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

ホルモン抵抗性前立腺癌に対するドセタキセル, プレドニゾロン併用療法

Between April 2004 and August 2005, we used docetaxel in combination with prednisolone to treat 14 patients with hormone-refractory prostate cancer (HRPC). Docetaxel was administered at a dose of 70 mg/m2 once every 21 days and oral prednisolone 5 mg was administered twice daily concurrently on days 1-21. The treatment was continued until disease progression or unacceptable adverse events occurred. Prostate specific antigen (PSA) was used as a tumor marker. PSA response was defined as a reduction from baseline of at least 50% that was maintained for 4 weeks. Five patients had measurable soft tissue lesions, which were nodal metastases in 4 and liver metastasis in 1. The median follow-up was 8.4 months. During follow-up, 5 patients died. The median treatment cycle was 7 cycles. Manifestations of hematologic toxicity included 11 patients (78%) with grade 3/4 neutropenia and only I with febrile neutropenia. Two patients with gastric hemorrhage and febrile neutropenia needed hospitalization. During follow-up, 8 patients (57%) achieved a PSA reduction from baseline of at least 50%. Three patients with nodal metastases and 1 patient with liver metastasis had partial response. Combined docetaxel and prednisolone was shown to be effective and feasible in Japanese patients.【目的】ホルモン抵抗性前立腺癌に対しドセタキセル+プレドニゾロン療法を行い, その有用性を検討した。【対象・方法】対象は2004年4月以降に再燃前立腺癌と診断された14例。観察期間は8.4ヵ月, 7コース(5.5コース)施行した。プレドニゾロン(10mg/日)連日投与を併用しドセタキセル70mg/m2を21日毎に点滴投与を繰り返した。全例, 転移巣を有しており, 測定可能病変は4例がリンパ節, 1例は肝臓であった。原則として外来通院治療とした。【結果】14例中8例(57%)で腫瘍マーカーが50%以上減少した。測定可能病変とでは肝臓の1例とリンパ節の2例がPRとなった。鎮痛剤を使用していた7例中4例が減量・中止可能であった。貧血が2例で改善し, 1例で発熱も改善した。血液有害事象では好中球減少ではgrade3/4が11例であった。PDのため4例, 高度の皮膚粘膜病変のため1例が中止し, ステロイドによる出血性胃潰瘍, 帯状疱疹のため1例ずつが休薬となった。発熱性好中球減少のため1例が入院を要した。【結語】好中球減少症を高頻度に認めるが外来治療が可能であり, また抗腫瘍効果, 疼痛の改善においても有用と思われた。(著者抄録

Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions

International audienceCongenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromus-cular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS

ホルモン抵抗性前立腺癌に対するリン酸エストラムスチン, エトポシド療法

A total of 42 patients with hormone-refractory prostate cancer received E-E therapy. Oral estramustine phosphate (EMP) was administered twice daily for a total daily dose of 560 mg every day and oral etoposide (E-E therapy, 50 mg/body/day) was given on days 1-21 and stopped on days 22-35. Treatment was continued until the disease progression was confirmed radiographically or PSA had increased from base line of at least 25%. The median follow-up period after E-E therapy was 77.4 months (range : 12.5 to 122.3). Nineteen patients (43%) achieved a PSA decrease of 50% or greater. The median survival time of the patients who had a decrease of 50% or greater in the PSA value (PSA responder) was 29.3 months and the patients who did not (PSA non-responder) was 14.1 months (p = 0.01). There were no significant differences between PSA responders and non-responders when taking into account variables. Excluding those patients with only PSA elevation, the survival time was 14.9 months with no significant difference between PSA responders and non-responders. The toxicities (grade 3 or more) were identified as anemia, leukocytopenia thrombocytopenia, cardiovascular events, and gastrointestinal and hepatic disorders, which occurred in 0, 5, 2, 2, 14, and 2% of the patients, respectively. E-E therapy was considered to be an active oral regimen and well-tolerated for outpatients with hormone-refractory prostate cancer in Japanese patients.【目的】日本人における再燃前立腺癌に対する経口リン酸エストラムスチン(EMP), エトポシド(VP-16)併用療法(EE療法)の効果および副作用について検討した。【方法】1995年以降, EE療法が施行された再燃前立腺癌患者42例が対象。EMP:560mgを連日投与, VP-16:50mgを21日投与し14日休薬を1サイクルとした。PSAが50%以上低下したものをresponderとし, 治療は画像上の増悪またはPSAが基準値より25%を認めるまで継続した。【結果】観察期間は77.4ヵ月。19例がresponderであった。42例の生存中央値は20.5ヵ月でありresponderでは29.3ヵ月, non-responderで14.1ヵ月(p=0.008)であった。群間でresponseに寄与する因子は存在しなかった。Grade 3以上の副作用は白血球減少(5%)が2例, 血小板減少(2%)が1例, 悪心が6例(14%), 肝機能障害が1例(2%), 深部静脈血栓症(2%)が1例に認めた。【結語】EE療法は抗腫瘍効果もあり, 副作用も容認でき日本人にも施行可能であった。(著者抄録