Yohta Shimada

Jikei University School of Medicine

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Toya Ohashi

Jikei University School of Medicine

Hiroshi Kobayashi

National Center for Global Health and Medicine

Hiroyuki Ida

Jikei University School of Medicine

Yoshikatsu Eto

Southern Tohoku General Hospital

Takashi Higuchi

Kanazawa University

Takahiro Fukuda

Tokyo National Hospital

Katsuhiko Yanaga

Sanno Medical Center

Yoshihiro Shirai

Jikei University School of Medicine

Tadashi Uwagawa

Jikei University School of Medicine

Takashi Horiuchi

Jikei University School of Medicine

Cooperative Institutions

Inserm

150

Centre National de la Recherche Scientifique

134

University of Michigan–Ann Arbor

126

Harvard University

119

Jikei University School of Medicine

107

Chinese Academy of Sciences

National Institutes of Health

Istituti di Ricovero e Cura a Carattere Scientifico

Consejo Superior de Investigaciones Científicas

Instituto de Salud Carlos III

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Oral administration of recombinant human acid α-glucosidase reduces specific antibody formation against enzyme in mouse

Molecular Genetics and Metabolism (2011)

Toya Ohashi Sayoko Iizuka Yohta Shimada Y. Eto Hiroyuki Ida

10.1016/j.ymgme.2011.01.009

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Citations (14)

Identification of Cryptic Novel α-Galactosidase A Gene Mutations: Abnormal mRNA Splicing and Large Deletions

JIMD Reports (2015)

Takashi Higuchi Masahisa Kobayashi Jin Ogata Eiko Kaneshiro Yohta Shimada

Anderson-Fabry (FD) disease is an inborn error of metabolism caused by a deficiency of α-galactosidase A (GLA), a lysosomal enzyme. Many male FD patients display a classic FD phenotype; however, some female patients have neither reduced leukocyte GLA enzyme activity level nor FD symptoms. Thus, GLA gene analysis is especially important for diagnosing suspected FD in female subjects. In this study, we revealed 4 novel GLA gene mutations in 5 independent families using GLA cDNA analysis and multiplex ligation-dependent probe amplification (MLPA) analysis. These distinct mutations included a large deletion mutation from intron 1 to exon 5 (c.195-471_c.691del5.5k, corresponding to g.8508_g.14069del5.5k), an insertion mutation of splicing enhancer sequence in intron 4 (c.639+329_c.639+330ins113, corresponding to g.12627_g.12628ins113), an insertion mutation of retrotransposon L1 in exon 4 (c.634_c.635, corresponding to g.12293_g.12294), and a non-SNP deep intronic point mutation in intron 3 (c.547+395G>C, corresponding to g.11727G>C). It is difficult to detect these mutations with direct sequencing of only the exonic element. When exonic mutations are not found in the GLA gene from suspected FD patients, GLA cDNA and MLPA analyses should be performed to detect large deletion/insertion and intronic mutations including transcription abnormalities.

Exon skipping

10.1007/8904_2015_475

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Citations (9)

Generation of induced pluripotent stem (iPS) cells derived from a murine model of Pompe disease and differentiation of Pompe-iPS cells into skeletal muscle cells

Molecular Genetics and Metabolism (2011)

Shiho Kawagoe Takashi Higuchi Xing-Li Meng Yohta Shimada Hiromi Shimizu

KLF4

Matrigel

10.1016/j.ymgme.2011.05.020

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Citations (29)

Purification and identification of SDS-solubilized ubiquitin-conjugates accumulated in brains of Niemann-Pick C disease mouse

Neuroscience Research (2009)

Yohta Shimada Takahiro Fukuda Toya Ohashi Koichi Sunahara Kiyoshi Ohkawa

Identification

Conjugate

10.1016/j.neures.2009.09.1404

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Citations (0)

Restoration of peripheral neuropathy in Fabry mice via intrathecal administration of an adeno-associated virus vector encoding mGLA cDNA

Molecular Genetics and Metabolism (2024)

Takashi Higuchi Yohta Shimada Yukari Takahashi Fusao Kato Toya Ohashi

Adeno-associated virus

Globotriaosylceramide

Dorsal root ganglion

Alpha-galactosidase

10.1016/j.ymgme.2024.108545

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Citations (1)

Vascular Endothelial Growth Factor Receptor Expression as a Prognostic Marker for Survival in Colorectal Cancer

Japanese Journal of Clinical Oncology (2009)

Natsuko Okita Yasuhide Yamada Daisuke Takahari Yoshinori Hirashima J Matsubara

Vascular endothelial growth factor (VEGF) and its receptors VEGF-R1, -R2 and -R3 play important roles in tumor angiogenesis and are associated with poor prognosis in several solid tumors. However, their functional significance remains unclarified. Here, we investigated the associations between the expression of these receptors and the clinical outcomes of colorectal cancer (CRC) patients.An immunohistochemical approach was used to detect VEGF-R1, -R2 and -R3 expression in 91 CRC patients who underwent surgery and received chemotherapy at the National Cancer Center Hospital. Statistical analysis was performed to determine the prognostic significance of these biomarkers.Immunoreactivity for VEGF-R2 and -R3 was localized in microvessels and that for VEGF-R1 in cancer cells and stromal microvessels. VEGF-R1 staining in cancer cells (>10% staining) was found in 84 patients (92%) and in stromal vessels in 75 patients (82%). VEGF-R2 staining in tumor vessels (>10% staining) was found in 84 patients (92%), whereas VEGF-R3 staining was found in 85 patients (93%). Strong positive staining (>60% staining) of VEGF-R1 in tumor cells, and VEGF-R1, -R2 and -R3 in vessels was identified in 58 (64%), 33 (36%), 52 (57%) and 60 (66%) patients, respectively. Univariate analysis revealed that VEGF-R1 strong positive staining correlated with shorter post-operative survival in patients with Stage II/III disease (P = 0.01), but neither VEGF-R2 nor R3 expression correlated with survival.VEGF-R1, -R2 and -R3 were highly expressed in CRC cells and stromal vessels. VEGF-R1 strong positive staining correlated with shorter survival after CRC surgery.

10.1093/jjco/hyp066

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Citations (28)

Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

Human Gene Therapy (2015)

Taichi Wakabayashi Yohta Shimada Kazumasa Akiyama Takashi Higuchi Takahiro Fukuda

Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II.

Mucopolysaccharidosis

Lysosomal storage disease

Hunter syndrome

Mucopolysaccharidosis I

Hematopoietic stem cell

Mucopolysaccharidosis type II

Hurler syndrome

10.1089/hum.2014.158

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Citations (54)

Minimum requirement of donor cells to reduce the glycolipid storage following bone marrow transplantation in a murine model of Fabry disease

The Journal of Gene Medicine (2011)

Takayuki Yokoi Hiroshi Kobayashi Yohta Shimada Yoshikatsu Eto Nobuyuki Ishige

Abstract Background Fabry disease (FD) is a lysosomal storage disorders characterized by a deficiency of the lysosomal enzyme, α‐galactosidase A. This results in the accumulation of glycolipids, mainly globotriaosylceramide (GL‐3), in the lysosomes of various organs. Although bone marrow transplantation and hematopoietic stem cell‐based gene therapy can offer the potential of a curative therapeutic outcome for FD, the minimum requirement of donor cells or gene‐corrected cells to reduce GL‐3 levels is not known. Methods Lethally‐irradiated FD mice were transplanted intravenously with normal bone marrow cells (Ly5.1 positive) mixed with those of FD mice (Ly5.2 positive) at various ratios to investigate the level of engraftment and enzyme activity necessary to effect a reduction in GL‐3 storage. Results Chimerism of whole white blood cells of recipients' peripheral blood remained stable at 8 weeks after transplantation, and chimerism of granulocytes, monocytes, B cells and T cells was equal to that of white blood cells. GL‐3 levels were significantly reduced in the lung and heart of animals with a 30% and 50% chimera, respectively. The extent of reduction in these mice was almost identical to that with 100% chimera. Conclusions In FD mice, reconstitution with 100% donor cells is not required to obtain a therapeutic effect following bone marrow transplantation. These results suggest that a 30% gene correction might be sufficient to reverse disease manifestations in FD. Copyright © 2011 John Wiley & Sons, Ltd.

Globotriaosylceramide

Chimera (genetics)

10.1002/jgm.1566

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Citations (10)

The generation of induced pluripotent stem cells (iPSCs) from patients with infantile and late-onset types of Pompe disease and the effects of treatment with acid-α-glucosidase in Pompe's iPSCs

Molecular Genetics and Metabolism (2014)

Takashi Higuchi Shiho Kawagoe Makoto Otsu Yohta Shimada Hiroshi Kobayashi

Lysosomal storage disease

Reprogramming

Periodic acid–Schiff stain

KLF4

10.1016/j.ymgme.2014.02.012

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Citations (26)

A phase I study of the chimeric monoclonal anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a single agent in subjects from Japan with advanced solid tumors: Safety, pharmacokinetics (PK)

Journal of Clinical Oncology (2005)

Hiroyuki Yasui Kuniaki Shirao Nobuyuki Yamamoto Yohta Shimada Yasuhide Yamada

3209 Background: Cetuximab is a monoclonal antibody that selectively binds to the Epidermal Growth Factor Receptor (EGFR). Cetuximab as a single agent is effective in patients with colorectal cancer refractory to irinotecan and oxaliplatin (Lenz ASCO 2004). This phase I study assessed the safety and PK profile of cetuximab as a single agent in Japanese patients with solid tumors. Methods: Monotherapy with cetuximab was examined across a 100–500mg/m2 dose range. Thirty patients with chemotherapy refractory, EGFR -expressing solid tumors were enrolled in cohorts of five to receive weekly IV infusions of 100 mg/m2 cetuximab following an initial dose of 100mg/m2 (cohort 1), or weekly IV infusions of 250mg/m2 following initial doses of 250 (cohort 2), 400 (cohort 3) or 500 mg/m2 (cohort 4). To investigate the PK profile, cetuximab infusion was skipped on day 8 in the 1st to 4th cohort. Following an initial dose of 400mg/m2, cetuximab was administered weekly IV infusion of 250mg/m2 in the last cohort (cohort 5). Blood samples for PK analysis were collected for up to eight weeks after the initial dose. Results: Thirty pts were enrolled in total (CRC 29 pts, NSCLC 1 pt), median age 54 (range: 37-73) with a median of 3 prior chemotherapy regimens (range: 1–5). Twenty-four pts (up to cohort 4) were evaluable, and no DLT has been observed to date. The most frequent adverse events were rash (71%), acne (58%), anorexia (50%), diarrhea (46%), fatigue (46%) and fever (38%), which were of Grade 1–2 in severity. The preliminary PK results in the first cohort were virtually identical to those observed in Caucasians. In preliminary efficacy results of 18 evaluable pts, 2 CRC pts had PR, 10 pts SD. Conclusions: Preliminary results suggest that Cetuximab is well tolerated as a single agent in Japanese patients with solid tumors at the cohort 1–4. An updated analysis will be provided. No significant financial relationships to disclose.

10.1200/jco.2005.23.16_suppl.3209

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Citations (4)