Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. 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.

Background We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. Conclusions We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

The t(16;21)(p11;q22) translocation is a non-random chromothe fused FUS/ERG protein is shown to function as a transcripsomal aberration observed in several types of human acute tional regulator. 8,11 myeloblastic leukemia (AML), whereas the der(16)t(1;16) and On the other hand, the der (16) A 46-year-old male engineer was admitted to our hospital because of fever in June 1994. Peripheral blood examination Introduction showed white blood cells 120 × 10 9 /l with 91% myeloblasts, hemoglobin 8.3 g/dl and platelets 104 × 10 9 /l. Bone marrow Chromosomal translocations in specific subtypes of leukemia examination revealed 91% myeloblasts that were positive for are recognized to play an important role in the process of myeloperoxidase (MPO) but negative for ␣-naphthyl butylate leukemogenesis by synthesis of chimeric proteins. 1,2 The esterase (␣-NBE) and chloroacetate esterase (CAE) stainings. t(16;21)(p11;q22) translocation is one of the non-random There was no abnormal feature in the eosinophils or monochromosomal aberrations observed in human acute myelocytes. In surface marker analysis the blasts from bone marrow blastic leukemia (AML), blastic crisis of chronic myelogenous were positive for CD13 (79.5%), CD33 (93.3%) and CD34 leukemia (CML) and myelodysplastic syndrome (MDS) that (64.5%). Chromosome analysis of bone marrow cells showed progressed to AML. 3-10 AML with t(16;21) has been classified 46,XY, der(16)t(16;21)(p11;q22)t(1;16)(q12;q13), der (21) An induction therapy was started with enocitabine, daunoruberythrophagocytosis. 3,4 Clinical prognosis of AML with icin, 6-mercaptopurine and prednisolone and complete t(16;21) seems to be poor. Recently, molecular characterizremission (CR) was achieved with normal karyotype. Despite ation of this translocation has revealed that the FUS gene (also two courses of consolidation therapy, the patient relapsed called TLS) encoding an RNA-binding protein on chromosome after 3 months from remission. The second CR was obtained 16 is fused with the ERG gene, a member of the ets gene by low-dose etoposide and aclarubicin treatment in March superfamily, on chromosome 21 to produce the FUS/ERG 1995. However, the second relapse occurred after 1 month chimeric transcript. [7][8][9][10][11] As a result, the RNA-binding domain with blastoma in the colon. The patient died of progressive of FUS is replaced with the DNA-binding domain of ERG and disease and pneumonia in May 1995. CytokinesCorrespondence: H Hamaguchi, Department of Hematology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, TokyoAll cytokines used in this study, ie recombinant human gra-180, Japan

We have recently found that all-trans retinoic acid (ATRA) upregulates thrombomodulin (TM) and downregulates tissue factor (TF) expression in acute myelogenous leukemia (AML) M3 cells (NB4) and acute monoblastic leukemia cells (U937) (Koyama et al, Blood 84:3001, 1994). We have further investigated the effects of ATRA on leukemic cells freshly isolated from patients at diagnosis. Increase of TM antigen was documented in all AML cells: M0 (n = 1), M2 (n = 5), M3 (n = 3), M4 (n = 3), M5 (n = 3), and M6 (n = 1). Decrease of TF antigen was observed in 4 M2, 1 M4, and all M3 and M5 patients. However, no TM and TF antigens were detected in all chronic lymphocytic leukemia cells (n = 3) with or without ATRA treatment. Changes of TM and TF antigen levels were associated with those of TM and TF cofactor levels on the cell surface. A stereoisomer of RA, 9-cis RA, is a high-affinity ligand for the RA receptors (RARs) and the retinoid X receptors, although ATRA and another isomer, 13-cis RA, solely bind to RARs. We have also studied the effects of 9-cis RA and 13-cis RA on the expressions of TM and TF in NB4 and U937 cells. A relatively wide range of 9-cis RA concentrations (0.01 to 1 mumol/L) compared with ATRA was optimal for prolongation of normal plasma-based recalcification time (reduction of cell surface TF activity), decrease of TF antigen, and increase of TM antigen on the surface and in the lysates of NB4 and U937 cells. Western blot analysis under nonreducing conditions showed that both ATRA and 9-cis RA markedly induced the prominent band at 75 kD of TM and reduced the band at 45 kD of TF. Northern blot analysis has shown similar changes of mRNA levels, which indicates that RAs regulate TM and TF expression in leukemic cells at transcriptional levels. Anticoagulant effects of ATRA, ie, upregulation of TM expression and downregulation of TF expression, are applied not only to established cell lines of specific subtypes (M3 and M5) but also to more universal AML (most cases of M3 and M5 and a part of the other types of AML) cells freshly isolated from patients. 9-cis RA may be more effective than ATRA as an inducer of differentiation of AML M3 cells and as an anticoagulant agent for patients with certain types of AML as well.

We describe a 40-year-old male who developed an isolated recurrence of granulocytic sarcoma (GS) of the brain 2 years following successful treatment of acute myeloblastic leukemia (AML; M2). Computed tomography (CT) scans and magnetic resonance (MR) images demonstrated a homogeneously enhanced tumor mass in the left temporal lobe and massive peritumoral edema. There was no evidence of relapse in the bone marrow. The patient underwent an emergency surgical resection of the tumor. Five courses of injection with cytarabine and prednisolone through an Ommaya reservoir and whole brain irradiation (total 40 Gy) were performed. Furthermore, prophylactic systemic chemotherapy with cytarabine and etoposide was added. He has been in complete remission for 21 months. Our results, together with other reported cases, indicate that a favorable outcome could be obtained by intensive and combined treatment for an isolated recurrence of GS of the brain if the bone marrow remained in complete remission.