1,059 results on '"Hiroshi Handa"'
Search Results
52. Characterization of Natural Aryl Hydrocarbon Receptor Agonists from Cassia Seed and Rosemary
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Yoshiaki Amakura, Morio Yoshimura, Masashi Takaoka, Haruka Toda, Tomoaki Tsutsumi, Rieko Matsuda, Reiko Teshima, Masafumi Nakamura, Hiroshi Handa, and Takashi Yoshida
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aryl hydrocarbon receptor ,health food ,cassia seed ,rosemary ,reporter gene assay ,Organic chemistry ,QD241-441 - Abstract
Many recent studies have suggested that activation of the aryl hydrocarbon receptor (AhR) reduces immune responses, thus suppressing allergies and autoimmune diseases. In our continuing study on natural AhR agonists in foods, we examined the influence of 37 health food materials on the AhR using a reporter gene assay, and found that aqueous ethanol extracts of cassia seed and rosemary had particularly high AhR activity. To characterize the AhR-activating substances in these samples, the chemical constituents of the respective extracts were identified. From an active ethyl acetate fraction of the cassia seed extract, eight aromatic compounds were isolated. Among these compounds, aurantio-obtusin, an anthraquinone, elicited marked AhR activation. Chromatographic separation of an active ethyl acetate fraction of the rosemary extract gave nine compounds. Among these compounds, cirsimaritin induced AhR activity at 10–102 μM, and nepitrin and homoplantagenin, which are flavone glucosides, showed marked AhR activation at 10–103 μM.
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- 2014
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53. DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes
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Gil Diamant, Liat Amir-Zilberstein, Yuki Yamaguchi, Hiroshi Handa, and Rivka Dikstein
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Biology (General) ,QH301-705.5 - Abstract
NF-κB is central for immune response and cell survival, and its deregulation is linked to chronic inflammation and cancer through poorly defined mechanisms. IκBα and A20 are NF-κB target genes and negative feedback regulators. Upon their activation by NF-κB, DSIF is recruited, P-TEFb is released, and their elongating polymerase II (Pol II) C-terminal domain (CTD) remains hypophosphorylated. We show that upon DSIF knockdown, mRNA levels of a subset of NF-κB targets are not diminished; yet much less IκBα and A20 protein are synthesized, and NF-κB activation is abnormally prolonged. Further analysis of IκBα and A20 mRNA revealed that a significant portion is uncapped, unspliced, and retained in the nucleus. Interestingly, the Spt5 C-terminal repeat (CTR) domain involved in elongation stimulation through P-TEFb is dispensable for IκBα and A20 regulation. These findings assign a function for DSIF in cotranscriptional mRNA processing when elongating Pol II is hypophosphorylated and define DSIF as part of the negative feedback regulation of NF-κB.
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- 2012
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54. Inhibitory Effect of N,N-Didesmethylgrossularine-1 on Inflammatory Cytokine Production in Lipopolysaccharide-Stimulated RAW 264.7 Cells
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Remy E. P. Mangindaan, Michio Namikoshi, Hiroshi Handa, Yasuaki Kabe, Jong-Soo Lee, Satoshi Sakamoto, Yuta Sato, and Taiko Oda
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LPS ,RAW 264.7 cells ,NF-κB ,TNF-α ,N,N-didesmethylgrossularine-1 ,natural product ,Biology (General) ,QH301-705.5 - Abstract
N,N-Didesmethylgrossularine-1 (DDMG-1), a compound with a rare α-carboline structure, was isolated from an Indonesian ascidian Polycarpa aurata as responsible for the observed inhibitory activity against TNF-α production in lipopolysaccharide-stimulated murine macrophage-like RAW264.7 cells. DDMG-1 inhibited the mRNA level of mTNF-α, IκB-α degradation, and binding of NF-κB to the target DNA site in LPS-stimulated RAW 264.7 cells. Moreover, DDMG-1 had an inhibitory effect on the production of IL-8, which is produced in CD14+-THP-1 cells stimulated by LPS. DDMG-1 is thus a promising drug candidate lead compound for the treatment of chronic inflammatory diseases, such as rheumatoid arthritis.
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- 2009
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55. Effects of Salmeterol and Fluticasone Propionate Combination versus Fluticasone Propionate on Airway Function and Eosinophilic Inflammation in Mild Asthma
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Makoto Hoshino, Hiroshi Handa, and Teruomi Miyazawa
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asthma ,fluticasone propionate ,impulse oscillometry ,salmeterol and fluticasone propionate ,sputum eosinophils ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Salmeterol and fluticasone propionate combination (SFC) provides better asthma control than fluticasone propionate (FP) alone, however, little is known on the effects of differential treatments on airway function and inflammation in patients with mild asthma. Methods: We randomized 27 mild persistent asthma patients treated with the equivalent of 400 μg beclomethasone dipropionate to receive SFC (50/100 μg, 13 patients) or FP (100 μg, 14 patients) twice daily for 8 weeks. We compared the effects of SFC and FP on pulmonary function assessed by spirometry and impulse oscillometry (IOS), eosinophil percentage of induced sputum and serum, and with asthma symptoms and control after each treatment. Results: We observed that SFC significantly improved forced expiratory volume in one second (p < 0.05), IOS measurements of total resistance R5 (p < 0.01), central resistance R20 (p < 0.05), and distal reactance X5 (p < 0.01) compared with FP. The percentage of eosinophils in sputum, but not in serum, decreased significantly more in the SFC group than in the FP group (p < 0.05). There was also a significant improvement in symptom control in the SFC group (p < 0.05). Conclusions: These findings suggest that SFC is more useful than FP in mild asthma cases. The clinical benefit of SFC provides evidence that IOS and induced sputum allows for the detection of changes in airway function and inflammation.
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- 2009
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56. The Neuroprotective Marine Compound Psammaplysene A Binds the RNA-Binding Protein HNRNPK
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Marco Boccitto, Nayoung Lee, Satoshi Sakamoto, Lynn A. Spruce, Hiroshi Handa, Jon Clardy, Steven H. Seeholzer, and Robert G. Kalb
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Psammaplysene A ,neurodegeneration ,foxo ,HNRNPK ,RNA metabolism ,Biology (General) ,QH301-705.5 - Abstract
In previous work, we characterized the strong neuroprotective properties of the marine compound Psammaplysene A (PA) in in vitro and in vivo models of neurodegeneration. Based on its strong neuroprotective activity, the current work attempts to identify the physical target of PA to gain mechanistic insight into its molecular action. Two distinct methods, used in parallel, to purify protein-binding partners of PA led to the identification of HNRNPK as a direct target of PA. Based on surface plasmon resonance, we find that the binding of PA to HNRNPK is RNA-dependent. These findings suggest a role for HNRNPK-dependent processes in neurodegeneration/neuroprotection, and warrant further study of HNRNPK in this context.
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- 2017
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57. Left and right lung asynchrony as a physiological indicator for unilateral bronchial obstruction in interventional bronchoscopy.
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Masamichi Mineshita, Hirotaka Kida, Hiroki Nishine, Hiroshi Handa, Takeo Inoue, and Teruomi Miyazawa
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Medicine ,Science - Abstract
BACKGROUND: In patients with bronchial obstruction, pulmonary function tests may not change significantly after intervention. The airflow asynchrony in both lungs due to unilateral bronchial obstruction may be applicable as a physiological indicator. The airflow asynchrony is reflected by the difference in the left and right lung sound development at tidal breathing. OBJECTIVES: To investigate the usefulness of left and right lung asynchrony due to unilateral bronchial obstruction as a physiological indicator for interventional bronchoscopy. METHODS: Fifty cases with central airway obstruction were classified into three groups: tracheal, bronchial and extensive obstruction. The gap index was defined as the absolute value of the average of gaps between the left and right lung sound intensity peaks for a 12-second duration. RESULTS: Before interventional bronchoscopy, the gap index was significantly higher in the bronchial (p
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- 2014
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58. The correlation between lung sound distribution and pulmonary function in COPD patients.
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Masamichi Mineshita, Hirotaka Kida, Hiroshi Handa, Hiroki Nishine, Naoki Furuya, Seiichi Nobuyama, Takeo Inoue, Shin Matsuoka, and Teruomi Miyazawa
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Medicine ,Science - Abstract
BACKGROUND: Regional lung sound intensity in chronic obstructive pulmonary disease (COPD) patients is influenced by the severity and distribution of emphysema, obstructed peripheral airways, and altered ribcage and diaphragm configurations and movements due to hyperinflation. Changes in the lung sound distribution accompanied by pulmonary function improvements in COPD patients were observed after bronchodilator inhalation. We investigated the association of lung sound distribution with pulmonary functions, and the effects of emphysematous lesions on this association. These studies were designed to acquire the basic knowledge necessary for the application of lung sound analysis in the physiological evaluation of COPD patients. METHODS: Pulmonary function tests and the percentage of upper- and lower-lung sound intensity (quantitative lung data [QLD]) were evaluated in 47 stable male COPD patients (54 - 82 years of age). In 39 patients, computed tomography taken within 6 months of the study was available and analyzed. RESULTS: The ratio of lower QLD to upper QLD showed significant positive correlations with FEV1 %predicted (%FEV1; ρ=0.45, p40%, n=20) and were stronger in less emphysematous patients (n=19, %FEV1; ρ=0.64, p
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- 2014
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59. Exhaled breath analysis for lung cancer detection using ion mobility spectrometry.
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Hiroshi Handa, Ayano Usuba, Sasidhar Maddula, Jörg Ingo Baumbach, Masamichi Mineshita, and Teruomi Miyazawa
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Medicine ,Science - Abstract
Conventional methods for lung cancer detection including computed tomography (CT) and bronchoscopy are expensive and invasive. Thus, there is still a need for an optimal lung cancer detection technique.The exhaled breath of 50 patients with lung cancer histologically proven by bronchoscopic biopsy samples (32 adenocarcinomas, 10 squamous cell carcinomas, 8 small cell carcinomas), were analyzed using ion mobility spectrometry (IMS) and compared with 39 healthy volunteers. As a secondary assessment, we compared adenocarcinoma patients with and without epidermal growth factor receptor (EGFR) mutation.A decision tree algorithm could separate patients with lung cancer including adenocarcinoma, squamous cell carcinoma and small cell carcinoma. One hundred-fifteen separated volatile organic compound (VOC) peaks were analyzed. Peak-2 noted as n-Dodecane using the IMS database was able to separate values with a sensitivity of 70.0% and a specificity of 89.7%. Incorporating a decision tree algorithm starting with n-Dodecane, a sensitivity of 76% and specificity of 100% was achieved. Comparing VOC peaks between adenocarcinoma and healthy subjects, n-Dodecane was able to separate values with a sensitivity of 81.3% and a specificity of 89.7%. Fourteen patients positive for EGFR mutation displayed a significantly higher n-Dodecane than for the 14 patients negative for EGFR (p
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- 2014
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60. Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing.
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Hitomi Miyazaki, Ken Higashimoto, Yukari Yada, Takaho A Endo, Jafar Sharif, Toshiharu Komori, Masashi Matsuda, Yoko Koseki, Manabu Nakayama, Hidenobu Soejima, Hiroshi Handa, Haruhiko Koseki, Susumu Hirose, and Kenichi Nishioka
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Genetics ,QH426-470 - Abstract
Molecular mechanisms for the establishment of transcriptional memory are poorly understood. 5,6-dichloro-1-D-ribofuranosyl-benzimidazole (DRB) is a P-TEFb kinase inhibitor that artificially induces the poised RNA polymerase II (RNAPII), thereby manifesting intermediate steps for the establishment of transcriptional activation. Here, using genetics and DRB, we show that mammalian Absent, small, or homeotic discs 1-like (Ash1l), a member of the trithorax group proteins, methylates Lys36 of histone H3 to promote the establishment of Hox gene expression by counteracting Polycomb silencing. Importantly, we found that Ash1l-dependent Lys36 di-, tri-methylation of histone H3 in a coding region and exclusion of Polycomb group proteins occur independently of transcriptional elongation in embryonic stem (ES) cells, although both were previously thought to be consequences of transcription. Genome-wide analyses of histone H3 Lys36 methylation under DRB treatment have suggested that binding of the retinoic acid receptor (RAR) to a certain genomic region promotes trimethylation in the RAR-associated gene independent of its ongoing transcription. Moreover, DRB treatment unveils a parallel response between Lys36 methylation of histone H3 and occupancy of either Tip60 or Mof in a region-dependent manner. We also found that Brg1 is another key player involved in the response. Our results uncover a novel regulatory cascade orchestrated by Ash1l with RAR and provide insights into mechanisms underlying the establishment of the transcriptional activation that counteracts Polycomb silencing.
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- 2013
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61. Characterization of CD56+ dendritic-like cells: a normal counterpart of blastic plasmacytoid dendritic cell neoplasm?
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Yohei Osaki, Akihiko Yokohama, Akio Saito, Kenichi Tahara, Kunio Yanagisawa, Yoshiyuki Ogawa, Takuma Ishizaki, Takeki Mitsui, Hiromi Koiso, Makiko Takizawa, Hideki Uchiumi, Takayuki Saitoh, Hiroshi Handa, Hirokazu Murakami, Norifumi Tsukamoto, and Yoshihisa Nojima
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Medicine ,Science - Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy. Plasmacytoid DCs (pDCs), which are defined as lineage marker (Lin)(-)HLA-DR(+)CD56(-)CD123(+)CD11c(-) cells, are considered to be the normal counterpart of BPDCNs. However, BPDCN can be distinguished from pDCs by uniform expression of CD56. In this study, to identify a normal counterpart of BPDCN, we searched for a Lin(-)HLA-DR(+)CD56(+) population and focused on a minor subpopulation of Lin(-)DR(+)CD56(+)CD123(+)CD11c(-) cells that we designated as pDC-like cells (pDLCs). pDLC constituted 0.03% of peripheral blood mononuclear cells (PBMCs), and the pDLC/pDC ratio was higher in bone marrow cells than in PBMCs. pDLC clearly expressed BDCA2, BDCA4, and myeloid antigens, which are frequently expressed by BPDCN. pDLCs exhibited modest expression of Toll-like receptors and produced less interferon-α after CpG stimulation, but presented very low endocytic ability unlike mDCs. These functional differences were attributed to the expression profile of transcriptional factors. After in vitro culture with Flt3-ligand and GM-CSF, pDLCs expressed CD11c and BDCA1. These data suggested that pDLCs are a distinct subpopulation, with an immunophenotype similar to BPDCNs. Moreover, our results indicate that pDLCs might be immature DCs and might contribute to the immunophenotypical diversity of BPDCNs.
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- 2013
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62. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study
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Matteo G. Della Porta, Cristina Picone, Cristiana Pascutto, Luca Malcovati, Hideto Tamura, Hiroshi Handa, Magdalena Czader, Sylvie Freeman, Paresh Vyas, Anna Porwit, Leonie Saft, Theresia M. Westers, Canan Alhan, Claudia Cali, Arjan A. van de Loosdrecht, and Kiyoyuki Ogata
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The current World Health Organization classification of myelodysplastic syndromes is based morphological evaluation of bone marrow dysplasia. In clinical practice, the reproducibility of the recognition of dysplasia is usually poor especially in cases that lack specific markers such as ring sideroblasts and clonal cytogenetic abnormalities.Design and Methods We aimed to develop and validate a flow cytometric score for the diagnosis of myelodysplastic syndrome. Four reproducible parameters were analyzed: CD34+ myeloblast-related and B-progenitor-related cluster size (defined by CD45 expression and side scatter characteristics CD34+ marrow cells), myeloblast CD45 expression and granulocyte side scatter value. The study comprised a “learning cohort” (n=538) to define the score and a “validation cohort” (n=259) to confirm its diagnostic value.Results With respect to non-clonal cytopenias, patients with myelodysplastic syndrome had increased myeloblast-related cluster size, decreased B-progenitor-related cluster size, aberrant CD45 expression and reduced granulocyte side scatter (P
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- 2012
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63. Identification of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a novel target of bisphenol A.
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Yuki Ito, Takumi Ito, Satoki Karasawa, Teruya Enomoto, Akihiro Nashimoto, Yasuyoshi Hase, Satoshi Sakamoto, Tsuneyo Mimori, Yoshihisa Matsumoto, Yuki Yamaguchi, and Hiroshi Handa
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Medicine ,Science - Abstract
Bisphenol A (BPA) forms the backbone of plastics and epoxy resins used to produce packaging for various foods and beverages. BPA is also an estrogenic disruptor, interacting with human estrogen receptors (ER) and other related nuclear receptors. Nevertheless, the effects of BPA on human health remain unclear. The present study identified DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a novel BPA-binding protein. DNA-PKcs, in association with the Ku heterodimer (Ku70/80), is a critical enzyme involved in the repair of DNA double-strand breaks. Low levels of DNA-PK activity are previously reported to be associated with an increased risk of certain types of cancer. Although the Kd for the interaction between BPA and a drug-binding mutant of DNA-PKcs was comparatively low (137 nM), high doses of BPA were required before cellular effects were observed (100-300 μM). The results of an in vitro kinase assay showed that BPA inhibited DNA-PK kinase activity in a concentration-dependent manner. In M059K cells, BPA inhibited the phosphorylation of DNA-PKcs at Ser2056 and H2AX at Ser139 in response to ionizing radiation (IR)-irradiation. BPA also disrupted DNA-PKcs binding to Ku70/80 and increased the radiosensitivity of M059K cells, but not M059J cells (which are DNA-PKcs-deficient). Taken together, these results provide new evidence of the effects of BPA on DNA repair in mammalian cells, which are mediated via inhibition of DNA-PK activity. This study may warrant the consideration of the possible carcinogenic effects of high doses of BPA, which are mediated through its action on DNA-PK.
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- 2012
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64. The murine stem cell virus promoter drives correlated transgene expression in the leukocytes and cerebellar Purkinje cells of transgenic mice.
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Miho Oue, Hiroshi Handa, Yasunori Matsuzaki, Kazutomo Suzue, Hirokazu Murakami, and Hirokazu Hirai
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Medicine ,Science - Abstract
The murine stem cell virus (MSCV) promoter exhibits activity in mouse hematopoietic cells and embryonic stem cells. We generated transgenic mice that expressed enhanced green fluorescent protein (GFP) under the control of the MSCV promoter. We obtained 12 transgenic founder mice through 2 independent experiments and found that the bodies of 9 of the founder neonates emitted different levels of GFP fluorescence. Flow cytometric analysis of circulating leukocytes revealed that the frequency of GFP-labeled leukocytes among white blood cells ranged from 1.6% to 47.5% across the 12 transgenic mice. The bodies of 9 founder transgenic mice showed various levels of GFP expression. GFP fluorescence was consistently observed in the cerebellum, with faint or almost no fluorescence in other brain regions. In the cerebellum, 10 founders exhibited GFP expression in Purkinje cells at frequencies of 3% to 76%. Of these, 4 mice showed Purkinje cell-specific expression, while 4 and 2 mice expressed GFP in the Bergmann glia and endothelial cells, respectively. The intensity of the GFP fluorescence in the body was relative to the proportion of GFP-positive leukocytes. Moreover, the frequency of the GFP-expressing leukocytes was significantly correlated with the frequency of GFP-expressing Purkinje cells. These results suggest that the MSCV promoter is useful for preferentially expressing a transgene in Purkinje cells. In addition, the proportion of transduced leukocytes in the peripheral circulation reflects the expression level of the transgene in Purkinje cells, which can be used as a way to monitor transgene expression properties in the cerebellum without invasive techniques.
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- 2012
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65. Repression of RNA polymerase II elongation in vivo is critically dependent on the C-terminus of Spt5.
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Hui Chen, Xavier Contreras, Yuki Yamaguchi, Hiroshi Handa, B Matija Peterlin, and Su Guo
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Medicine ,Science - Abstract
The stalling of RNA polymerase II (RNAPII) at the promoters of many genes, including developmental regulators, stress-responsive genes, and HIVLTR, suggests transcription elongation as a critical regulatory step in addition to initiation. Spt5, the large subunit of the DRB sensitivity-inducing factor (DSIF), represses or activates RNAPII elongation in vitro. How RNAPII elongation is repressed in vivo is not well understood. Here we report that CTR1 and CTR2CT, the two repeat-containing regions constituting the C-terminus of Spt5, play a redundant role in repressing RNAPII elongation in vivo. First, mis-expression of Spt5 lacking CTR1 or CTR2CT is inconsequential, but mis-expression of Spt5 lacking the entire C-terminus (termed NSpt5) dominantly impairs embryogenesis in zebrafish. Second, NSpt5 de-represses the transcription of hsp70-4 in zebrafish embryos and HIVLTR in cultured human cells, which are repressed at the RNAPII elongation step under non-inducible conditions. Third, NSpt5 directly associates with hsp70-4 chromatin in vivo and increases the occupancy of RNAPII, positive transcription elongation factor b (P-TEFb), histone H3 Lys 4 trimethylation (H3K4Me3), and surprisingly, the negative elongation factor A (NELF-A) at the locus, indicating a direct action of NSpt5 on the elongation repressed locus. Together, these results reveal a dominant activity of NSpt5 to de-repress RNAPII elongation, and suggest that the C-terminus of Spt5 is critical for repressing RNAPII elongation in vivo.
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- 2009
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66. Adenine nucleotide translocator transports haem precursors into mitochondria.
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Motoki Azuma, Yasuaki Kabe, Chikanori Kuramori, Masao Kondo, Yuki Yamaguchi, and Hiroshi Handa
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Medicine ,Science - Abstract
Haem is a prosthetic group for haem proteins, which play an essential role in oxygen transport, respiration, signal transduction, and detoxification. In haem biosynthesis, the haem precursor protoporphyrin IX (PP IX) must be accumulated into the mitochondrial matrix across the inner membrane, but its mechanism is largely unclear. Here we show that adenine nucleotide translocator (ANT), the inner membrane transporter, contributes to haem biosynthesis by facilitating mitochondrial accumulation of its precursors. We identified that haem and PP IX specifically bind to ANT. Mitochondrial uptake of PP IX was inhibited by ADP, a known substrate of ANT. Conversely, ADP uptake into mitochondria was competitively inhibited by haem and its precursors, suggesting that haem-related porphyrins are accumulated into mitochondria via ANT. Furthermore, disruption of the ANT genes in yeast resulted in a reduction of haem biosynthesis by blocking the translocation of haem precursors into the matrix. Our results represent a new model that ANT plays a crucial role in haem biosynthesis by facilitating accumulation of its precursors into the mitochondrial matrix.
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- 2008
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67. A Quantitative Computed Tomography Analysis of Fissure Integrity and Emphysema Destruction in Japanese Patients with Severe Chronic Obstructive Pulmonary Disease.
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Masamichi Mineshita, Hiroki Nishine, Hiroshi Handa, Hirotaka Kida, and Takeo Inoue
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- 2024
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68. Optogenetic interrogation of TDP-43 cytotoxicity in a zebrafish ALS model
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Kazuhide, Asakawa, Hiroshi, Handa, and Koichi, Kawakami
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Pharmacology - Abstract
TAR DNA-binding protein 43 (TDP-43) is an evolutionarily conserved RNA/DNA-binding protein that is nuclear-enriched in healthy cells, but deposited in the cytoplasm as aggregates in affected neurons in certain neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We have previously developed an optogenetic TDP-43 variant (opTDP-43h) whose oligomerization status can be modulated via the CRY2olig tag, which self-assembles upon absorption of blue light. Illumination of zebrafish spinal motor neurons expressing opTDP-43h with a blue light triggers its cytoplasmic mislocalization, eventually leading to cytoplasmic deposition of opTDP-43h aggregates. Intriguingly, a light illumination-dependent transient opTDP-43 mislocalization can halt motor axon outgrowth, even in the absence of cytoplasmic deposition of opTDP-43 aggregates. These observations point toward an oligomerization-dependent, but aggregation-independent, cytotoxic effect of TDP-43 that might contribute to pathogenesis of ALS. In the present review, we would like to overview the zebrafish ALS model based on the optogenetic TDP-43, and then discuss about the potential mechanisms of TDP-43 cytotoxicity that trigger and/or promote motor neuron degeneration in ALS.
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- 2023
69. Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders
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Junichi Yamamoto, Takumi Ito, Yuki Yamaguchi, and Hiroshi Handa
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Ubiquitin-Protein Ligases ,General Chemistry ,Adaptor Proteins, Signal Transducing ,Peptide Hydrolases ,Thalidomide - Abstract
Progress in strategies aimed at breaking down therapeutic target proteins has led to a paradigm shift in drug discovery. Thalidomide and its derivatives are the only protein degraders currently used in clinical practice. Our understanding of the molecular mechanism of action of thalidomide and its derivatives has advanced dramatically since the identification of cereblon (CRBN) as their direct target. The binding of thalidomide derivatives to CRBN, a substrate recognition receptor for Cullin 4 RING E3 ubiquitin ligase (CRL4), induces the recruitment of non-native substrates to CRL4
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- 2022
70. Dysregulated TDP-43 proteostasis perturbs excitability of spinal motor neurons during brainstem-mediated fictive locomotion in zebrafish
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Kazuhide Asakawa, Hiroshi Handa, and Koichi Kawakami
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Spinal motor neurons (SMNs) are the primary target of degeneration in amyotrophic lateral sclerosis (ALS). Degenerating motor neurons accumulate cytoplasmic TAR DNA-binding protein 43 (TDP-43) aggregates in most ALS cases. This SMN pathology can occur without mutation in the coding sequence of the TDP-43-encoding gene, TARDBP. Whether and how wild-type TDP-43 drives pathological changes in SMNs in vivo remain largely unexplored. In this study, we develop a two-photon calcium imaging setup in which tactile-evoked neural responses of motor neurons in the brainstem and spinal cord can be monitored using the calcium indicator GCaMP. We devise a piezo-assisted tactile stimulator that reproducibly evokes a brainstem descending neuron upon tactile stimulation of the head. A direct comparison between caudal primary motor neurons (CaPs) with or without TDP-43 overexpression in contiguous spinal segments demonstrates that CaPs overexpressing TDP-43 display attenuated Ca2+transients during fictive escape locomotion evoked by the tactile stimulation. These results show that excessive amounts of TDP-43 protein reduce the neuronal excitability of SMNs and potentially contribute to asymptomatic pathological lesions of SMNs and movement disorders in patients with ALS.
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- 2023
71. Data from Durvalumab Combined with Immunomodulatory Drugs (IMiD) Overcomes Suppression of Antitumor Responses due to IMiD-induced PD-L1 Upregulation on Myeloma Cells
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Hideto Tamura, Rimpei Morita, Koiti Inokuchi, Mika Sunakawa-Kii, Hiroshi Handa, Takumi Ito, Junichi Yamamoto, and Mariko Ishibashi
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We previously showed that the interaction of programmed death-ligand 1 (PD-L1) on multiple myeloma (MM) cells with PD-1 not only inhibits tumor-specific cytotoxic T-lymphocyte activity via the PD-1 signaling pathway but also induces drug resistance via PD-L1–mediated reverse signals. We here examined the regulation of PD-L1 expression by immunomodulatory drugs (IMiDs) and antimyeloma effects of the anti–PD-L1 antibody durvalumab in combination with IMiDs. IMiDs induced PD-L1 expression on IMiD-insensitive MM cells and plasma cells from patients newly diagnosed with MM. Gene-expression profiling analysis demonstrated that not only PD-L1, but also a proliferation-inducing ligand (APRIL), was enhanced by IMiDs. PD-L1 induction by IMiDs was suppressed by using the APRIL inhibitor recombinant B-cell maturation antigen (BCMA)-Ig, the antibody against BCMA, or an MEK/ERK inhibitor in in vitro and in vivo assays. In addition, its induction was abrogated in cereblon (CRBN)-knockdown MM cells, whereas PD-L1 expression was increased and strongly induced by IMiDs in Ikaros-knockdown cells. These results demonstrated that PD-L1 upregulation by IMiDs on IMiD-insensitive MM cells was induced by (i) the BCMA–APRIL pathway via IMiD-mediated induction of APRIL and (ii) Ikaros degradation mediated by CRBN, which plays a role in inhibiting PD-L1 expression. Furthermore, T-cell inhibition induced by PD-L1–upregulated cells was effectively recovered after combination treatment with durvalumab and IMiDs. PD-L1 upregulation by IMiDs on MM cells might promote aggressive myeloma behaviors and immune escape in the bone marrow microenvironment.
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- 2023
72. Supplementary information from Durvalumab Combined with Immunomodulatory Drugs (IMiD) Overcomes Suppression of Antitumor Responses due to IMiD-induced PD-L1 Upregulation on Myeloma Cells
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Hideto Tamura, Rimpei Morita, Koiti Inokuchi, Mika Sunakawa-Kii, Hiroshi Handa, Takumi Ito, Junichi Yamamoto, and Mariko Ishibashi
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Supplementary Materials and methods; Supplementary Table S1: Cell characteristics and phenotypes of MM cell lines; Supplementary Table S2: Characteristics of patients with newly diagnosed MM in Figure 1H; Supplementary Table S3: Primer and shRNA sequence; Supplementary Table S4: Four hundred four genes differentially expressed in MM cell lines treated with or without POM; Supplementary Figure S1: Antitumor effect of LEN and POM on MM cell lines; Supplementary Figure S2: Relationship of POM sensitivity with CRBN expression; Supplementary Figure S3: DNA copy numbers of PD-L1 in MM cell lines; Supplementary Figure S4: The level of cell-surface expression of PD-L2; Supplementary Figure S5: Cell-surface expression of BCMA and TACI on MM cell lines treated with IMiDs; Supplementary Figure S6: Enrichment plots for the gene sets of the MAPK/ERK pathway; Supplementary Figure S7: In vivo analysis using a murine xenograft model of human myeloma MM.1S cells inoculated into the flanks of NOG mice; Supplementary Figure S8: PD-L1 mRNA expression in CRBN-knockout and Ikaros- and Aiolos-knockdown cells after 3-day cultivation with LEN or POM; Supplementary Figure S9: Ikaros binding sites in the promoter of the PD-L1 gene; Supplementary Figure S10: Cell proliferation and T-cell activation of CD8+ T cells on day 4 when co-cultivation of T cells with untreated or LEN-pretreated U266 cells was treated with durvalumab and LEN; Supplementary Figure S11: APRIL protein and mRNA expression in CRBN-knockout and Ikaros- and Aiolos-knockdown MOSTI-1 cells after 3-day cultivation with LEN or POM.
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- 2023
73. Supplementary Tables S1 to S5 and Supplemental Figures 1 to 15 from SLAMF3-Mediated Signaling via ERK Pathway Activation Promotes Aggressive Phenotypic Behaviors in Multiple Myeloma
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Hideto Tamura, Koiti Inokuchi, Hiroki Sugimori, Takeshi Odajima, Junji Tanaka, Norio Komatsu, Keiichi Moriya, Asaka Onodera, Yasuko Kuribayashi-Hamada, Yuta Kaito, Mika Sunakawa, Toshio Asayama, Shigeki Ito, Sakae Tanosaki, Yutaka Tsukune, Norina Tanaka, Yoichi Imai, Hiroshi Handa, Makoto Sasaki, Asako Tsubota, Risa Takahashi, and Mariko Ishibashi
- Abstract
Table S1. Primer sequences Table S2. Patient characteristics in cell - surface SLAMF3 and CD138 expression analysis. Table S3. One hundred and sixty-eight gene sets that were significantly upregulated in SLAMF3-KMS34 cells compared with Î"SLAMF3 cells (NOM P-value
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- 2023
74. Molecular Landscape of Myeloid Neoplasms with Der(1;7)(q10;p10)
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Rurika Okuda, Yotaro Ochi, Kazuhisa Chonabayashi, Nobuhiro Hiramoto, Masashi Sanada, Hiroshi Handa, Senji Kasahara, Shinya Sato, Nobuhiro Kanemura, Toshiyuki Kitano, Mizuki Watanabe, Wolfgang Kern, Maria Creignou, Yuichi Shiraishi, Mitsumasa Watanabe, Kensuke Usuki, Shinsaku Imashuku, Eva Hellström-Lindberg, Torsten Haferlach, Shigeru Chiba, Nobuo Sezaki, Lee-Yung Shih, Yasushi Miyazaki, Yoshinori Yoshida, Takayuki Ishikawa, Kazuma Ohyashiki, Yoshiko Atsuta, Yusuke Shiozawa, Satoru Miyano, Hideki Makishima, Yasuhito Nannya, and Seishi Ogawa
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
75. Application of Magnetic Nanoparticle in Cancer Surgery
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Kisyo Mihara, Tatsuya Onishi, Sachiko Matsuda, Satoshi Sakamoto, Hiroshi Handa, Akihiro Kuwahata, Masaki Sekino, Moriaki Kusakabe, and Yuko Kitagawa
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Electrical and Electronic Engineering - Published
- 2022
76. Two‐year outcomes of tirabrutinib monotherapy in Waldenström’s macroglobulinemia
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Naohiro Sekiguchi, Shinya Rai, Wataru Munakata, Kenshi Suzuki, Hiroshi Handa, Hirohiko Shibayama, Tomoyuki Endo, Yasuhito Terui, Noriko Iwaki, Noriko Fukuhara, Hiro Tatetsu, Shinsuke Iida, Takayuki Ishikawa, Daisuke Iguchi, and Koji Izutsu
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Cancer Research ,Pyrimidines ,Oncology ,Imidazoles ,Quality of Life ,Humans ,General Medicine ,Waldenstrom Macroglobulinemia - Abstract
The phase II study of tirabrutinib monotherapy at a daily dose of 480 mg under fasting conditions for treatment-naïve and relapsed/refractory Waldenström's macroglobulinemia (ONO-4059-05 study) demonstrated a promising efficacy and tolerable safety profile. We conducted an unplanned analysis with a median follow-up of 24.8 months to update the efficacy and safety results and to report patient-reported quality of life. Of 27 enrolled patients, 22 patients continued receiving the study drug. The major response assessed by an independent review committee was observed in 25 patients (93%), including one and five patients who newly achieved complete response and very good partial response, respectively, after the primary analysis. The progression-free and overall survival rates at 24 months were 92.6% and 100%, respectively. Serum IgM levels in all patients except one declined and were maintained at low levels, although transient increases occurred after temporal interruption of the study drug. The disease-related symptoms including recurrent fever and hyperviscosity mostly disappeared. Health-related quality of life, assessed by cancer-specific questionnaires, was mostly maintained. Grade 3-4 neutropenia, lymphopenia, and leukopenia were newly recognized in three, two, and one patient, respectively. Grade 3 treatment-related hypertriglyceridemia was also recognized. Nine patients experienced grade 1-2 bleeding events (33%), one patient experienced grade 2 treatment-related atrial fibrillation, and one patient experienced grade 1 treatment-related hypertension. Treatment-related skin adverse events were observed in 14 patients (52%). Taken together, tirabrutinib has durable efficacy with an acceptable safety profile for treatment-naïve and refractory/relapsed Waldenström's macroglobulinemia.
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- 2022
77. Supplementary Figure 1 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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Hironobu Sasano, Noriaki Ohuchi, Hiroshi Handa, Takanori Ishida, Kunio Kitada, Jun-ichi Akahira, Yasuhiro Miki, Takashi Suzuki, and Shuji Nagasaki
- Abstract
Supplementary Figure 1 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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- 2023
78. Supplementary Figure 2 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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Hironobu Sasano, Noriaki Ohuchi, Hiroshi Handa, Takanori Ishida, Kunio Kitada, Jun-ichi Akahira, Yasuhiro Miki, Takashi Suzuki, and Shuji Nagasaki
- Abstract
Supplementary Figure 2 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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- 2023
79. Supplementary Figure Legends 1-2 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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Hironobu Sasano, Noriaki Ohuchi, Hiroshi Handa, Takanori Ishida, Kunio Kitada, Jun-ichi Akahira, Yasuhiro Miki, Takashi Suzuki, and Shuji Nagasaki
- Abstract
Supplementary Figure Legends 1-2 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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- 2023
80. Data from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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Hironobu Sasano, Noriaki Ohuchi, Hiroshi Handa, Takanori Ishida, Kunio Kitada, Jun-ichi Akahira, Yasuhiro Miki, Takashi Suzuki, and Shuji Nagasaki
- Abstract
17β-Hydroxysteroid dehydrogenase type 12 (17β-HSD12) has been shown to be involved in elongation of very long chain fatty acid (VLCFA) as well as in biosynthesis of estradiol (E2). 17β-HSD12 expression was also reported in breast carcinomas but its functions have remained unknown. In this study, we examined the correlation between mRNA expression profiles determined by microarray analysis and tissue E2 concentrations obtained from 16 postmenopausal breast carcinoma cases. No significant correlations were detected between 17β-HSD12 expression and E2 concentration. We then immunolocalized this enzyme in 110 cases of invasive ductal carcinoma. 17β-HSD12 immunoreactivity in breast carcinoma cells was significantly associated with poor prognosis of the patients. We further examined the biological significance of 17β-HSD12 using cell-based studies. Small interfering RNA–mediated knockdown of 17β-HSD12 in SK-BR-3 (estrogen receptor–negative breast carcinoma cell line) resulted in significant growth inhibition, which was recovered by the addition of VLCFAs such as arachidonic acid. The status of 17β-HSD12 immunoreactivity was also correlated with adverse clinical outcome in cyclooxygenase 2 (COX2)–positive breast cancer patients but not in COX2-negative patients. Therefore, these findings indicated that 17β-HSD12 was not necessarily related to intratumoral E2 biosynthesis, at least in human breast carcinoma, but was rather correlated with production of VLCFAs such as arachidonic acid, which may subsequently be metabolized to prostaglandins by COX2 and result in tumor progression of the patients. [Cancer Res 2009;69(4):1392–9]
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- 2023
81. Supplementary Table 1 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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Hironobu Sasano, Noriaki Ohuchi, Hiroshi Handa, Takanori Ishida, Kunio Kitada, Jun-ichi Akahira, Yasuhiro Miki, Takashi Suzuki, and Shuji Nagasaki
- Abstract
Supplementary Table 1 from 17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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- 2023
82. Post-azacitidine clone size predicts outcome of patients with myelodysplastic syndromes and related myeloid neoplasms
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Yasuhito Nannya, Magnus Tobiasson, Shinya Sato, Elsa Bernard, Shigeki Ohtake, June Takeda, Maria Creignou, Lanying Zhao, Manabu Kusakabe, Yuhei Shibata, Nobuhiko Nakamura, Mizuki Watanabe, Nobuhiro Hiramoto, Yusuke Shiozawa, Yuichi Shiraishi, Hiroko Tanaka, Kenichi Yoshida, Nobuyuki Kakiuchi, Hideki Makishima, Masahiro Marshall Nakagawa, Kensuke Usuki, Mitsumasa Watanabe, Kazunori Imada, Hiroshi Handa, Masataka Taguchi, Toru Kiguchi, Kazuma Ohyashiki, Takayuki Ishikawa, Akifumi Takaori-Kondo, Hisashi Tsurumi, Senji Kasahara, Shigeru Chiba, Tomoki Naoe, Satoru Miyano, Elli Papaemmanuil, Yasushi Miyazaki, Eva Hellström Lindberg, and Seishi Ogawa
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Hematology - Abstract
Azacitidine is a mainstay of therapy for MDS-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their post-treatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pre- (n=449) and post- (n=289) treatment bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their post-treatment clone size on treatment outcomes. In Cox proportional hazard modeling, multi-hit TP53 mutation (HR, 2.03; 95% CI, 1.42-2.91; P
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- 2023
83. Waldenström macroglobulinemia and non-IgM-type lymphoplasmacytic lymphoma are genetically similar
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Maaya Awata-Shiraiwa, Akihiko Yokohama, Yukihiro Kanai, Nanami Gotoh, Tetsuhiro Kasamatsu, Hiroshi Handa, Takayuki Saitoh, Hirokazu Murakami, Junko Hirato, Hayato Ikota, and Norifumi Tsukamoto
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Hematology ,General Medicine - Abstract
Introduction Waldenström macroglobulinemia (WM) represents a subset of lymphoplasmacytic lymphoma (LPL) with the immunoglobulin (Ig)M paraprotein. MYD88 L265P and CXCR4 mutations are common mutations in WM patients, and mutations in ARID1A and KMT2D (MLL2) have also been reported. However, little information has been accumulated on genetic changes in LPL with other paraproteins like IgG. Methods We therefore aimed to evaluate genetic differences between WM and LPL with non-IgM paraprotein (non-IgM-type LPL) using targeted next-generation sequencing (NGS) in 20 Japanese patients (10 with WM, 10 with non-IgM-type LPL). Results Mutations were detected in ARID1A (10%), CXCR4 (20%), MYD88 (90%), and KMT2D (0%) for WM patients, and in ARID1A (10%), CXCR4 (20%), MYD88 (70%), and KMT2D (10%) for non-IgM-type LPL patients. No significant differences were identified. No mutations were detected in NOTCH2, PRDM1, CD274 (PD-L1), PDCD1LG2 (PD-L2), RAG2, MYBBP1A, TP53, or CD79B. Discussion Mutant allele frequency in MYD88 L265P did not differ significantly between WM and non-IgM-type LPL. Most mutations detected by NGS were subclonal following MYD88 L265P, although one non-IgM-type LPL patient harbored only CXCR4 S338X mutation. Our NGS analyses reveal genetic characteristics in LPL patients and suggest genetic similarities between these two subsets of LPL, WM and non-IgM-type.
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- 2023
84. Integrator complex subunit 15 controls mRNA splicing and is critical for eye development
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Noriyuki Azuma, Tadashi Yokoi, Taku Tanaka, Emiko Matsuzaka, Yuki Saida, Sachiko Nishina, Miho Terao, Shuji Takada, Maki Fukami, Kohji Okamura, Kayoko Maehara, Tokiwa Yamasaki, Jun Hirayama, Hiroshi Nishina, Hiroshi Handa, and Yuki Yamaguchi
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Genetics ,General Medicine ,Molecular Biology ,Genetics (clinical) - Abstract
The eye and brain are composed of elaborately organized tissues, development of which is supported by spatiotemporally precise expression of a number of transcription factors and developmental regulators. Here we report the molecular and genetic characterization of Integrator complex subunit 15 (INTS15). INTS15 was identified in search for the causative gene(s) for an autosomal-dominant eye disease with variable individual manifestation found in a large pedigree. While homozygous INTS15 knockout mice are embryonic lethal, mutant mice lacking a small C-terminal region of INTS15 show ocular malformations similar to the human patients. INTS15 is highly expressed in the eye and brain during embryogenesis and stably interacts with the Integrator complex to support snRNA 3′ end processing. Its knockdown resulted in missplicing of a large number of genes, probably as a secondary consequence, and substantially affected genes associated with eye and brain development. Moreover, studies using human iPS-derived neural progenitor cells showed that INTS15 is critical for axonal outgrowth in retinal ganglion cells. This study suggests a new link between general transcription machinery and a highly specific hereditary disease.
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- 2023
85. <scp>DNA</scp> damage‐induced cellular senescence is regulated by <scp>53BP1</scp> accumulation in the nuclear foci and phase separation
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Tsukasa Oda, Nanami Gotoh, Tetsuhiro Kasamatsu, Hiroshi Handa, Takayuki Saitoh, and Nobuo Sasaki
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Cell Biology ,General Medicine - Published
- 2023
86. Reduction of blood group A antigen on erythrocytes in a patient with myelodysplastic syndrome harboring somatic mutations in RUNX1 and GATA2
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Akira Hayakawa, Rie Sano, Yoichiro Takahashi, Takafumi Okawa, Rieko Kubo, Megumi Harada, Haruki Fukuda, Akihiko Yokohama, Hiroshi Handa, Reika Kawabata‐Iwakawa, Hatsue Tsuneyama, Junichi Tsukada, and Yoshihiko Kominato
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GATA2 Transcription Factor ,Erythrocytes ,Myelodysplastic Syndromes ,Core Binding Factor Alpha 2 Subunit ,Mutation ,Immunology ,Leukocytes, Mononuclear ,Humans ,Immunology and Allergy ,Hematology ,ABO Blood-Group System - Abstract
Reduction of blood group ABO antigens on red blood cells (RBCs) is well known in patients with leukemias, and this reduction of ABO expression is strongly associated with DNA methylation of the ABO promoter. Previously, we reported a two-nucleotide deletion in RUNX1 encoding an abnormally elongated protein lacking the trans-activation domain in a patient with myelodysplastic syndrome (MDS) showing A-antigen loss on RBCs. This prompted us to investigate the underlying mechanism responsible for A-antigen reduction on RBCs in another patient with MDS.Screening of somatic mutations was carried out using a targeted sequencing panel with genomic DNA from peripheral blood mononuclear cells from the patient and eleven MDS controls without A- or B-antigen loss. DNA methylation of the ABO promoter was examined by bisulfite genomic sequencing. Transient transfection assays were performed for functional evaluation of mutations.Screening of somatic mutations showed missense mutations in RUNX1 and GATA2 in the patient, while no mutation was found in exons of those genes in the controls. There was no significant difference in ABO promoter methylation between the patient and the controls. Transient transfection experiments into COS-7 and K562 cells suggested that the amino acid substitutions encoded by those mutations reduced or lost the trans-activation potential of the ABO expression.Considering the discrepancy between the variant frequencies of these mutations and the ratios of the RBCs with A-antigens loss, the antigen reduction might be associated with these somatic mutations and hypermethylation of the ABO promoter.
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- 2021
87. An Autopsy Case of Multicentric Castleman Disease Presenting with Severe Jaundice
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Hiroki Tojima, Yuichi Yamazaki, Ken Sato, Yuka Yoshida, Megumi Shimizu, Hiroshi Handa, Hideaki Yokoo, Takeshi Kobayashi, Toshio Uraoka, and Satoru Kakizaki
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Male ,multicentric Castleman disease ,medicine.medical_specialty ,severe jaundice ,Bilirubin ,Jaundice ,Case Report ,Autopsy ,030204 cardiovascular system & hematology ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,autopsy ,0302 clinical medicine ,Cholestasis ,Internal medicine ,Ascites ,Internal Medicine ,medicine ,Humans ,Bile Duct Disorder ,Aged ,business.industry ,interleukin-6 ,Castleman Disease ,nutritional and metabolic diseases ,General Medicine ,medicine.disease ,eye diseases ,chemistry ,Biliary tract ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Infiltration (medical) ,Liver Failure - Abstract
A 70-year-old man with multicentric Castleman disease (MCD) was admitted to our hospital with jaundice and ascites. Elevations in his bilirubin and interleukin-6 levels were noted, and computed tomography revealed hepatic atrophy and portal vein and bile duct disorders. Steroid therapy was started for MCD, but he died of hepatic failure. An autopsy revealed that the MCD activity was mild, but advanced fibrosis and cholestasis were observed in the liver. Mild infiltration of interleukin-6-positive plasma cells was noted in the highly fibrotic area of the liver. Although rare, liver and biliary tract damage may be also considered organ disorders of MCD.
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- 2021
88. PLZF and its fusion proteins are pomalidomide-dependent CRBN neosubstrates
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Takumi Ito, Yuki Yamaguchi, Junichi Yamamoto, Nobuyuki Shimizu, Hiroshi Handa, and Tomoko Asatsuma-Okumura
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Acute promyelocytic leukemia ,QH301-705.5 ,Ubiquitin-Protein Ligases ,Medicine (miscellaneous) ,Article ,General Biochemistry, Genetics and Molecular Biology ,Target validation ,hemic and lymphatic diseases ,medicine ,Humans ,Promyelocytic Leukemia Zinc Finger Protein ,Amino Acid Sequence ,Biology (General) ,Multiple myeloma ,Adaptor Proteins, Signal Transducing ,Lenalidomide ,Chemistry ,Cereblon ,medicine.disease ,Pomalidomide ,Fusion protein ,Thalidomide ,HEK293 Cells ,Ubiquitin ligases ,Cancer research ,Mantle cell lymphoma ,General Agricultural and Biological Sciences ,Sequence Alignment ,medicine.drug - Abstract
Pomalidomide and lenalidomide are immunomodulatory agents that were derived from thalidomide. Cereblon (CRBN) is a common direct target of thalidomide and related compounds and works as a Cullin Ring 4 E3 ubiquitin ligase (CRL4) with DDB1, CUL4, and ROC1. The substrate specificity of CRL4CRBN is modulated by thalidomide-related compounds. While lenalidomide is approved for the treatment of several diseases including multiple myeloma, 5q- syndrome, mantle cell lymphoma, and follicular lymphoma, pomalidomide is approved only for the treatment of lenalidomide-resistant multiple myeloma. Here we show that PLZF/ZBTB16 and its fusion proteins are pomalidomide-dependent neosubstrates of CRL4CRBN. PLZF joins to RARα or potentially other partner genes, and the translocation causes leukemias, such as acute promyelocytic leukemia and T-cell acute lymphoblastic leukemia. We demonstrate that pomalidomide treatment induces PLZF-RARα degradation, resulting in antiproliferation of leukemic cells expressing PLZF-RARα. This study highlights a potential therapeutic role of pomalidomide as a degrader of leukemogenic fusion proteins., Shimizu et al. identify PLZF/ZBTB16 and its fusion proteins as pomalidomide-dependent neosubstrates of the cereblon E3 ligase. The authors also report that pomalidomide induces their degradation and thereby exerts its anti-cancer effect in leukemic cells expressing the fusion proteins.
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- 2021
89. Multiple keratoacanthomas induced by treatment with dasatinib and bosutinib for chronic myeloid leukemia: A case report and literature review
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Keiji Kosaka, Masahito Yasuda, Jain Kim, Shintaro Saito, Akihito Uehara, Hiroshi Handa, and Sei‐ichiro Motegi
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Dermatology ,General Medicine - Published
- 2022
90. Outcomes of transplant-eligible patients with myelodysplastic syndrome with excess blasts registered in a prospective observational study: The JALSG-CS11-MDS-SCT
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Ken Ishiyama, Noriharu Nakagawa, Kensuke Usuki, Satoru Takada, Tatsuki Tomikawa, Hiroshi Handa, Yuna Katsuoka, Daiki Hirano, Nobuo Sezaki, Masahiko Sumi, Shin Fujisawa, Yasuhiro Taniguchi, Atsuko Mugitani, Takuro Yoshimura, Eiichi Ohtsuka, Ken Takase, Youko Suehiro, Shuichi Ota, Tomohiro Kajiguchi, Tomoya Maeda, Masahide Yamamoto, Shigeki Ohtake, Akira Katsumi, Hitoshi Kiyoi, Itaru Matsumura, and Yasushi Miyazaki
- Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndromes (MDS). However, whether bridging therapy (BRT) including azacitidine (AZA) and combination chemotherapy (CCT) prior to allo-SCT should be performed is unclear. We analyzed BRT and the outcomes of patients with myelodysplastic syndrome with excess blasts (MDS-EB) who were registered in a prospective observational study in order to clarify the optimal allo-SCT strategy for high-risk MDS. A total of 371 patients were included in this study. Among 188 patients (50.7%) who were considered for allo-SCT, 141 actually underwent allo-SCT. Among the patients who underwent allo-SCT, 64 received AZA, 29 received CCT and 26 underwent allo-SCT without BRT as an initial treatment. The multivariate analysis identified BRT as independent factors influencing overall survival (AZA vs. without BRT, hazard ratio [HR] 3.33, 95% confidence interval [95%CI] 1.44–7.70, P = 0.005; CCT vs. without BRT, HR 3.82, 95%CI 1.60–9.14, P = 0.003). In a multivariate analysis, BRT showed an independent association with progression-free survival (AZA vs. without BRT, HR 2.23, 95%CI 1.03–4.83, P = 0.041; CCT vs. without BRT, HR 2.94, 95%CI 1.29–6.69, P = 0.010). Transplant-eligible patients with MDS-EB should undergo upfront allo-SCT without BRT.
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- 2022
91. [Spontaneous disappearance of the inhibitor during emicizumab therapy in a patient with mild hemophilia A]
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Akira, Matsumoto, Yoshiyuki, Ogawa, Yuri, Uchiyama, Tetsuya, Ishikawa, Chiaki, Naito, Nobuhiko, Kobayashi, Yuri, Miyazawa, Takuma, Ishizaki, Madoka, Inoue, Yuichi, Moteki, Saki, Kitazawa, Masami, Murakami, Naomichi, Matsumoto, and Hiroshi, Handa
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Male ,Factor VIII ,Antibodies, Bispecific ,Humans ,Hemorrhage ,Middle Aged ,Hemophilia A ,Antibodies, Monoclonal, Humanized - Abstract
From a young age, a 63-year-old Japanese man had experienced difficulties with hemostasis during tooth extraction and epistaxis and swelling of bruised areas. He had previously been diagnosed with mild hemophilia (FVIII:C 8.5%) at age of 60 due to swelling of a right hip bruise and was administered FVIII concentrate for the first time. He had frequent bleeding around his shoulder joints and was given FVIII concentrates every time, but his hemostasis was poor. He was referred to our hospital because his FVIII activity decreased to1% and a low-titer inhibitor (2.0 BU/ml) was detected. Because of a shoulder hematoma and new subcutaneous bleeding on both forearms, recombinant FVIIa was used to perform the hemostatic treatment. Following hemostasis, emicizumab was administered subcutaneously every 2 weeks at a dose of 3.0 mg/kg. Approximately 2 months after starting emicizumab, inhibitors were no longer detected, and FVIII activity increased to 8% after 9 months. We encountered a case of mild hemophilia A with an inhibitor that was first diagnosed in old age. The incidence of inhibitors in non-severe hemophilia A is about 10%, and about 70% of those resolves spontaneously. In this case, suppression of bleeding by emicizumab may have contributed to the spontaneous disappearance of the inhibitor.
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- 2022
92. History of IMiDs and Protein Degradation as a Pharmacological Modality
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Junichi Yamamoto, Tomoko Asatsuma‐Okumura, Takumi Ito, Yuki Yamaguchi, and Hiroshi Handa
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- 2022
93. Two cases of follicular lymphoma with MYC gene abnormalities that presented with bone marrow necrosis
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Yuri Miyazawa, Hisashi Takei, Nobuhiko Kobayashi, Naoki Akashi, Yukiko Sairenji, Manato Sugisaki, Chiaki Naito, Tetsuya Ishikawa, Hiroaki Shimizu, Takuma Ishizaki, Akihiko Yokohama, Norifumi Tsukamoto, Yuka Yoshida, Nozomi Matsumura, Yoshiyasu Takayama, and Hiroshi Handa
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Necrosis ,Bone Marrow ,Lymphoma, Non-Hodgkin ,Genes, myc ,Humans ,General Medicine ,Lymphoma, Follicular - Abstract
Bone marrow necrosis (BMN) occurs most frequently in hematological malignancies and sometimes in non-hematological disorders. Lymphoid diseases causing necrosis are regarded as high-grade disease. B-lymphoblastic leukemia/lymphoma is the most common malignant cause of BMN. Here, we present two patients with follicular lymphoma (FL) and MYC gene abnormalities who developed BMN. In one case of BMN, the necrosis disappeared in response to chemotherapy, and the patient survived with complete remission. In the other case, BMN remained even after chemotherapy, and effective chemotherapy could not be administered due to suppressed hematopoiesis, which led to the lymphoma worsening and the patient's death. Indolent lymphomas, such as FL, as in these cases, have the potential to develop BMN. It is important to detect the development of BMN and administer chemotherapy early to improve patient prognosis, since severe BMN prevents patients from receiving effective treatment.
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- 2022
94. Circulating cell-free DNA in the peripheral blood plasma of patients is an informative biomarker for multiple myeloma relapse
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Tadao Ishida, Arinobu Tojo, Norio Komatsu, Hideto Tamura, Junya Makiyama, Norina Tanaka, Masahiro Kizaki, Hiroshi Yasui, Yoichi Imai, Yutaka Tsukune, Junji Tanaka, Kota Sato, Kazuaki Yokoyama, Kanya Kondoh, Hiroshi Handa, Yuta Kaito, Seiya Imoto, Makoto Sasaki, Masayuki Kobayashi, and Toyotaka Kawamata
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Hematology ,General Medicine ,Disease ,medicine.disease ,Circulating Cell-Free DNA ,Surgical oncology ,Internal medicine ,Monoclonal ,medicine ,Biomarker (medicine) ,Surgery ,Paraproteins ,Liquid biopsy ,business ,Multiple myeloma - Abstract
Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatment of MM, currently known biomarkers of relapse, including serum free-light chains and monoclonal paraproteins, are not associated with genetic changes. We therefore performed a multicenter study to examine the usefulness of circulating cell-free DNA (cfDNA) present in the peripheral blood (PB) plasma of patients as a biomarker for MM relapse. We identified several driver mutations by combined analysis of next-generation sequencing and existing databases of candidate oncogenes. Furthermore, relapse was detected more sensitively by monitoring the circulating cfDNA with these driver mutations than by conventional serum free-light chain examination. These results suggest the potential utility of cfDNA in the PB plasma of patients as a relevant early biomarker for MM relapse.
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- 2021
95. Sub-lethal doses of chemotherapeutic agents induce senescence in T cells and upregulation of PD-1 expression
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Tetsuhiro Kasamatsu, Maaya Awata-Shiraiwa, Rei Ishihara, Yuki Murakami, Yuta Masuda, Nanami Gotoh, Tsukasa Oda, Akihiko Yokohama, Ikuko Matsumura, Hiroshi Handa, Norifumi Tsukamoto, Hirokazu Murakami, and Takayuki Saitoh
- Subjects
General Medicine ,General Biochemistry, Genetics and Molecular Biology - Abstract
Cellular senescence refers to a pause in the cell cycle, usually in response to internal and/or external stress, including telomere dysfunction, abnormal cellular growth, and DNA damage. Several chemotherapeutic drugs, such as melphalan (MEL) and doxorubicin (DXR), induce cellular senescence in cancer cells. However, it is not clear whether these drugs induce senescence in immune cells. We evaluated the induction of cellular senescence in T cells were derived from human peripheral blood mononuclear cells (PBMNCs) in healthy donors using sub-lethal doses of chemotherapeutic agents. The PBMNCs were kept overnight in RPMI 1640 medium with 2% phytohemagglutinin and 10% fetal bovine serum and then cultured in RPMI 1640 with 20 ng/mL IL-2 and sub-lethal doses of chemotherapeutic drugs (2 µM MEL and 50 nM DXR) for 48 h. Sub-lethal doses of chemotherapeutic agents induced phenotypes associated with senescence, such as the formation of γH2AX nuclear foci, cell proliferation arrest, and induction of senescence-associated beta-galactosidase (SA-β-Gal) activity, (control vs. MEL, DXR; median mean fluorescence intensity (MFI) 1883 (1130–2163) vs. 2233 (1385–2254), 2406.5 (1377–3119), respectively) in T cells. IL6 and SPP1 mRNA, which are senescence-associated secretory phenotype (SASP) factors, were significantly upregulated by sublethal doses of MEL and DXR compared to the control (P = 0.043 and 0.018, respectively). Moreover, sub-lethal doses of chemotherapeutic agents significantly enhanced the expression of programmed death 1 (PD-1) on CD3 + CD4 + and CD3 + CD8 + T cells compared to the control (CD4 + T cells; P = 0.043, 0.043, and 0.043, respectively, CD8 + T cells; P = 0.043, 0.043, and 0.043, respectively). Our results suggest that sub-lethal doses of chemotherapeutic agents induce senescence in T cells and tumor immunosuppression by upregulating PD-1 expression on T cells.
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- 2022
96. The levels of serum soluble CD86 are correlated with the expression of CD86 variant 3 gene and are prognostic indicators in patients with myeloma
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Ryosuke Kinoshita, Mariko Ishibashi, Hiroshi Handa, Makoto Sasaki, Yoichi Imai, Norina Tanaka, Shigeki Ito, Mika Sunakawa-Kii, Yuta Kaito, Toshio Asayama, Norio Komatsu, Junji Tanaka, Takeshi Odajima, Hiroki Sugimori, Hiroki Yamaguchi, Koiti Inokuchi, and Hideto Tamura
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Cancer Research ,Genetics ,Cell Biology ,Hematology ,Molecular Biology - Published
- 2023
97. Expression of activated integrin β7 in multiple myeloma patients
- Author
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Masaki Ri, Shinsuke Iida, Naoki Hosen, Koichiro Minauchi, Shuji Ozaki, Shigeo Fuji, Shingen Nakamura, Hiroyuki Takamatsu, Ishikazu Mizuno, Yoichi Imai, Ichiro Hanamura, Hirohisa Nakamae, Eiju Negoro, Hiroshi Handa, Satoshi Yoshihara, Kenshi Suzuki, Yawara Kawano, Masahiro Kizaki, Rikio Suzuki, Junya Kuroda, Noriko Nishimura, Yasuyuki Nagata, Yoshimitsu Shimomura, Nobuhiko Uoshima, Hiroshi Kosugi, and Hiroshi Gomyo
- Subjects
Male ,medicine.medical_specialty ,Integrin beta Chains ,Plasma Cells ,Integrin ,Bone Marrow Cells ,Immunotherapy, Adoptive ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Humans ,Medicine ,Multiple myeloma ,Aged ,Hematology ,medicine.diagnostic_test ,biology ,business.industry ,Flow Cytometry ,medicine.disease ,Chimeric antigen receptor ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Bone marrow ,Car t cells ,Multiple Myeloma ,business ,030215 immunology - Abstract
Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin β7 is constitutively activated in MM cells, and chimeric antigen receptor (CAR) T cells targeting activated integrin β7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin β7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin β7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin β7 was highly expressed in MM cells even in heavily treated patients. It also showed high expression in many CD38lo/−CD138−CD19+B cells, which reportedly include clonotypic B cells, in the bone marrow of MM patients. Taken together, these results suggest that CAR T-cell therapy targeting activated integrin β7 has the potential to benefit many patients with relapsed or refractory MM.
- Published
- 2021
98. Changes in Pulmonary Function Test Results and Respiratory Symptoms Before and After Airway Stent Removal
- Author
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Masahide Oki, Hiroshi Handa, Hideo Saka, Yoshihito Kogure, Hideyuki Niwa, Arisa Yamada, Atsushi Torii, Masahiko Ando, and Masamichi Mineshita
- Subjects
Pulmonary and Respiratory Medicine ,Airway Obstruction ,Treatment Outcome ,Bronchoscopy ,Silicones ,Humans ,Stents ,Constriction, Pathologic ,Device Removal ,Respiratory Function Tests - Abstract
Background: Airway stenting is a useful form of palliation for patients with airway stenosis/fistulas; the stent can be removed after addressing the cause of the airway disorder. Patients with airway stents often complain of coughing and difficulty with expectoration, so the use of such stents can negatively affect pulmonary function and worsen symptoms. Objectives: The aim of this study was to compare pulmonary function and respiratory symptoms before and after stent removal. Methods: Patients who would later undergo simple airway stent removal were prospectively recruited in two institutions. All stents were removed using both rigid and flexible bronchoscopes with patients under general anesthesia. Pulmonary function tests were performed before stent removal and at 1 and 4 weeks after stent removal. All patients self-reported their respiratory symptoms using a 100-mm visual analog scale (VAS). Results: Of the 31 patients enrolled, 28 (23 with malignant stenoses, 3 with benign stenoses, and 2 with fistulas [21 silicone and 7 metallic stents]) were included in analyses. Pulmonary function measurements before stent removal and at 1 and 4 weeks after stent removal were as follows: vital capacity, 3.00, 3.04, and 3.08 L (p = 0.387); forced expiratory volume in 1 s, 1.96, 1.96, and 2.12 L (p = 0.034); and peak expiratory flow, 3.60, 4.28, and 5.06 L/s, respectively (p < 0.001). Symptoms (cough, sputum production, difficulty with expectoration, and dyspnea) evaluated using the VAS improved significantly after stent removal. No complications were encountered during removal. Conclusion: Removal of unnecessary airway stents improves pulmonary function and respiratory symptoms. Any stent that is no longer functioning should be removed.
- Published
- 2022
99. Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
- Author
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Hiroshi Handa, Koichi Kawakami, and Kazuhide Asakawa
- Subjects
0301 basic medicine ,Heterogeneous nuclear ribonucleoprotein ,Review ,Biology ,TARDBP ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,mental disorders ,medicine ,Animals ,Humans ,Coding region ,Motor Neuron Disease ,Amyotrophic lateral sclerosis ,Molecular Biology ,Pharmacology ,Amyotrophic Lateral Sclerosis ,nutritional and metabolic diseases ,Cell Biology ,Motor neuron ,medicine.disease ,nervous system diseases ,DNA-Binding Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Cytoplasm ,Molecular Medicine ,Neuroscience ,030217 neurology & neurosurgery ,Intracellular ,Function (biology) - Abstract
Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In most ALS cases, cytoplasmic TDP-43 aggregation occurs in the absence of mutations in the coding sequence of TARDBP. Thus, a major challenge in ALS research is to understand the nature of pathological changes occurring in wild-type TDP-43 and to explore upstream events in intracellular and extracellular milieu that promote the pathological transition of TDP-43. Despite the inherent obstacles to analyzing TDP-43 dynamics in in vivo motor neurons due to their anatomical complexity and inaccessibility, recent studies using cellular and animal models have provided important mechanistic insights into potential links between TDP-43 and motor neuron vulnerability in ALS. This review is intended to provide an overview of the current literature on the function and regulation of TDP-43-containing RNP granules or membraneless organelles, as revealed by various models, and to discuss the potential mechanisms by which TDP-43 can cause selective vulnerability of motor neurons in ALS.
- Published
- 2021
100. Evaluation of Droplet Countermeasures by a Particle Visualization System in Simulated Bronchoscopy
- Author
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Hirotaka Kida, Takeo Inoue, Hiroshi Handa, Masamichi Mineshita, and Kei Morikawa
- Subjects
Pulmonary and Respiratory Medicine ,Aerosols ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,medicine.diagnostic_test ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Real-time computing ,COVID-19 ,Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences ,Critical Care and Intensive Care Medicine ,Visualization ,Bronchoscopy ,Exhalation ,Particle ,Medicine ,Humans ,business ,Environmental Monitoring - Published
- 2021
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