagnosis was a primary angiosarcoma of the tongue (clinical stage, T3N2bM0, Stage IV). As his tumor had been growing rapidly, he emergently underwent partial right‐sided tongue resection and right neck dissection without reconstructive surgery. The histopathological diagnosis was pT3N0. Postoperatively, the patient showed no signs of recurrence or metastasis during the 1‐year follow‐up. As for angiosarcomas, surgical resection is the only curative treatment, and surgery should be performed as soon as possible after the final diagnosis

Synthesis of Homopolymers, Diblock Copolymers, and Multiblock Polymers by Organocatalyzed Group Transfer Polymerization of Various Acrylate Monomers

The group transfer polymerization (GTP) with <i>N</i>-(trimethylsilyl)­bis­(trifluoromethanesulfonyl)­imide (Me₃SiNTf₂) and 1-methoxy-1-triisopropylsiloxy-2-methyl-1-propene (<i>i</i>Pr-SKA) has been studied using methyl acrylate (MA), ethyl acrylate (EA), <i>n</i>-butyl acrylate (<i>n</i>BA), 2-ethylhexyl acrylate (EHA), cyclohexyl acrylate (<i>c</i>HA), dicyclopentanyl acrylate (d<i>c</i>PA), <i>tert</i>-butyl acrylate (<i>t</i>BA), 2-methoxyethyl acrylate (MEA), 2-(2-ethoxyethoxy)­ethyl acrylate (EEA), 2-(dimethylamino)­ethyl acrylate (DMAEA), allyl acrylate (AlA), propargyl acrylate (PgA), 2-(triisopropylsiloxy)­ethyl acrylate (TIPS-HEA), and triisopropylsilyl acrylate (TIPSA). Except for <i>t</i>BA and DMAEA, the GTPs of all other monomers described above proceeded rapidly in a living manner and produced well-defined homo acrylate polymers. The living nature of the GTPs of such acrylate monomers was further applied to the postpolymerizations of MA, EA, <i>n</i>BA, and MEA and also to the sequential GTPs of diverse acrylate monomers for preparing di- and multiblock acrylate polymers. In greater detail, the AB and BA diblock copolymers, (ABC)₄ dodecablock terpolymer, (ABCD)₃ dodecablock quaterpolymer, and ABCDEF hexablock sestopolymer were synthesized by sequential GTP methods using various acrylate monomers

Impact of respiratory bacterial infections on mortality in Japanese patients with COVID-19: a retrospective cohort study

Abstract Background Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. Methods We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. Results Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil–lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. Conclusions Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies

Additional file 1 of Impact of respiratory bacterial infections on mortality in Japanese patients with COVID-19: a retrospective cohort study

Additional file 1. Identification of organisms in ventilator-associated pneumoniacase