Kooperativer Bibliotheksverbund

In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. 19 ( 2022-11-08), p. 1425-1433

Abstract: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( 〈 40%) on admission, and ventricular tachycardia or fibrillation on admission day were associated with worse 90-day survival. Severe histologic damage (damaged cardiomyocytes comprising ≥50% of the total cardiomyocytes) was associated with a worse 90-day prognosis in patients with lymphocytic myocarditis. Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/CIRCULATIONAHA.121.058869

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2022

detail.hit.zdb_id: 1466401-X

In: Nature, Springer Science and Business Media LLC, Vol. 609, No. 7928 ( 2022-09-22), p. 754-760

Abstract: Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1–5 . 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.

Type of Medium: Online Resource

ISSN: 0028-0836 , 1476-4687

URL: Article

DOI: 10.1038/s41586-022-05163-5

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 120714-3

detail.hit.zdb_id: 1413423-8

SSG: 11

In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 23, No. 2 ( 2017-02), p. 361-363

Type of Medium: Online Resource

ISSN: 1083-8791

URL: Article

DOI: 10.1016/j.bbmt.2016.10.024

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 3056525-X

detail.hit.zdb_id: 2057605-5

In: Infection and Immunity, American Society for Microbiology, Vol. 76, No. 2 ( 2008-02), p. 781-787

Abstract: The Mongolian gerbil model of Helicobacter pylori infection resembles human gastritis. In this study, we investigated the role of NF-κB activation in H. pylori -infected gerbils. Activated macrophages were significantly increased in H. pylori -infected gastric mucosa and were identified as being important cells with potent activation of NF-κB, which plays an important part in producing proinflammatory cytokines. Macrophage depletion by the administration of clodronate resulted in milder inflammation in gerbils infected with H. pylori . In macrophages, the inhibition of IκB kinase β (IKKβ), which is a critical kinase for NF-κB activation, resulted in lower proinflammatory cytokine expression caused by heat-killed H. pylori cells. Furthermore, treatment with IKKβ inhibitor resulted in milder inflammation in gerbils with H. pylori gastritis. Collectively, our data suggest that H. pylori -mediated gastric inflammation critically depends on the efficient recruitment and activation of macrophages, with sufficient NF-κB activation.

Type of Medium: Online Resource

ISSN: 0019-9567 , 1098-5522

URL: Article

DOI: 10.1128/IAI.01046-07

Language: English

Publisher: American Society for Microbiology

Publication Date: 2008

detail.hit.zdb_id: 1483247-1

In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 210, No. 12 ( 2013-11-18), p. 2627-2639

Abstract: Polycomb group (PcG) proteins are essential regulators of hematopoietic stem cells. Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). In our patient cohort, EZH2 mutations were also found and often coincided with tet methylcytosine dioxygenase 2 (TET2) mutations. Consistent with these findings, deletion of Ezh2 alone was enough to induce MDS/MPN-like diseases in mice. Furthermore, concurrent depletion of Ezh2 and Tet2 established more advanced myelodysplasia and markedly accelerated the development of myelodysplastic disorders including both MDS and MDS/MPN. Comprehensive genome-wide analyses in hematopoietic progenitor cells revealed that upon deletion of Ezh2, key developmental regulator genes were kept transcriptionally repressed, suggesting compensation by Ezh1, whereas a cohort of oncogenic direct and indirect polycomb targets became derepressed. Our findings provide the first evidence of the tumor suppressor function of EZH2 in myeloid malignancies and highlight the cooperative effect of concurrent gene mutations in the pathogenesis of myelodysplastic disorders.

Type of Medium: Online Resource

ISSN: 1540-9538 , 0022-1007

URL: Article

DOI: 10.1084/jem.20131144

Language: English

Publisher: Rockefeller University Press

Publication Date: 2013

detail.hit.zdb_id: 1477240-1

In: Experimental Hematology, Elsevier BV, Vol. 41, No. 8 ( 2013-08), p. S54-

Type of Medium: Online Resource

ISSN: 0301-472X

URL: Article

DOI: 10.1016/j.exphem.2013.05.212

Language: English

Publisher: Elsevier BV

Publication Date: 2013

detail.hit.zdb_id: 2005403-8

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2697-2697

Abstract: Introduction POEMS syndrome is a rare systemic disorder characterized by various symptoms, including polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy (M-protein), and skin changes, which is based on the presence of monoclonal plasma cells (PC). We previously reported the analysis of the clonal immunoglobulin λ light-chain variable region (IGLV) gene rearrangements in POEMS syndrome using next-generation sequencing (NGS), and the clone identification rate was 36.7% (Kawajiri-Manako C, Am J Hematol. 2018;93(9):1161). EuroFlow-based next-generation flow (EuroFlow-NGF) has also been standardized for detecting minimal residual disease in multiple myeloma (MM). However, multiparameter flow cytometry (MFC) utility in detecting clonal PC of POEMS syndrome remains unknown. Therefore, to clarify the feasibility of detecting the clonality with MFC, we analyzed PC of bone marrow samples in patients with POEMS syndrome by MFC and validated gating strategies of PC in POEMS syndrome. Methods Patients with newly diagnosed or relapsed POEMS syndrome (n=25) at Chiba University Hospital from April 2019 to July 2021 were included in this study. Primary bone marrow aspirations were performed after obtaining informed consent following the Declaration of Helsinki. The collected bone marrow samples were analyzed by the SRL-Flow protocols (single-tube 8-color: CD138/CD27/CD38/CD56/CD45/CD19/CyIgκ/CyIgλ), which is highly correlated with EuroFlow-NGF (Takamatsu H, Int J Hematol. 2019;109(4): 377). Furthermore, 21 cases for which data files were available from SRL Inc. were reanalyzed by gating PC with lower expression of CD45 regarding the previous study (Dao LN, Blood. 2011;117(24):6438). This study was approved by the ethics committee of Chiba University Graduate School of Medicine. Results Among 25 patients, the median age was 59 (25-77) years, and 13 (52.0%) were men. The types of M-proteins identified by immunofixation electrophoresis (IFE) were IgA-λ in 12 (48.0%), IgG-λ in 9 (36.0%), IgA-κ in 1 (4.0%), IgG-κ in 1 (4.0%), and negative in 2 patients (8.0%), respectively. The median serum VEGF level was 3,240 (747-9,060) pg/ml. SRL-Flow identified the clonal PC in 9 of 25 (36.0%, λ in 7 and κ in 2): 7 of 23 IFE-positive cases (30.4%) and 2 of 2 IFE-negative cases (100%). The median clone size was 0.03 (0.01-3.78)%, smaller than MM. Interestingly, the clone size was not correlated with the level of serum VEGF (r = -0.17). Aberrant expression of clonal PC in POEMS syndrome was similar to MM: CD19-56+ in 5 (55.6%), CD19-56- in 2 (22.2%), CD19dim56- in 1 (11.1%), and CD19-56dim in 1 (11.1%) patient, respectively. No clone was detected in PC with CD19+56-. The clone identification rate by single-tube 8-color SRL-Flow protocols was lower than expected. Therefore, we reanalyzed the data by gating PC with lower expression of CD45 and CD38. In the reanalysis, we gated broadly for CD38 dim-to-bright and CD138 dim-to-bright cells and narrowly for CD38 dim and CD45 negative-to-dim cells. As a result, we identified the clonal PC in 15 of 21 cases (71.4%, λ in 13 and κ in 2): 13 of 19 IFE-positive cases (68.4%) and 2 of 2 IFE-negative cases (100%)). Of the 15 cases in which monoclonal PC were identified by reanalysis, 8 were negative by SRL-Flow. Of these, 6 were identified by selective gating of CD45- and CD38 dim, and 2 were identified by selective gating of CD45- and CD38+. The median clone size was 0.008 (0.001-3.27)%, smaller than that of MM, and the clone size was not correlated with the level of serum VEGF (r = -0.15). The aberrant expression of the clonal PC in POEMS remained similar to MM for CD19 and CD56 expression: CD19-56+ in 3 (20.0%), CD19-56- in 7 (46.7%), CD19-56dim in 4 (26.7%), and CD19dim 56- in 1 (6.7%) patient, respectively. No clone was detected in PC with CD19+56-. Conclusions EuroFlow-based SRL-Flow protocols detected the clonal PC in about one-third of POEMS patients. Aberrant immunophenotype of clonal PC in POEMS syndrome was similar to MM for CD19 and CD56 expression; however, CD45 and CD38 expression of POEMS PC tended to be downregulated. Selective gating of PC with CD38dim and CD45 negative-to-dim detected clonal PC in 71.4% of cases. This novel gating strategy is more accessible and might improve the identification rate of clonal PC in POEMS syndrome. Disclosures Tsukamoto: Daiichi Sankyo: Honoraria. Yokote: Kowa Company, Ltd.: Honoraria, Other: Scholarship; MSD K.K.: Honoraria, Other: Scholarship, Courses endowed by company; Astellas Pharma Inc.: Honoraria, Other: Scholarship; Mitsubishi Tanabe Pharma Corporation: Honoraria, Other: Scholarship; Amgen K.K.: Honoraria; Taisho Pharmaceutical Co., Ltd.: Honoraria, Other: Scholarship, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Other: Scholarship; Janssen Pharmaceutical K.K.: Honoraria; Kao Corporation: Other: Schlarship; Novo Nordisk Pharma Ltd.: Honoraria, Other: Scholarship; Teijin Pharma Limited: Other: Scholarship; Pfizer Japan Inc.: Honoraria, Other: Scholarship; Kyowa Kirin Co., Ltd.: Honoraria; Eli Lilly Japan K.K.: Honoraria, Other: Scholarship; Takeda Pharmaceutical Company Limited: Honoraria, Other: Scholarship; Sanofi K.K.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria, Other: Scholarship; AstraZeneca K.K.: Honoraria; Daiichi Sankyo Company, Limited: Honoraria, Other: Scholarship; Novartis Pharma K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria, Other: Scholarship; Shionogi Co., Ltd.: Other: Scholarship; Bayer Yakuhin, Ltd.: Other: Scholarship. Nakaseko: Novartis Pharma KK.: Honoraria. Takamatsu: Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Sakaida: Bristol Myers Squibb: Research Funding; Chugai: Research Funding; Ono: Research Funding; Kyowa Kirin: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150900

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 131, No. 19 ( 2018-05-10), p. 2173-2176

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2017-07-795385

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 10 ( 2015-09-03), p. 1172-1183

Abstract: Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous hematologic malignancies. Ezh1 is essential to maintain hematopoiesis in the setting of Ezh2 loss.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2015-03-634428

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1661-1661

Abstract: Introduction: LR11 is a type I membrane protein that plays a key role in the migration of undifferentiated vascular smooth muscle cells, and circulating soluble LR11 (sLR11) has been known as a biomarker for coronary stenosis. We have previously found that LR11 is highly expressed in acute leukemia, diffuse large B cell lymphoma (DLBCL), and follicular lymphoma (FL) cells. Soluble LR11 were detected in the patients' serum, and our retrospective cohort demonstrated that serum sLR11 level is significantly increased at diagnosis and normalized at remission (Sakai et al. Clin Chim Acta. 2012, Ohwada et al. 2011 ASH annual meeting). Furthermore, high serum sLR11 level had a significant association with relapse and inferior progression-free survival (PFS) in patients with FL (Kawaguchi et al. Br J Haematol. 2013). Based on these findings, we have conducted a multicenter prospective observational study to validate the clinical impact of serum sLR11 in patients with newly diagnosed DLBCL. Patients and Methods: Ninety-seven consecutive patients with newly diagnosed DLBCL between 2010 and 2013 in Chiba University Hospital and affiliated hospitals were enrolled. Serum samples were collected at diagnosis and when the patients reached complete remission. Clinical and laboratorial data were collected prospectively. Serum sLR11 levels were measured with enzyme-linked immunosorbent assay. Normal control samples were obtained from 75 healthy adult volunteers who had given informed consent. Results: The patients had a median age of 69 years (range, 18-94). Ninety percent of patients were treated with R-CHOP-based regimen, and 80% of them achieved complete remission (CR). Serum sLR11 levels of DLBCL patients were significantly elevated than those of normal controls (21.2 ±27.6 ng/ml vs. 8.8 ±1.8 ng/ml, p 〈 0.0001), and paired sample analysis showed elevated serum sLR11 level at diagnosis was significantly decreased at complete remission (17.4 ± 16.4 ng/ml vs. 11.0 ± 4.2 ng/ml, p=0.0008). Serum sLR11 levels were significantly high in "poor" risk patients categorized by Revised-International Prognostic Index (R-IPI) (poor vs. very-good/good: 33.0 ± 37.1 ng/ml vs. 11.0 ± 4.2 ng/ml, p 〈 0.0001), and also in those with bone marrow invasion (present vs. absent: 48.7 ± 59.5 ng/ml vs. 17.0 ± 15.3 ng/ml, p=0.01). Multiple stepwise liner regression analysis revealed that serum sLR11 level at diagnosis was independently associated with serum LDH and beta-2-microgloblin levels (B2MG) (r2=0.43, serum LDH: p=0.0007, serum B2MG: p 〈 0.0001). At the median follow-up period of 13.8 months, 2-year progression free survival (PFS) and overall survival (OS) were significantly inferior in patients with serum sLR11 〉 =18 ng/ml, compared to those with 〈 18 ng/ml (2-year PFS: 47% vs. 85%, p 〈 0.0001, 2-year OS: 49% vs. 89%, p 〈 0.0001). Furthermore, among 44 poor-risk patients determined by R-IPI, patients with serum sLR11 〉 =18 ng/ml showed a trend toward lower PFS than those with 〈 18 ng/ml (2-year PFS: 41% vs. 64%, p=0.06). Conclusion: Here we have prospectively validated that serum sLR11 is a simple and powerful indicator of tumor burden and aggressive disease character with poor prognosis. By combining with previously established prognostic indexes, sLR11 may enable us to identify high-risk patients who are candidates for more aggressive treatment strategy such as up-front autologous stem cell transplantation, or combination of novel targeted agents. Figure 1 Figure 1A. OS according to serum sLR11 at diagnosis. Figure 1B. PFS in patients with "Poor" R-IPI risk, according to serum sLR11 at diagnosis. Figure 1. Figure 1A. OS according to serum sLR11 at diagnosis. Figure 1B. PFS in patients with "Poor" R-IPI risk, according to serum sLR11 at diagnosis. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1661.1661

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7