びまん性大細胞型B細胞リンパ腫患者における病理組織中EBV DNA量とEBERの予後に関する重要性

藤田保健衛生大

Mindin/F-spondin Family: Novel ECM Proteins Expressed in the Zebrafish Embryonic Axis

AbstractF-spondin is a secreted protein expressed at high levels by the floor plate cells. The C-terminal half of the protein contains six thrombospondin type 1 repeats, while the N-terminal half exhibited virtually no similarity to any other protein until recently, when aDrosophilagene termedM-spondinwas cloned; its product was found to share two conserved domains with the N-terminal half of F-spondin. We report the molecular cloning of four zebrafish genes encoding secreted proteins with these conserved domains. Two are zebrafish homologs ofF-spondin,while the other two, termedmindin1andmindin2,encode mutually related novel proteins, which are more related to theDrosophilaM-spondin than to F-spondin. During embryonic development, all four genes are expressed in the floor plate cells. In addition to the floor plate,mindin1is expressed in the hypochord cells, whilemindin2is expressed in the sclerotome cells. When ectopically expressed, Mindin proteins selectively accumulate in the basal lamina, suggesting that Mindins are extracellular matrix (ECM) proteins with high affinity to the basal lamina. We also report the spatial distribution of one of the F-spondin proteins, F-spondin2. F-spondin2 is localized to the thread-like structure in the central canal of the spinal cord, which is likely to correspond to Reissner's fiber known to be present in the vertebrate phylum. In summary, our study has defined a novel gene family of ECM molecules in the vertebrate, all of which may potentially be involved in development of the midline structure

Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia ; A subgroup analysis of the CEDMIC trial

Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2–79.4) and 79.6% (71.0–86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2–80.9%) and 78.0% (65.3–87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT

Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBVencoded RNA.We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-a, and arginase 1, suggesting the immune regulatory role of BART miRNAs.The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma.These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV1 B-cell lymphoma. (Blood. 2018;131(23):2552-2567)

Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane in Burkitt lymphoma with a very high risk of tumor lysis syndrome: a case series with literature review

Abstract Background Tumor lysis syndrome is an oncological emergency triggered by the rapid release of intracellular materials from lysed malignant cells. Intensive chemotherapy is challenging for patients with severe renal dysfunction and a high risk of tumor lysis syndrome. Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA) could work not only as a renal replacement therapy, but also as a novel method to control intracellular materials, including cytokines and damage-associated molecular patterns. We aimed to describe two cases of patients with Burkitt’s lymphoma with a very high risk of tumor lysis syndrome who were successfully treated with a combination of chemotherapy and SHEDD-fA. Case presentation The first case was of a 67-year-old man who was admitted to the intensive care unit for respiratory failure and diagnosed with Burkitt’s lymphoma. Extremely high lactate dehydrogenase levels and anuria, indicating severe acute kidney injury, are considered to be associated with a very high risk of tumor lysis syndrome. SHEDD-fA was initiated prophylactically to prevent exacerbation of tumor lysis syndrome. To ensure the blood concentration of antitumor drugs, SHEDD-fA was stopped temporarily and restarted 6 h after the completion of chemotherapy. No tumor lysis syndrome-related complications were observed. The second case involved a 68-year-old man who was admitted to the intensive care unit due to exacerbation of Burkitt’s lymphoma complicated by severe pneumonia and disseminated intravascular coagulation. The patient exhibited metabolic acidosis, hyperkalemia, hyperuricemia, and anuria. SHEDD-fA was performed immediately. As in the first case, we temporarily discontinued SHEDD-fA before chemotherapy and restarted it 6 h after the completion of chemotherapy. No tumor lysis syndrome-associated complications were observed and renal function recovered. Interleukin-6, interleukin-8, and high-mobility group box-1 protein levels in the blood were lower on the outlet side than on the inlet side. Conclusions SHEDD-fA allows safe and effective administration of chemotherapy in patients with severe renal dysfunction and a very high risk of tumor lysis syndrome. Our findings indicate that blood purification modality may need to be selected according to tumor lysis syndrome severity

Isolation and characterization of 2-hydroxy-9,10-anthraquinone from Streptomyces olivochromogenes (ERINLG-261) with antimicrobial and antiproliferative properties

Abstract Currently Streptomyces is one of the most important antibiotic producing microorganisms against several diseases. In the present study Streptomyces olivochromogenes ERINLG-261 was isolated from the soil samples of the Mudumalai hills, Western Ghats, India. Morphological, physiological, biochemical and 16S rRNA studies strongly suggested that this isolate belonged to the genus Streptomyces. ERINLG-261 showed good antimicrobial activity against different bacteria and fungi in Micromonospora fermentation medium. The active ethyl acetate extract was packed in column chromatography over silica gel which led to the isolation of 2-hydroxy-9,10-anthraquinone as the active principle. The isolated compound showed good antimicrobial activity against tested bacteria and fungi in minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) studies. The compound showed moderate in vitro antiproliferative activity against A549 and COLO320 cells. The compound was subjected to molecular docking studies for the inhibition of Topoisomerase, TtgR and Beta-lactamase enzymes which are targets for antimicrobials. Docking results of the compound showed low docking energy with these enzymes indicating its usefulness as antimicrobial agent. This is the first report of antimicrobial and antiproliferative activity of 2-hydroxy-9,10-anthraquinone isolated from Streptomyces olivochromogenes along with molecular docking studies

Utility of cerebrospinal fluid liquid biopsy in distinguishing CNS lymphoma from cerebrospinal infectious/demyelinating diseases

Abstract Background Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. Methods In this study, we extracted cell‐free DNA from the CSF (CSF‐cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet‐digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. Results Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF‐cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF‐cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18–93 days). Conclusions These results suggest that mutation analysis using CSF‐cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform