Publications by authors named "Takahiro Kamiya"

38 Publications

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

J Clin Immunol 2021 Feb 1. Epub 2021 Feb 1.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Purpose: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID).

Methods: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID.

Results: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival.

Conclusions: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-021-00966-zDOI Listing
February 2021

Duodenal nodular lymphoid hyperplasia in a patient with IgA deficiency.

Clin Case Rep 2020 Dec 8;8(12):3594-3595. Epub 2020 Sep 8.

Department of Hematology National Cancer Center Hospital Tokyo Japan.

Most patients with IgA deficiency are asymptomatic, but duodenal nodular lymphoid hyperplasia is one symptom known to be associated with common variable immunodeficiency (CVID), including selective IgA deficiency and agammaglobulinemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.3298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752382PMC
December 2020

Cytomegalovirus Laryngitis in Primary Combined Immunodeficiency Diseases.

J Clin Immunol 2021 Jan 8;41(1):243-247. Epub 2020 Oct 8.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00873-9DOI Listing
January 2021

[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

Rinsho Ketsueki 2020 ;61(8):870-873

Division of Hematology, Department of Medicine, Keio University School of Medicine.

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.61.870DOI Listing
October 2020

Interleukin-6-producing Intravascular Large B-cell Lymphoma with Lymphadenopathy Mimicking the Histology of Multicentric Castleman Disease.

Intern Med 2020 Dec 4;59(23):3061-3065. Epub 2020 Aug 4.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Japan.

An inguinal lymph node biopsy of a woman with a one-month history of a progressive fever, fatigue, dyspnea, skin rash, and lymphadenopathy revealed a well-preserved basic structure, hyperplastic germinal centers, and an interfollicular region containing polyclonal plasma cell sheets, suggesting plasma cell-type multicentric Castleman disease (MCD). We initiated prednisolone and anti-interleukin (IL)-6 antibody (tocilizumab), without success. A biopsy specimen re-evaluation detected CD20-positive atypical large B cells infiltrating the small vessels within and around the lymph node and its capsule. We diagnosed her with intravascular large B-cell lymphoma (IVLBCL). Lymphoma cells were weakly positive for IL-6 by immunohistochemical staining. IL-6 from lymphoma cells may have caused the MCD-like presentation as a paraneoplastic etiology. Malignant lymphoma should be excluded before diagnosing MCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.5046-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759707PMC
December 2020

Inherited chromosomally integrated human herpesvirus-6 in a patient with XIAP deficiency.

Transpl Infect Dis 2020 Oct 8;22(5):e13331. Epub 2020 Jun 8.

Deprtment of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Human herpesvirus-6 (HHV-6) is a common pathogen affecting the human population. Primary HHV-6 infection generally occurs during infancy and causes exanthema subitum. Moreover, HHV-6 may exhibit inherited chromosomally integrated HHV-6 (iciHHV-6) in certain individuals. Although iciHHV-6 is generally known to be nonpathogenic, it may cause reactivation in patients with primary immunodeficiency disease (PID). XIAP deficiency is a rare PID characterized by recurrent hemophagocytic lymphohistiocytosis (HLH). It has been reported that the Epstein-Barr virus primarily causes HLH; however, the other pathogens, including HHV-6, can also cause this complication. We encountered a case of XIAP deficiency accompanied by iciHHV-6. He suffered from recurrent HLH, for which allogeneic bone marrow transplantation (BMT) was performed as a curative therapy. During the course of BMT, the patient experienced HLH three times, but there was no reactivation of endogenous HHV-6 from iciHHV-6. Finally, the patient achieved complete donor chimerism and a decline in HHV-6 DNA copy number in whole blood. This case report demonstrates no evidence of reactivation of iciHHV-6 during BMT in a patient with XIAP deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tid.13331DOI Listing
October 2020

The prognostic value of the controlling nutritional status score in patients with multiple myeloma.

Leuk Lymphoma 2020 08 19;61(8):1894-1900. Epub 2020 Apr 19.

Department of Hematology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

The Controlling Nutritional Status (CONUT) score predicts the prognosis in several tumors. However, its prognostic significance in multiple myeloma (MM) remains unclear. The present study investigated the correlation between the CONUT score and the survival outcomes of MM patients. A total of 178 patients newly diagnosed with MM were retrospectively enrolled. Patients with a high CONUT score (≥5) had a significantly shorter median overall survival (OS) than those with a low CONUT score (≤4) (33 vs. 57 months,  < .001). In a multivariate analysis among patients with International Staging System (ISS) score of ≤2, a high CONUT score was an independent prognostic covariate for the OS after adjusting for other significant factors (hazard ratio 2.364; 95% confidence interval 1.324-4.220,  = .004). Our results suggest that the CONUT score is a predictor of a poor outcome in patients with MM, particularly in low-ISS-score cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1749608DOI Listing
August 2020

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome.

Pediatr Diabetes 2019 11 24;20(7):1035-1040. Epub 2019 Jul 24.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T-(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β-cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16-year-old adolescent with late-onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin-dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC-peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β-cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D-associated IPEX syndrome improves Treg deficiency and prevents elimination of β-cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β-cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pedi.12895DOI Listing
November 2019

The prognostic value of geriatric nutritional risk index in patients with follicular lymphoma.

Ann Hematol 2019 Jul 30;98(7):1777-1779. Epub 2019 Apr 30.

Division of Hematology, Keio University School of Medicine, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-019-03703-0DOI Listing
July 2019

Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells.

J Clin Invest 2019 05 12;129(5):2094-2106. Epub 2019 Mar 12.

Department of Pediatrics and National University Cancer Institute Singapore, National University of Singapore, Singapore.

A key mechanism of tumor resistance to immune cells is mediated by expression of peptide-loaded HLA-E in tumor cells, which suppresses natural killer (NK) cell activity via ligation of the NK inhibitory receptor CD94/NKG2A. Gene expression data from approximately 10,000 tumor samples showed widespread HLAE expression, with levels correlating with those of KLRC1 (NKG2A) and KLRD1 (CD94). To bypass HLA-E inhibition, we developed a way to generate highly functional NK cells lacking NKG2A. Constructs containing a single-chain variable fragment derived from an anti-NKG2A antibody were linked to endoplasmic reticulum-retention domains. After retroviral transduction in human peripheral blood NK cells, these NKG2A Protein Expression Blockers (PEBLs) abrogated NKG2A expression. The resulting NKG2Anull NK cells had higher cytotoxicity against HLA-E-expressing tumor cells. Transduction of anti-NKG2A PEBL produced more potent cytotoxicity than interference with an anti-NKG2A antibody and prevented de novo NKG2A expression, without affecting NK cell proliferation. In immunodeficient mice, NKG2Anull NK cells were significantly more powerful than NKG2A+ NK cells against HLA-E-expressing tumors. Thus, NKG2A downregulation evades the HLA-E cancer immune-checkpoint, and increases the anti-tumor activity of NK cell infusions. Because this strategy is easily adaptable to current protocols for clinical-grade immune cell processing, its clinical testing is feasible and warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI123955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486333PMC
May 2019

Epstein-Barr Virus-Associated γδ T-Cell Lymphoproliferative Disorder Associated With Hypomorphic Mutation.

Front Pediatr 2019 4;7:15. Epub 2019 Feb 4.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an EBV-associated lymphoproliferative disease characterized by repeated or sustainable infectious mononucleosis (IM)-like symptoms. EBV is usually detected in B cells in patients who have IM or Burkitt's lymphoma and even in patients with X-linked lymphoproliferative syndrome, which is confirmed to have vulnerability to EBV infection. In contrast, EBV infects T cells (CD4 T, CD8 T, and γδT) or NK cells mono- or oligoclonally in CAEBV patients. It is known that the CAEBV phenotypes differ depending on which cells are infected with EBV. CAEBV is postulated to be associated with a genetic immunological abnormality, although its cause remains undefined. Here we describe a case of EBV-related γδT-cell proliferation with underlying hypomorphic mutation. The immunological phenotype consisted of γδT-cell proliferation in the peripheral blood. A presence of EBV-infected B cells and γδT cells mimicked γδT-cell-type CAEBV. Although the patient had normal expression of CD132 (common γ chain), the phosphorylation of STAT was partially defective, indicating impaired activation of the downstream signal of the JAK/STAT pathway. Although the patient was not diagnosed as having CAEBV, this observation shows that CAEBV might be associated with immunological abnormality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2019.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369201PMC
February 2019

The prognostic value of circulating myeloblasts in patients with myelodysplastic syndromes treated with azacitidine.

Med Oncol 2019 Jan 31;36(3):25. Epub 2019 Jan 31.

Department of Hematology, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, 240-8555, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12032-019-1247-3DOI Listing
January 2019

Novel Cardinium strains in non-marine ostracod (Crustacea) hosts from natural populations.

Mol Phylogenet Evol 2019 01 21;130:406-415. Epub 2018 Sep 21.

Royal Belgian Institute of Natural Sciences, OD Nature, Freshwater Biology, Brussels, Belgium; University of Ghent, Dept Biology, Ghent, Belgium.

Endosymbiotic bacteria are known from many metazoan taxa, where they manipulate host biology and reproduction. Here, we used classic PCR amplification and direct DNA sequencing with universal primers for four different endosymbionts to test for their presence in more than 300 specimens of three recent non-marine ostracod superfamilies from different geographic areas and aquatic habitats. We verified these results with "high throughput" amplicon sequencing of 16S of nine selected specimens and evolutionary placement algorithms. The phylogenetic position of endosymbionts detected in ostracod hosts was compared to known endosymbionts from other metazoans. While Wolbachia, Spiroplasma and Rickettsia are absent, we find evidence for the general presence of Cardinium bacteria in natural populations of various non-marine ostracod species. Phylogenetic reconstructions based on Cardinium 16S data and estimates of genetic distances both indicate that Cardinium from ostracods are distantly related to Cardinium from Diptera and Nematoda but represent novel strains with a monophyletic origin. Cardinium bacteria from different ostracod hosts have genetic distances of up to 3.8%, providing evidence against recent and frequent horizontal transmissions amongst the three ostracod superfamilies. High throughput sequencing reveals more than 400 different 16S amplicon sequence variants in the investigated ostracods as well as the presence of different Cardinium strains within individual Eucypris virens and Heterocypris hosts. These results call for future, more in-depth investigations. Mapping Cardinium infections on COI trees of non-marine ostracod hosts shows that the occurrence of these endosymbionts is not linked to genetic species identity or phylogenetic host groups and, except for one ostracod morphospecies, prevalence never reaches 100%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ympev.2018.09.008DOI Listing
January 2019

A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells.

Blood Adv 2018 03;2(5):517-528

Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRαβ, we combined an antibody-derived single-chain variable fragment specific for CD3ε with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3ε, blocking surface CD3 and TCRαβ expression. In 25 experiments, median TCRαβ expression in T lymphocytes was reduced from 95.7% to 25.0%; CD3/TCRαβ cell depletion yielded virtually pure TCRαβ-negative T cells. Anti-CD3ε PEBLs abrogated TCRαβ-mediated signaling, without affecting immunophenotype or proliferation. In anti-CD3ε PEBL-T cells, expression of an anti-CD19-41BB-CD3ζ CAR induced cytokine secretion, long-term proliferation, and CD19 leukemia cell killing, at rates meeting or exceeding those of CAR-T cells with normal CD3/TCRαβ expression. In immunodeficient mice, anti-CD3ε PEBL-T cells had markedly reduced GVHD potential; when transduced with anti-CD19 CAR, these T cells killed engrafted leukemic cells. PEBL blockade of surface CD3/TCRαβ expression is an effective tool to prepare allogeneic CAR-T cells. Combined PEBL and CAR expression can be achieved in a single-step procedure, is easily adaptable to current cell manufacturing protocols, and can be used to target other T-cell molecules to further enhance CAR-T-cell therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017012823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851418PMC
March 2018

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies.

Blood Adv 2017 Nov 21;1(25):2348-2360. Epub 2017 Nov 21.

Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Effective immunotherapies for T-cell malignancies are lacking. We devised a novel approach based on chimeric antigen receptor (CAR)-redirected T lymphocytes. We selected CD7 as a target because of its consistent expression in T-cell acute lymphoblastic leukemia (T-ALL), including the most aggressive subtype, early T-cell precursor (ETP)-ALL. In 49 diagnostic T-ALL samples (including 14 ETP-ALL samples), median CD7 expression was >99%; CD7 expression remained high at relapse (n = 14), and during chemotherapy (n = 54). We targeted CD7 with a second-generation CAR (anti-CD7-41BB-CD3ζ), but CAR expression in T lymphocytes caused fratricide due to the presence of CD7 in the T cells themselves. To downregulate CD7 and control fratricide, we applied a new method (protein expression blocker [PEBL]), based on an anti-CD7 single-chain variable fragment coupled with an intracellular retention domain. Transduction of anti-CD7 PEBL resulted in virtually instantaneous abrogation of surface CD7 expression in all transduced T cells; 2.0% ± 1.7% were CD7 vs 98.1% ± 1.5% of mock-transduced T cells (n = 5; < .0001). PEBL expression did not impair T-cell proliferation, interferon-γ and tumor necrosis factor-α secretion, or cytotoxicity, and eliminated CAR-mediated fratricide. PEBL-CAR T cells were highly cytotoxic against CD7 leukemic cells in vitro and were consistently more potent than CD7 T cells spared by fratricide. They also showed strong anti-leukemic activity in cell line- and patient-derived T-ALL xenografts. The strategy described in this study fits well with existing clinical-grade cell manufacturing processes and can be rapidly implemented for the treatment of patients with high-risk T-cell malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017009928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729624PMC
November 2017

A new species of Cavernocypris Hartmann, 1964 (Crustacea: Ostracoda) from caves in South Korea.

Zootaxa 2017 May 17;4268(3):360-376. Epub 2017 May 17.

Lake Biwa Museum, 1091 Oroshimo, Kusatsu, Shiga 525-0001, Japan.

Surveys of caves in South Korea yielded a new species of the ostracod genus Cavernocypris Hartmann, 1964, herein described as Cavernocypris danielopoli Smith & Kamiya n. sp. This is the fifth described species in this widely distributed genus, and can be discriminated from its congeners by the highly triangular shape of the carapace in lateral view, caused by a large dorsal protrusion on the left valve. A second triangular-shaped morphotype was also collected, differing from the first by a lower carapace and less pronounced dorsal protrusion. As it is not clear at present if this represents a separate species or intraspecific variation, it is left in open nomenclature. The lack of a pigmented eye, a highly triangular carapace and no carapace pigmentation suggests that Cavernocypris danielopoli Smith & Kamiya n. sp. is the most adapted species in the genus to a stygobiotic lifestyle. Another Korean species, Cavernocypris coreana (McKenzie, 1972), found in caves and spring discharges, has a reduced number of antennule segments, common for stygobiotic species, but this feature is lacking in the new species. This suggests that within the genus, species have followed different evolutionary pathways to adapt to the subterranean realm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11646/zootaxa.4268.3.3DOI Listing
May 2017

Seven new species of the genus Xestoleberis (Ostracoda: Podocopida: Cytheroidea) from the Fiji Archipelago.

Zootaxa 2016 Dec 18;4208(4):zootaxa.4208.4.2. Epub 2016 Dec 18.

Graduate School of Natural Science and Technology, Kanazawa University, Ishikawa, Japan..

The genus Xestoleberis has a global distribution, and although they are predominant in shallow marine environments adapted to both sediment and algal habitats, only two species of this genus, Xestoleberis curta (Brady, 1866) and Xestoleberis variegata Brady, 1880, have previously been reported from the Fiji archipelago. Herein we report seven new species of the genus Xestoleberis from intertidal environments of fringing reef flats of the Fiji Islands: Xestoleberis becca n. sp., Xestoleberis concava n. sp., Xestoleberis gracilariaii n. sp., Xestoleberis marcula n. sp., Xestoleberis natuvuensis n. sp., Xestoleberis penna n. sp. and Xestoleberis petrosa n. sp. With the exception of X. becca n. sp., Xestoleberis species show restricted distribution within Fijian waters. The possible causes for their distribution patterns are suggested to be physical barriers imposed by the fast flowing Bligh Water currents, and islands separated by deep ocean waters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11646/zootaxa.4208.4.2DOI Listing
December 2016

Poly (ADP-ribose) polymerase inhibitors selectively induce cytotoxicity in TCF3-HLF-positive leukemic cells.

Cancer Lett 2017 02 25;386:131-140. Epub 2016 Nov 25.

Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8519, Japan. Electronic address:

Poly (ADP-ribose) polymerase (PARP) is an indispensable component of the DNA repair machinery. PARP inhibitors are used as cutting-edge treatments for patients with homologous recombination repair (HRR)-defective breast cancers harboring mutations in BRCA1 or BRCA2. Other tumors defective in HRR, including some hematological malignancies, are predicted to be good candidates for treatment with PARP inhibitors. Screening of leukemia-derived cell lines revealed that lymphoid lineage-derived leukemia cell lines, except for those derived from mature B cells and KMT2A (MLL)-rearranged B-cell precursors, were relatively sensitive to PARP inhibitors. By contrast, acute myelogenous leukemia cell lines, except for RUNX1-RUNXT1 (AML1-ETO)-positive lines, were relatively resistant. Intriguingly, TCF3 (E2A)-HLF-positive leukemia was sensitive to PARP inhibitors. TCF3-HLF expression suppressed HRR activity, suggesting that PARP inhibitor treatment induced synthetic lethality. Furthermore, TCF3-HLF expression decreased levels of MCPH1, which regulates the expression of BRCA1, resulting in attenuation of HRR activity. The PARP inhibitor olaparib was also effective in an in vivo xenograft model. Our results suggest a novel therapeutic approach for treating refractory leukemia, particularly the TCF3-HLF-positive subtype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2016.11.021DOI Listing
February 2017

Sperm length variations in five species of cypridoidean non-marine ostracods (Crustacea).

Cell Tissue Res 2016 Nov 23;366(2):483-497. Epub 2016 Jul 23.

College of Science and Engineering, School of Natural System, University of Kanazawa, Kakuma, Kanazawa, 920-1192, Japan.

Spermatozoa of the ostracod superfamily Cypridoidea include some of the longest in the animal kingdom, but unlike other so-called giant spermatozoa, they are aflagellate, probably evolved only once, and represent an exceptionally old trait. Sperm length variations within cypridoidean species remain poorly known, a lack that hinders the development of hypotheses to explain their length and variation. For this study, the lengths of 500 spermatozoa from each of five species of freshwater cypridoidean ostracods, Candonopsis tenuis (Brady, 1886), Fabaeformiscandona subacuta (Yang, 1982), Heterocypris rotundata (Bronshtein, 1928), Ilyocypris japonica Okubo, 1990, and Notodromas trulla Smith and Kamiya, 2014, were measured, including the lengths of the posterior and anterior regions. No overall pattern in sperm variation was discernible. Length variations between species, between males of the same species, and within individual males varied from low (Candonopsis tenuis) to extraordinarily large (Notodromas trulla and Fabaeformiscandona subacuta). Sperm competition, cryptic female choice, sperm heteromorphism, and testis size are unlikely to explain all of the variations observed. Age structures of the populations sampled might play a role in explaining some intraspecific variation. The differing amounts of variation in sperm characters revealed in this study suggest that multiple evolutionary trends and pressures shape sperm lengths in this superfamily.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00441-016-2459-xDOI Listing
November 2016

A new species of the genus Paracypria (Crustacea: Ostracoda: Cypridoidea) from the Fiji Islands.

Zootaxa 2016 Aug 30;4158(3):433-42. Epub 2016 Aug 30.

Division of Natural System, Graduate School of Natural Science and Technology, Kanazawa University, Ishikawa, Japan.; Email:

A new marine species of the genus Paracypria (Paracypria fijiensis n. sp.) is reported from the Fiji Islands, a small island archipelago in the South Pacific Ocean. This is the first report of a Paracypria species from the Fiji Islands. Descriptions of soft parts and valves of Paracypria fijiensis n. sp. are presented herein, and morphological comparisons are made with existing Paracypria species from Australia, Japan and New Caledonia. Although eight coastal sites were sampled across the Fiji Islands, the new Paracypria species was found at only three sites. Large numbers of P. fijiensis n. sp. were recorded from intertidal flats, indicating it to be highly tolerant of the dynamic intertidal zone conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11646/zootaxa.4158.3.8DOI Listing
August 2016

Expanded and armed natural killer cells for cancer treatment.

Cytotherapy 2016 11 3;18(11):1422-1434. Epub 2016 Aug 3.

Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

The capacity of natural killer (NK) cells to recognize and kill transformed cells suggests that their infusion could be used to treat cancer. It is difficult to obtain large numbers of NK cells ex vivo by exposure to cytokines alone but the addition of stimulatory cells to the cultures can induce NK cell proliferation and long-term expansion. Some of these methods have been validated for clinical-grade application and support clinical trials testing feasibility and safety of NK cell administration. Early data indicate that ex vivo expansion of NK cells from healthy donors or from patients with cancer is robust, allowing multiple infusions from a single apheresis. NK cells can transiently expand in vivo after infusion. Allogeneic NK cells are not direct effectors of graft-versus-host disease but this may occur if donor NK cells are infused after allogeneic hematopoietic stem cell transplant, which may activate T cell alloreactivity. NK cells can be directed with antibodies, or engineered using either transient modification by electroporation of mRNA or prolonged gene expression by viral transduction. Thus, expanded NK cells can be armed with activating receptors that enhance their natural anti-tumor capacity or with chimeric antigen receptors that can redirect them towards specific tumor targets. They can also be induced to express cytokines that promote their autonomous growth, further supporting their in vivo expansion. With the implementation of these approaches, expanded and armed NK cells should ultimately become a powerful component of immunotherapy of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcyt.2016.06.013DOI Listing
November 2016

Ewing sarcoma/primitive neuroectodermal tumor of the kidney treated with chemotherapy including ifosfamide.

Pediatr Int 2016 Aug 21;58(8):766-9. Epub 2016 Jun 21.

Department of Pediatrics, St Luke's International Hospital, Tokyo, Japan.

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the kidney is extremely rare, and is usually diagnosed after nephrectomy without neoadjuvant chemotherapy. Although ifosfamide and etoposide improve survival to a great extent in ES/PNET, the use of nephrotoxic agent, particularly ifosfamide, is a concern after nephrectomy. We describe the case of a 14-year-old female patient with abdominal mass who was diagnosed with ES/PNET of the right kidney after nephrectomy. Adjuvant chemotherapy including ifosfamide and etoposide were given. The estimated glomerular filtration rate decreased to 75% after the end of therapy. There was no evidence of recurrence 70 months after initial diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ped.12963DOI Listing
August 2016

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma.

Cancer Immunol Res 2016 07 13;4(7):574-81. Epub 2016 May 13.

Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Viral infection of the liver is a major risk factor for hepatocellular carcinoma (HCC). Natural killer (NK) cells recognize virally infected and oncogenically transformed cells, suggesting a therapeutic role for NK-cell infusions in HCC. Using the K562-mb15-41BBL cell line as a stimulus, we obtained large numbers of activated NK cells from the peripheral blood of healthy donors. Expanded NK cells exerted remarkably high cytotoxicity against HCC cell lines, which was generally much higher than that of unstimulated or IL2-activated NK cells. In immunodeficient NOD/scid IL2RGnull mice engrafted with Hep3B, treatment with expanded NK cells markedly reduced tumor growth and improved overall survival. HCC cells exposed for 48 hours to 5 μmol/L of sorafenib, a kinase inhibitor currently used for HCC treatment, remained highly sensitive to expanded NK cells. HCC cell reductions of 39.2% to 53.8% caused by sorafenib in three cell lines further increased to 80.5% to 87.6% after 4 hours of culture with NK cells at a 1:1 effector-to-target ratio. NK-cell cytotoxicity persisted even in the presence of sorafenib. We found that NKG2D, an NK-cell-activating receptor, was an important mediator of anti-HCC activity. We therefore enhanced its signaling capacity with a chimeric NKG2D-CD3ζ-DAP10 receptor. This considerably increased the anti-HCC cytotoxicity of expanded NK cells in vitro and in immunodeficient mice. The NK expansion and activation method applied in this study has been adapted to clinical-grade conditions. Hence, these results warrant clinical testing of expanded NK-cell infusions in patients with HCC, possibly after genetic modification with NKG2D-CD3ζ-DAP10. Cancer Immunol Res; 4(7); 574-81. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-15-0229DOI Listing
July 2016

Acute megakaryoblastic leukemia with acquired trisomy 21 and GATA1 mutations in phenotypically normal children.

Eur J Pediatr 2015 Apr 30;174(4):525-31. Epub 2014 Sep 30.

Department of Pediatrics, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan,

Unlabelled: GATA1 mutations are found almost exclusively in children with myeloid proliferations related to Down syndrome (DS). Here, we report two phenotypically and cytogenetically normal children with acute megakaryoblastic leukemia (AMKL) whose blasts had both acquired trisomy 21 and GATA1 mutation. Patient 1 was diagnosed with transient abnormal myelopoiesis in the neonatal period. Following spontaneous improvement of the disease, leukemic blasts increased 7 months later. He received less intensive chemotherapy, and he is now 6 years old in complete remission. Patient 2 was diagnosed with AMKL at the age of 18 months. Although he received intensive chemotherapy and a cord blood transplantation, he died without gaining remission. In both cases, trisomy 21 and GATA1 mutation were detected only in leukemic blasts, but not in germline samples. Based on a literature review, we identified reports describing 14 non-DS AMKL with GATA1 mutation and acquired trisomy 21. Of those, 12 cases were diagnosed during the neonatal period, whereas the remaining 2 cases were diagnosed at the age of 22 and 31 months, respectively.

Conclusion: These cases suggest that GATA1 mutation may cooperate with the additional chromosome 21 in developing myeloid proliferations even in non-DS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-014-2430-3DOI Listing
April 2015

The freshwater ostracod (Crustacea) genus Notodromas Lilljeborg, 1853 (Notodromadidae) from Japan; taxonomy, ecology and lifestyle.

Zootaxa 2014 Jul 25;3841(2):239-56. Epub 2014 Jul 25.

College of Science and Engineering, School of Natural System, University of Kanazawa, Kakuma, Kanazawa 920-1192, Japan; Email: unknown.

Although Notodromas monacha (O. F. Müller, 1776) was first reported from Japan over 85 years ago, detailed comparisons between Japanese and European specimens reveal that the Japanese specimens have been misidentified. The Japanese specimens are described as a new species, Notodromas trulla n. sp., herein. This species differs from Notodromas monacha by the morphology of the male fifth limbs and sexual organs, and the morphology of the female carapace. Like other Notodromas species, it is at least partially neustonic, spending considerable amounts of time hanging upside down from the water surface, facilitated by an oval concavity on its ventral surface. It is found in rice fields and small, shallow ponds with few or no floating plants and a muddy substrate, and in suitable habitats can be very abundant. However, evidence suggests that this conspicuous species has experienced a significant and widespread population decline in Japan; reported as abundant in rice fields, swamps and ponds in the 1940s-70s, this species has been collected from only a small number of localities in recent years. 
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11646/zootaxa.3841.2.4DOI Listing
July 2014

Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15.

Blood 2014 Aug 8;124(7):1081-8. Epub 2014 Jul 8.

Department of Pediatrics, National University of Singapore, Singapore;

Natural killer (NK) cell survival and, hence, cytotoxicity requires cytokine support. We determined whether expression of interleukin-15 (IL-15) in a nonsecretory, membrane-bound form could sustain NK cell growth. We linked the human IL15 gene to that encoding CD8α transmembrane domain (mbIL15). After retroviral transduction, human NK cells expressed mbIL15 on the cell surface; IL-15 secretion was negligible. Survival of mbIL15-NK cells without interleukin-2 (IL-2) after 7-day culture was vastly superior to that of mock-transduced NK cells (P < .001, n = 15) and of NK cells expressing nonmembrane-bound IL-15 (P = .025, n = 9); viable mbIL15-NK cells were detectable for up to 2 months. In immunodeficient mice, mbIL15-NK cells expanded without IL-2 and were detectable in all tissues examined (except brain) in much higher numbers than mock-transduced NK cells (P < .001). Expansion further increased with IL-2. The primary mechanism of mbIL15 stimulation was autocrine; it activated IL-15 signaling and antiapoptotic signaling. NK cells expressing mbIL15 had higher cytotoxicity against leukemia, lymphoma, and solid tumor cells in vitro and against leukemia and sarcoma cells in xenograft models. Thus, mbIL15 confers independent growth to NK cells and enhances their antitumor capacity. Infusion of mbIL15-NK cells would allow NK cell therapy without the potential adverse effects of cytokine administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2014-02-556837DOI Listing
August 2014