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

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Reduced Myocardial Flow Reserve in Non–Insulin-Dependent Diabetes Mellitus

AbstractObjectives. We analyzed myocardial flow reserve (MFR) in patients with non–insulin-dependent (type II) diabetes mellitus (NIDDM) without symptoms and signs of ischemia.Background. Diminished MFR in diabetes has been suggested. However, it remains controversial whether MFR is related to glycemic control, mode of therapy or gender in NIDDM.Methods. Myocardial blood flow (MBF) was measured at baseline and during dipyridamole loading in 25 asymptomatic, normotensive, normocholesterolemic patients with NIDDM and 12 age-matched control subjects by means of positron emission tomography and nitrogen-13 ammonia, after which MFR was calculated.Results. Baseline MBF in patients with NIDDM ([mean ± SD] 74.0 ± 24.0 ml/min per 100 g body weight) was comparable to that in control subjects (73.0 ± 17.0 ml/min per 100 g). However, MBF during dipyridamole loading was significantly lower in patients with NIDDM (184 ± 99.0 ml/min per 100 g, p < 0.01) than in control subjects (262 ± 120 ml/min per 100 g), as was MFR (NIDDM: 2.77 ± 0.85; control subjects: 3.8 ± 1.0, p < 0.01). A significantly decreased MFR was seen in men (2.35 ± 0.84) compared with women with NIDDM (3.18 ± 0.79, p < 0.05); however, no significant differences were found in terms of age, hemoglobin a1c and baseline MBF. MFR was comparable between the diet (2.78 ± 0.80) and medication therapy groups (2.76 ± 0.77) and was inversely correlated with average hemoglobin A1c for 5 years (r = −0.55, p < 0.01) and fasting plasma glucose concentration (r = −0.57, p < 0.01) but not age or lipid fractions.Conclusions. Glycemic control and gender, rather than mode of therapy, is related to MFR in NIDDM

Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5

G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist

Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study of ustekinumab in Japanese patients with active polymyositis and dermatomyositis who have not adequately responded to one or more standard-of-care treatments

Objectives To evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM).Methods Fifty-one Japanese adults diagnosed with active PM/DM who did not respond adequately to one or more standard-of-care treatments were randomised 1:1 to receive UST (n=25) or placebo (n=26). Participants received body weight-range based intravenous administration of UST (6 mg/kg) or placebo at week 0 followed by 90 mg subcutaneous (SC) administration of UST or placebo every 8 weeks from week 8 to week 24. At week 24, placebo group crossed over to receive body weight-range based intravenous administration of UST, and thereafter, all participants received/were to receive SC administration of UST 90 mg every 8 weeks (week 32 through to week 72). The primary efficacy endpoint was the proportion of participants who achieved minimal improvement (≥20) in the International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at week 24.Results No statistically significant difference was seen in the proportion of participants who achieved minimal improvement (≥20) in IMACS TIS at week 24 between the treatment groups (UST 64.0% vs placebo 61.5%, p=0.94) based on the primary estimand of the primary endpoint analysis.Conclusions UST was safe and well tolerated but did not meet the primary efficacy endpoint in adult Japanese participants with active PM/DM based on the primary analysis at week 24 in the study.Trial registration number NCT03981744

Cribriform pattern 4/intraductal carcinoma of the prostate and persistent prostate‐specific antigen after radical prostatectomy

Abstract Objectives The objective of this study is to identify the effect of cribriform pattern 4 carcinoma/intraductal carcinoma of the prostate (CC/IDCP) on persistent prostate‐specific antigen (PSA) levels after robot‐assisted radical prostatectomy (RARP) in patients with localized prostate cancer (PCa). Patients and Methods This retrospective study included 730 consecutive patients with localized PCa who underwent RARP at Mie University (n = 392) and Aichi Medical University (n = 338) between 2015 and 2021. Patients with clinically metastatic PCa (cN1 and cM1) and those who received neoadjuvant and/or adjuvant therapy before biochemical recurrence were excluded. We evaluated the effects of CC/IDCP on persistent PSA levels after RARP. Persistent PSA was defined as PSA level ≥0.2 ng/mL at 1 month postoperatively and consecutively thereafter. Using factors from logistic regression analysis, models were developed to predict persistent PSA levels. Results Approximately 6.3% (n = 46) of the patients had persistent PSA levels. Patients with biopsy CC/IDCP (bCC/IDCP) and pathological CC/IDCP (pCC/IDCP) based on RARP specimens were 11.6% (85/730) and 36.5% (267/730), respectively. Multivariate analysis of the prediction of persistent PSA levels using preoperative factors revealed that PSA density, percentage of positive cancer cores, biopsy grade group and bCC/IDCP were independent prognostic factors. Furthermore, multivariate analysis of the prediction of persistent PSA levels using postoperative factors, excluding pN1, revealed that pathological grade group, pCC/IDCP, seminal vesicle invasion and lymphovascular invasion were independent prognostic factors. In the receiver operating characteristic curve analysis for predicting persistent PSA after RARP, areas under the receiver operating characteristic curve for the model with preoperative factors, postoperative factors, including pN1, and postoperative factors, excluding pN1, were 0.827, 0.833 and 0.834, respectively. Conclusions bCC/IDCP predicted persistent PSA after RARP in the overall population, while pCC/IDCP predicted persistent PSA only when the pN1 population was excluded. This may be useful for predicting susceptible patients with worse outcomes