Publications by authors named "Katsushi Tajima"

45 Publications

Clarithromycin As an Alternative and Prophylactic Agent in a Hematopoietic Stem Cell Transplantation Patient.

Am J Case Rep 2021 Jun 15;22:e931731. Epub 2021 Jun 15.

Medical Mycology Research Center, Chiba University, Chiba, Japan.

BACKGROUND Nocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, who usually receive the prophylactic use of sulfamethoxazole/trimethoprim (ST) against Pneumocystis jiroveci. However, the ST prophylaxis, sensitive to Nocardia species, sometimes induces renal toxicities. Therefore, alternative prophylactic or therapeutic drugs are required for nocardiosis in HSCT patients. CASE REPORT A 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9; 22) received allogenic peripheral blood HSCT from a haplo-identical sibling donor. He developed graft versus host disease (GVHD) with grade II, and was treated with prednisolone and cyclosporine A with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, the prophylactic ST was ceased because of its renal toxicity. He developed a pulmonary nodular lesion with elevated ß-D-glucan and Aspergillus galactomannan antigen. Repeated blood and sputum culture isolated no pathogens. Voriconazole treatment administered once improved these lesions and laboratory findings. One month later, he presented with right pleuritic chest pain and multiple ring-enhancing cavitation lesions along the ribs. A needle biopsy demonstrated Nocardia elegans, which is an extremely rare infection induced by Nocardia species, in the cavitation lesions, shown by 16S rRNA gene sequencing. He was started on doripenem and liposomal amphotericin B, and a subsequent treatment kept him free from Nocardia elegans infection, without any adverse effects, while continuing the cyclosporine A and prednisolone treatment for chronic GVHD. CONCLUSIONS Clarithromycin has fewer adverse effects than ST. This case suggests that clarithromycin is an appropriate alternative and prophylactic therapy for patients with nocardiosis and ST toxicities.
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http://dx.doi.org/10.12659/AJCR.931731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216568PMC
June 2021

Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair.

Genes Cells 2021 May 18;26(5):328-335. Epub 2021 Mar 18.

National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Sciences and Technology (QST), Chiba, Japan.

SIRT2 and SIRT3 protein deacetylases maintain genome integrity and stability. However, their mechanisms for maintaining the genome remain unclear. To examine the roles of SIRT2 and SIRT3 in DSB repair, I-SceI-based GFP reporter assays for HR, single-strand annealing (SSA) and nonhomologous end joining (NHEJ) repair were performed under SIRT2- or SIRT3-depleted conditions. SIRT2 or SIRT3 depletion inhibited HR repair equally to RAD52 depletion, but did not affect SSA and NHEJ repairs. SIRT2 or SIRT3 depletion disturbed the recruitment of RAD51 to DSB sites, an essential step for RAD51-dependent HR repair, but not directly through RAD52 deacetylation. SIRT2 or SIRT3 depletion decreased the colocalization of γH2AX foci with RPA1, and thus, they might be involved in initiating DSB end resection for the recruitment of RAD51 to DSB sites at an early step in HR repair. These results show the novel underlying mechanism of the SIRT2 and SIRT3 functions in HR for genome stability.
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http://dx.doi.org/10.1111/gtc.12842DOI Listing
May 2021

Nodal histiocytic sarcoma with prominent eosinophilic infiltration: expression of eotaxin-2 on tumor cells.

Diagn Pathol 2021 Jan 12;16(1). Epub 2021 Jan 12.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

Background: Histiocytic sarcoma (HS) is a rare neoplasm showing morphological and immunophenotypic features of mature tissue histiocytes. We report a patient with nodal HS exhibiting prominent reactive eosinophilic infiltration.

Case Presentation: A 68-year-old man presented with intermittent left lower abdominal pain and weight loss over 3 months. A computed tomography scan revealed multiple abdominal nodules. Open biopsy of the mesenteric tumors was performed for definitive diagnosis. Histologically, the tumor was comprised of a diffuse noncohesive proliferation of pleomorphic large cells, including multinucleated cells. Neoplastic cells were positive for histiocytic markers (CD68, CD163, and LIGHT) and PD-L1 but lacked markers of Langerhans cells, follicular dendritic cells, and epithelial cells. Frequent reactive inflammatory cells were intermingled in the background. Interestingly, prominent eosinophilic infiltration was also noted. Spindle neoplastic cells were prone to be present around areas with little to no eosinophilic infiltration and exhibiting fibrosis and lymphatic vessel proliferation. Conversely, polygonal neoplastic cells were prone to be present around areas with relatively large amounts of eosinophilic infiltration without fibrosis or lymphatic vessel proliferation. Immunohistochemically, the tumor cells and reactive eosinophils expressed eotaxin-2 and eotaxin-3, respectively.

Conclusion: We revealed that eotaxins induced the selective migration of eosinophils into tissues in this case. These eosinophils may affect the tumor remodeling and tumor biology characteristics of HS, such as fibrosis and lymphatic vessel proliferation.
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http://dx.doi.org/10.1186/s13000-020-01061-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805230PMC
January 2021

Impact of comorbidity and relative dose intensity on outcomes in diffuse large B-cell lymphoma patients treated with R-CHOP.

J Cancer Res Clin Oncol 2020 Nov 10;146(11):2995-3002. Epub 2020 Jun 10.

Department of Hematology, Yamagata Prefectural Central Hospital, 1800, Aoyagi, Yamagata, 990-2292, Japan.

Background: Comorbidity and relative dose intensity (RDI) have been associated with survival in diffuse large B-cell lymphoma (DLBCL) patients, but both relationships remain unaddressed in the same patients.

Methods: A retrospective review of consecutive DLBCL patients treated from January 2010 to October 2018 was performed. Data for the clinical characteristics of the patients, including the Charlson Comorbidity Index (CCI) and RDI, on their outcomes were evaluated.

Results: A total of 211 patients with a median age of 72 years (range 19-90 years) were analyzed. CCI ≥ 2 was associated with poor event-free survival (EFS) and overall survival (OS). RDI < 70% was associated with worse EFS and OS. A multivariate analysis revealed that RDI < 70% was only a poor risk factor for the reduction of OS in elderly DLBCL patients (65 years <) and independent from the presence of CCI. The relationship between CCI and RDI in elderly patients was analyzed in four groups, based on CCI ≥ 2 or less and RDI ≥ 70% or less. The group with CCI ≥ 2 and RDI < 70% had a poorer OS and EFS, as compared to the other three groups. The group with CCI < 2 and RDI ≥ 70% had a superior OS but an identical EFS, as compared to the two groups with CCI < 2 and RDI < 70% and CCI ≥ 2 and RDI ≥ 70%.

Conclusions: CCI ≥ 2 was associated with a poorer outcome, but maintaining RDI ≥ 70% may improve the outcome, especially in elderly DLBCL patients.
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http://dx.doi.org/10.1007/s00432-020-03279-7DOI Listing
November 2020

Characterization of reemergent anti-B red blood cell antibodies in a patient with recurrent acute myeloid leukemia with ABO-incompatible allogeneic peripheral blood stem cell transplantation.

Transfusion 2019 11 10;59(11):3319-3323. Epub 2019 Sep 10.

Department of Laboratory Medicine, Yamagata Prefectural Central Hospital, Yamagata, Japan.

Background: Isohemagglutinins against ABO antigens absent on both recipient and donor red blood cells (RBCs) increase or decrease after ABO-incompatible hematopoietic stem cell transplantation (HSCT). However, few reports have described the changes in the isohemagglutinin titers and the characteristics in patients with recurrent hematologic conditions after ABO-incompatible HSCT.

Case Report: A 59-year-old female with acute erythroid leukemia received a peripheral blood stem cell transplant from her HLA-haploidentical daughter. The patient was typed as group O with anti- A (4+) and B (4+) isohemagglutinins, while the donor was typed as group B. The bone marrow cells achieved complete donor cell chimerism on Day 13 after HSCT. On Day 120, the patient showed 97% B RBC type with persistent anti-A (3+) and without anti-B antibodies. On Day 375, her leukemia relapsed, and recipient type O RBCs and anti-B antibodies sequentially reemerged. However, clinicolaboratory hemolysis and erythroid aplasia were not detected in the patient.

Results: The post-HSCT sera agglutinated the allo B RBCs, but not the donor B RBCs, while the pre-HSCT sera agglutinated both RBCs. The burst-forming/colony-forming units of erythroid formation from the donor peripheral blood stem cells were impaired by only the pre-HSCT sera and not by the post-HSCT sera.

Conclusion: To our knowledge, this is the first report investigating the characteristic changes of isohemagglutinins between the pre- and post-HSCT sera in a patient with recurrent acute myeloid leukemia. The present study suggests that the plasma cells producing anti-donor B RBCs in the patient have been selectively eliminated or induced into an anergic state by the post-HSCT immunologic reconstruction.
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http://dx.doi.org/10.1111/trf.15510DOI Listing
November 2019

Giant cellulitis-like Sweet syndrome as an initial clinical presentation of acute myeloblastic leukemia with t(6;9)(p23;q34): DEK-CAN and internal duplications of FMS-like tyrosine kinase 3.

Ann Hematol 2019 Mar 18;98(3):787-788. Epub 2019 Jan 18.

Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, 990-2292, Japan.

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http://dx.doi.org/10.1007/s00277-019-03613-1DOI Listing
March 2019

Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites.

PLoS Genet 2018 03 28;14(3):e1007277. Epub 2018 Mar 28.

Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences (NIRS), Anagawa, Inage-ku, Chiba, Japan.

The p300 and CBP histone acetyltransferases are recruited to DNA double-strand break (DSB) sites where they induce histone acetylation, thereby influencing the chromatin structure and DNA repair process. Whether p300/CBP at DSB sites also acetylate non-histone proteins, and how their acetylation affects DSB repair, remain unknown. Here we show that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DSB sites. Using in vitro acetylated RAD52, we identified 13 potential acetylation sites in RAD52 by a mass spectrometry analysis. An immunofluorescence microscopy analysis revealed that RAD52 acetylation at DSBs sites is counteracted by SIRT2- and SIRT3-mediated deacetylation, and that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, inhibition of ataxia telangiectasia mutated (ATM) protein by siRNA or inhibitor treatment demonstrated that the acetylation of RAD52 at DSB sites is dependent on the ATM protein kinase activity, through the formation of RAD52, p300/CBP, SIRT2, and SIRT3 foci at DSB sites. Our findings clarify the importance of RAD52 acetylation in HR and its underlying mechanism.
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http://dx.doi.org/10.1371/journal.pgen.1007277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891081PMC
March 2018

meningitis in a diffuse large B-cell lymphoma patient with CD4-positive lymphocytopenia and persistent oligoclonal CD8-positive lymphocytes in the peripheral blood.

Int J Clin Exp Pathol 2018 1;11(1):455-461. Epub 2018 Jan 1.

Medical Mycology Research Center, Chiba University Chuo-Ku, Chiba, Japan.

Nocardiosis, sometimes presenting with multiple granulomatous lesions, is a rare opportunistic infection occurring in immunocompromised patients. However, its immunological features remain largely unaddressed. We investigated the immunological characteristics of human nocardiosis and examined the component cells of the granulomatous lesions. A 66-year-old man with diffuse large B-cell lymphoma presented with fever and multiple nodules in the lung during chemotherapy. The blood culture formed white colonies, but their characterization was difficult by routine microbiological laboratory methods. Matrix-assisted laser desorption ionization-time of flight mass spectrometry identified the colonies as . Meanwhile, the patient suddenly experienced an epileptic seizure without a brain abscess. His cerebrospinal fluid (CSF) showed neutrophilic pleocytosis (108/mm). The conventional agar culturing failed to isolate colonies, but culturing with brain-heart infusion agar generated colonies. These colonies were completely concordant with those from the blood, as confirmed by 16S rRNA gene sequencing. Therefore, the patient had developed meningitis through sepsis induced by . His CD4-positive T-lymphocyte counts were low, and oligoclonal CD8-positive αβ T-lymphocytes were present in the blood prior to the first and after three cycles of chemotherapy. He had bone marrow granulomatous lesions comprising lymphoma and CD8-positive αβ T-cells. Treatment with sulfamethoxazole/trimethoprim relieved all of his symptoms. The combined analysis by microbiological and molecular methods determined the cause of his epileptic seizure. His immunological characteristics, including low CD4-positive or CD8-positive αβ T-lymphocytes, may have contributed to the unusual clinical presentations by , which rarely involves the central nervous system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957946PMC
January 2018

Epstein-Barr virus clonality and plasmacytosis in a patient with atypical angioimmunoblastic T cell lymphoma.

Ann Hematol 2018 Mar 30;97(3):537-539. Epub 2017 Nov 30.

Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, 990-2292, Japan.

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http://dx.doi.org/10.1007/s00277-017-3189-1DOI Listing
March 2018

Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients.

Eur J Haematol 2018 Jan 16;100(1):27-35. Epub 2017 Oct 16.

Division of Hematology and Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan.

Objectives: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study).

Methods: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL1 ) were the post-treatment factors investigated to predict the molecular response.

Results: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL1 was the only significant landmark for predicting DMR by multivariate analysis.

Conclusions: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL1 was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS.
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http://dx.doi.org/10.1111/ejh.12969DOI Listing
January 2018

Pseudo-grey platelet syndrome in a pregnant patient.

Br J Haematol 2017 09 23;178(6):836. Epub 2017 Jun 23.

Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan.

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http://dx.doi.org/10.1111/bjh.14808DOI Listing
September 2017

Intra- and extracellular plasminogen activator inhibitor-1 regulate effect of vitronectin against radiation-induced endothelial cell death.

Vascul Pharmacol 2016 12 17;87:150-158. Epub 2016 Sep 17.

Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba, Japan. Electronic address:

Plasminogen activator inhibitor-1 (PAI-1) is induced by radiation resulting in endothelial cell impairment, potentially leading to multiple organ failure. Vitronectin (VN) is a 75-kDa glycoprotein (VN) cleaved into two forms (VN or VN) by furin, which is regulated by intracellular PAI-1. VN protects against radiation-induced endothelial cell death, but the mechanisms involved in VN processing and its interactions with intra- and extracellular PAI-1 remain unclear. We examined these processes in cells in vitro using recombinant proteins or overexpression of VN and PAI-1 genes, including furin-susceptible (T) and furin-resistant VN (A). VN processing was analyzed using a mutant PAI-1 with relatively weaker binding to VN. VN function was evaluated by survival of radiation-damaged endothelial cells. Wild-type, but not mutant PAI-1 inhibited furin-dependent VN processing. Gene transfer revealed that furin-susceptible VN was processed more than the furin-resistant form, but processing of both was inhibited by PAI-1 overexpression. Intracellular PAI-1 formed a complex with VN (T) in cells and media, and the VN form was secreted preferentially. Only VN protected against radiation-induced endothelial cell death, in which its effect was abolished by wild-type but not mutant PAI-1. These findings indicate that intracellular PAI-1 inhibits VN processing and protects against radiation-induced endothelial cell death.
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http://dx.doi.org/10.1016/j.vph.2016.09.006DOI Listing
December 2016

Differentiation and Molecular Properties of Mesenchymal Stem Cells Derived from Murine Induced Pluripotent Stem Cells Derived on Gelatin or Collagen.

Stem Cells Int 2016 25;2016:9013089. Epub 2016 Aug 25.

Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan.

The generation of induced-pluripotential stem cells- (iPSCs-) derived mesenchymal stem cells (iMSCs) is an attractive and promising approach for preparing large, uniform batches of applicable MSCs that can serve as an alternative cell source of primary MSCs. Appropriate culture surfaces may influence their growth and differentiation potentials during iMSC derivation. The present study compared molecular properties and differentiation potential of derived mouse iPS-MSCs by deriving on gelatin or collagen-coated surfaces. The cells were derived by a one-step method and expressed CD73 and CD90, but CD105 was downregulated in iMSCs cultured only on gelatin-coated plates with increasing numbers of passages. A pairwise scatter analysis revealed similar expression of MSC-specific genes in iMSCs derived on gelatin and on collagen surfaces as well as in primary mouse bone marrow MSCs. Deriving iMSCs on gelatin and collagen dictated their osteogenic and adipose differentiation potentials, respectively. Derived iMSCs on gelatin upregulated Bmp2 and Lif prior to induction of osteogenic or adipose differentiation, while PPARγ was upregulated by deriving on collagen. Our results suggest that extracellular matrix components such as gelatin biases generated iMSC differentiation potential towards adipose or bone tissue in their derivation process via up- or downregulation of these master genes.
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http://dx.doi.org/10.1155/2016/9013089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014975PMC
September 2016

Successful high-dose dexamethasone treatment of acquired pure red cell aplasia following ABO major mismatched allogeneic hematopoietic stem cell transplantation.

Rinsho Ketsueki 2016 06;57(6):760-4

Department of Hematology, Nagano Red Cross Hospital.

A 46-year-old man was diagnosed with acute myelomonocytic leukemia involving inv(16)(p13.1q22) in August 2007. He received a human leukocyte antigen-identical, ABO major-mismatched (donor: A, recipient: O) bone marrow transplantation from an unrelated donor in June 2009. Cyclosporin A (CsA) and short-course methotrexate were used for graft versus host disease prophylaxis. Although granulocyte and platelet engraftment were achieved, the patient exhibited persistent anemia and was dependent on red blood cell (RBC) transfusions. Bone marrow aspiration on day 63 revealed the near absence of erythroid precursors, a finding consistent with pure red cell aplasia. No CBFβ-MYH11 transcripts were detected. The recipient's anti-A IgM antibody titer was 1:64, and his anti-A IgG antibody titer was 1:1024. The discontinuation of CsA, and the initiation of rituximab and donor lymphocyte infusions were all ineffective against his anemia. He was treated with high-dose dexamethasone (DEXA) (40 mg/day DEXA, days 657-660, days 757-760; 20 mg/day DEXA, days 764-767, days 772-775) in April 2010. A follow-up examination performed at 7 months after the high-dose DEXA treatment showed the patient's anti-A antibody titer to have dropped to an undetectable level. His hemoglobin levels also returned to normal (Hb: 13.4 g/dl), and he no longer required RBC transfusions.
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http://dx.doi.org/10.11406/rinketsu.57.760DOI Listing
June 2016

High prevalence of diffuse large B-cell lymphoma in occult hepatitis B virus-infected patients in the Tohoku district in Eastern Japan.

J Med Virol 2016 12 6;88(12):2206-2210. Epub 2016 Jun 6.

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.

Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jmv.24584DOI Listing
December 2016

Characteristics of three-dimensional prospectively isolated mouse bone marrow mesenchymal stem/stromal cell aggregates on nanoculture plates.

Cell Tissue Res 2016 10 21;366(1):113-27. Epub 2016 Apr 21.

Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba-city, Chiba, 263-8555, Japan.

Three-dimensional (3-D) aggregate culturing is useful for investigating the functional properties of mesenchymal stem/stromal cells (MSCs). For 3-D MSC analysis, however, pre-expansion of MSCs with two-dimensional (2-D) monolayer culturing must first be performed, which might abolish their endogenous properties. To avoid the need for 2-D expansion, we used prospectively isolated mouse bone marrow (BM)-MSCs and examined the differences in the biological properties of 2-D and 3-D MSC cultures. The BM-MSCs self-assembled into aggregates on nanoculture plates (NCP) that have nanoimprinted patterns with a low-cellular binding texture. The 3-D MSCs proliferated at the same rate as 2-D-cultured cells by only diffusion culture and secreted higher levels of pro-angiogenic factors such as vascular endothelial growth factor and hepatocyte growth factor (HGF). Conditioned medium from 3-D MSC cultures promoted more capillary formation than that of 2-D MSCs in an in vitro tube formation assay. Matrigel-implanted 3-D MSC aggregates tended to induce angiogenesis in host mice. The 3-D culturing on NCP induced alpha-fetoprotein (AFP) expression in MSCs without the application of AFP- or endodermal-inducible factors, possibly via an HGF-autocrine mechanism, and maintained their differentiation ability for adipocytes, osteocytes, and chondrocytes. Prospectively isolated mouse BM-MSCs expressed low/negative stemness-related genes including Oct3/4, Nanog, and Sox2, which were not enhanced by NCP-based 3-D culturing, suggesting that some of these cells differentiate into meso-endodermal layer cells. Culturing of prospectively isolated MSCs on NCP in 3-D allows the analysis of the biological properties of more closely endogenous BM-MSCs and might contribute to tissue engineering and repair.
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http://dx.doi.org/10.1007/s00441-016-2405-yDOI Listing
October 2016

Comparison of Absorbents and Drugs for Internal Decorporation of Radiocesium: Advances of Polyvinyl Alcohol Hydrogel Microsphere Preparations Containing Magnetite and Prussian Blue.

Biol Pharm Bull 2016 25;39(3):353-60. Epub 2015 Dec 25.

Internal Decorporation Research Team, Research Program for Radiation Medicine, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences.

Radiocesium nuclides, used as a gamma ray source in various types of industrial equipments and found in nuclear waste, are strictly controlled to avoid their leakage into the environment. When large amounts of radiocesium are accidentally incorporated into the human body, decorporation therapy should be considered. Although standard decorporation methods have been studied since the 1960s and were established in the 1970s with the drug Radiogardase(®) (a Prussian blue preparation), application of recent advances in pharmacokinetics and ethical standards could improve these methods. Here we designed a modern dosage form of hydrogel containing cesium-absorbents to alleviate intestinal mucosa irritation due to the cesium-binding capacity of the absorbents. The effectiveness of the dosage form on fecal excretion was confirmed by quantitative mouse experiments. The total cesium excretion rate of the crystal form (1.37±0.09) was improved by the hydrogel form (1.52±0.10) at the same dose of Prussian blue, with a longer gastrointestinal tract transit time. Using a mouse model, we compared the effects of several drugs on fecal and urinary excretion of internal cesium, without the use of absorbents. Only phenylephrine hydrochloride significantly enhanced cesium excretion (excretion rate of 1.17±0.08) via the urinary pathway, whereas none of the diuretic drugs tested had this effect. These findings indicate that modifying the dosage form of cesium absorbents is important for the decorporation of internal radiocesium contamination.
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http://dx.doi.org/10.1248/bpb.b15-00728DOI Listing
December 2016

Quantification of damage due to low-dose radiation exposure in mice: construction and application of a biodosimetric model using mRNA indicators in circulating white blood cells.

J Radiat Res 2016 Jan 19;57(1):25-34. Epub 2015 Nov 19.

Board, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

Biodosimetry, the measurement of radiation damage in a biologic sample, is a reliable tool for increasing the accuracy of dose estimation. Although established chromosome analyses are suitable for estimating the absorbed dose after high-dose irradiation, biodosimetric methodology to measure damage following low-dose exposure is underdeveloped. RNA analysis of circulating blood containing radiation-sensitive cells is a candidate biodosimetry method. Here we quantified RNA from a small amount of blood isolated from mice following low-dose body irradiation (<0.5 Gy) aimed at developing biodosimetric tools for situations that are difficult to study in humans. By focusing on radiation-sensitive undifferentiated cells in the blood based on Myc RNA expression, we quantified the relative levels of RNA for DNA damage-induced (DDI) genes, such as Bax, Bbc3 and Cdkn1a. The RNA ratios of DDI genes/Myc in the blood increased in a dose-dependent manner 4 h after whole-body irradiation at doses ranging from 0.1 to 0.5 Gy (air-kerma) of X-rays, regardless of whether the mice were in an active or resting state. The RNA ratios were significantly increased after 0.014 Gy (air-kerma) of single X-ray irradiation. The RNA ratios were directly proportional to the absorbed doses in water ranging from 0.1 to 0.5 Gy, based on gamma-irradiation from (137)Cs. Four hours after continuous irradiation with gamma-rays or by internal contamination with a beta-emitter, the increased RNA ratios resembled those following single irradiation. These findings indicate that the RNA status can be utilized as a biodosimetric tool to estimate low-dose radiation when focusing on undifferentiated cells in blood.
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http://dx.doi.org/10.1093/jrr/rrv066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708920PMC
January 2016

Regression of diffuse large B-cell lymphoma in sphenoid and ethmoid sinuses following treatment with loxoprofen.

Leuk Lymphoma 2016 7;57(3):721-3. Epub 2015 Jul 7.

a Department of Neurology , Hematology, Metabolism, Endocrinology and Diabetology (DNHMED), Yamagata University School of Medicine , Yamagata , Japan.

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http://dx.doi.org/10.3109/10428194.2015.1070154DOI Listing
December 2016

An isolated myeloid blast crisis presenting as optic nerve sarcoma in a patient with chronic myeloid leukaemia treated with imatinib.

Br J Haematol 2015 Aug 1;170(3):290. Epub 2015 Jun 1.

Research Centre for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba-shi, Chiba, Japan.

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http://dx.doi.org/10.1111/bjh.13503DOI Listing
August 2015

A prospective analysis of clinical efficacy and safety in chronic myeloid leukemia-chronic phase patients with imatinib resistance or intolerance as evaluated using European LeukemiaNet 2013 criteria.

Eur J Haematol 2015 Dec 25;95(6):558-65. Epub 2015 Mar 25.

Department of Hematology and Oncology, Iwate Medical University, Morioka, Japan.

Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML).

Methods: From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations.

Results: The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were 'warning' and 'failure' patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR(4.5) rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent.

Conclusions: Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of <1% at 3 months of dasatinib administration is a landmark for good therapeutic outcome.
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http://dx.doi.org/10.1111/ejh.12536DOI Listing
December 2015

Estimation of secondary measles transmission from a healthcare worker in a hospital setting.

Int J Infect Dis 2014 Jul 26;24:11-3. Epub 2014 Apr 26.

Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology (DNHMED), Yamagata University Faculty of Medicine, Yamagata, Japan.

Measles among healthcare workers (HCWs) is associated with a significant risk of nosocomial transmission to susceptible patients. When a measles case occurs in the healthcare setting, most guidelines recommend exhaustive measures. To evaluate the effects of measures against measles transmission in the healthcare setting precisely, it is essential to determine whether secondary transmission generally occurs. This study describes, for the first time, the actual secondary transmission rate for a measles-infected HCW in a ward with no special air ventilation capacity. The routine treatment of a number of immunocompromised patients occurs in this ward, and thus patients as well as HCWs have a thorough understanding and practice of standard and extended precautions. Our paired serum sample study revealed that none of the people in the ward exposed to the HCW at the catarrhal stage over a period of 4 days exhibited elevated levels of antibodies against measles. We suggest that strict adherence to standard and expanded precautions among patients and HCWs may be effective for preventing the transmission of a highly airborne disease, such as measles.
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http://dx.doi.org/10.1016/j.ijid.2014.03.1377DOI Listing
July 2014

Radiation increases the cellular uptake of exosomes through CD29/CD81 complex formation.

Biochem Biophys Res Commun 2014 Apr 22;446(4):1165-71. Epub 2014 Mar 22.

Research Center for Radiation Emergency Medicine, National Institute of Radiological Science, 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan. Electronic address:

Exosomes mediate intercellular communication, and mesenchymal stem cells (MSC) or their secreted exosomes affect a number of pathophysiologic states. Clinical applications of MSC and exosomes are increasingly anticipated. Radiation therapy is the main therapeutic tool for a number of various conditions. The cellular uptake mechanisms of exosomes and the effects of radiation on exosome-cell interactions are crucial, but they are not well understood. Here we examined the basic mechanisms and effects of radiation on exosome uptake processes in MSC. Radiation increased the cellular uptake of exosomes. Radiation markedly enhanced the initial cellular attachment to exosomes and induced the colocalization of integrin CD29 and tetraspanin CD81 on the cell surface without affecting their expression levels. Exosomes dominantly bound to the CD29/CD81 complex. Knockdown of CD29 completely inhibited the radiation-induced uptake, and additional or single knockdown of CD81 inhibited basal uptake as well as the increase in radiation-induced uptake. We also examined possible exosome uptake processes affected by radiation. Radiation-induced changes did not involve dynamin2, reactive oxygen species, or their evoked p38 mitogen-activated protein kinase-dependent endocytic or pinocytic pathways. Radiation increased the cellular uptake of exosomes through CD29/CD81 complex formation. These findings provide essential basic insights for potential therapeutic applications of exosomes or MSC in combination with radiation.
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http://dx.doi.org/10.1016/j.bbrc.2014.03.067DOI Listing
April 2014

Expression of mRNAs for the diacylglycerol kinase family in immune cells during an inflammatory reaction.

Biomed Res 2014 ;35(1):61-8

Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585, Japan.

Phosphoinositide metabolism is intimately involved in cellular signal transduction. In response to extracellular stimuli, it generates diacylglycerol (DG), which serves as a lipid second messenger molecule to activate various proteins in various organs under pathophysiological conditions. Diacylglycerolkinase (DGK) constitutes an enzyme family that catalyzes conversion of DG to phosphatidic acid. It is therefore regarded as a regulator of the DG signal. Previous studies have revealed the critical role of α and ζ types of DGK in T cell functions. Nevertheless, little is known about the expression patterns of the DGK family in immune cells of various kinds. After examination of the expression profile of DGK isozymes in immune cells that are isolated from human blood, we investigated whether their mRNA expression levels would be changed during an inflammatory reaction. Results showed that DGK isozyme mRNAs are widely expressed in immune cells, except for DGKβ and DGKι. During an inflammatory reaction, DGKε mRNA was increased transiently in the initial phase (20-40 min) of stimulation with both LPS and IL-2 in T cell-derived HUT-102 cells and macrophage-derived RAW264 cells. At the organismal level, an intraperitoneal injection of LPS also induced upregulation of DGKε mRNA in the spleen in a similar,but not identical, manner. These results suggest that DGKε is involved in inflammatory processes of the cellular immune system.
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http://dx.doi.org/10.2220/biomedres.35.61DOI Listing
October 2014

Acute kidney injury and inflammatory immune reconstitution syndrome in mixed genotype (A/E) hepatitis B virus co-infection in HIV-associated lymphoma.

Int J Clin Exp Pathol 2013 15;6(3):536-42. Epub 2013 Feb 15.

Department of Radiation Emergency Medicine, National Institute of Radiological Sciences Chiba, Japan.

We report a first case of HIV-associated lymphoma (HAL) presenting with acute kidney injury (AKI) and inflammatory immune reconstitution syndrome (IRIS). A 39-year-old male, treated with nonsteroidal anti-inflammatory drugs (NSAIDs) for one month prior to admission, developed AKI, left testicular tumor, and recurrent swelling of the right parotid gland. A resected testicular tumor exhibited features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Renal biopsy showed hydro-degeneration of renal tubules, interstitial inflammatory cells, and a small number of lymphoma cells in the sub-capsule, compatible with acute interstitial nephritis. His renal dysfunction rapidly recovered following chemotherapy and combination antiretroviral therapy (cART). He developed pneumonia concomitantly with a decrease in HIV-RNA level and an increase in CD4+ cells after the first cycle of chemotherapy, which spontaneously resolved after the second cycle of chemotherapy without additional anti-infection drugs; thus, his pneumonia fulfilled the diagnostic criteria for IRIS. We suggest that IRIS may frequently develop during chemotherapy for HAL, but may be overlooked. He was coinfected with hepatitis B virus (HBV), which genotypes known as is associated with liver-related mortality and response to antiviral therapy; recently, an intimate interplay between HIV and HBV in the onset of lymphoma has been reported. Therefore, we addressed the HBV genotype in the patient. The analysis revealed that he exhibited a mixed genotype (A/E) not native to Japan and primarily found in Europe and North America or West Africa. These findings suggest that universal vaccination for juveniles against HBV is warranted in Japan.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563184PMC
August 2013

Soft J-tipped guide wire-induced cardiac perforation in a patient with right ventricular lipomatosis and wall thinning.

Intern Med 2012 15;51(18):2609-12. Epub 2012 Sep 15.

Departments of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University School of Medicine, Japan.

Cardiac tamponade caused by perforation is a rare but potentially lethal complication of central venous catheter (CVC) insertion. We herein report a case of cardiac perforation associated with the use of a soft J-tipped guide wire. Twenty minutes after the insertion of a CVC, the patient developed unexpected cardiac arrest. An autopsy revealed 400 mL of pericardial blood. The right ventricular wall was 1 mm thick with about 10 myocyte layers, which is one-third that of the normal heart. A histological analysis revealed widespread fatty infiltration of the right ventricular wall (right ventricular lipomatosis).
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http://dx.doi.org/10.2169/internalmedicine.51.7794DOI Listing
April 2013
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