56 results on '"Eri Okada"'
Search Results
2. Polydactyly-derived allogeneic chondrocyte cell-sheet transplantation with high tibial osteotomy as regenerative therapy for knee osteoarthritis
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Kosuke Hamahashi, Eriko Toyoda, Miya Ishihara, Genya Mitani, Tomonori Takagaki, Nagatoshi Kaneshiro, Miki Maehara, Takumi Takahashi, Eri Okada, Ayako Watanabe, Yoshihiko Nakamura, Reiko Kato, Ryo Matoba, Takehiko Takagi, Hidenori Akutsu, Akihiro Umezawa, Hiroyuki Kobayashi, Tadashi Akamatsu, Masayuki Yamato, Teruo Okano, Masahiko Watanabe, and Masato Sato
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Medicine - Abstract
Abstract Allogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.
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- 2022
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3. Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases
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Atsushi Kondo, China Nagano, Shinya Ishiko, Takashi Omori, Yuya Aoto, Rini Rossanti, Nana Sakakibara, Tomoko Horinouchi, Tomohiko Yamamura, Sadayuki Nagai, Eri Okada, Yuko Shima, Koichi Nakanishi, Takeshi Ninchoji, Hiroshi Kaito, Hiroki Takeda, Hiroaki Nagase, Naoya Morisada, Kazumoto Iijima, and Kandai Nozu
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Medicine ,Science - Abstract
Abstract Gitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy–Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.
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- 2021
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4. Cartilage repair and inhibition of the progression of cartilage degeneration after transplantation of allogeneic chondrocyte sheets in a nontraumatic early arthritis model
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Naoki Takatori, Masato Sato, Eriko Toyoda, Takumi Takahashi, Eri Okada, Miki Maehara, and Masahiko Watanabe
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Medicine (General) ,R5-920 ,Cytology ,QH573-671 - Abstract
Introduction: Using a rat model of nontraumatic early arthritis induced by intra-articular administration of low-dose monoiodoacetic acid (MIA), we transplanted allogeneic chondrocyte sheets and examined the effects on tissue repair. Methods: MIA (0.2 mg/50 μl) was injected into the right knee of 20 male Wistar rats. Four weeks later, rats were randomly allocated into three groups: Group A was examined 4 weeks after administration of MIA; Group B, 8 weeks after MIA injection and chondrocyte sheet transplantation, and Group C, 8 weeks after MIA injection but without chondrocyte sheet transplantation. Allogeneic chondrocyte sheets were transplanted into the right knee of Group B rats. Pain was assessed as the weight distribution ratio of the damaged to undamaged limb. The OARSI score was used for histological scoring. Results: The limb weight distribution ratio indicated significantly less pain in Group B. Histological scoring showed significant differences in cartilage repair and inhibition of the progression of cartilage degeneration between Groups B and C, but not between Groups A and B, or Groups A and C. Conclusions: These findings suggest that, in this rat model of nontraumatic early arthritis induced by low-dose MIA injection, allogeneic chondrocyte sheet transplantation induces cartilage repair and suppresses cartilage degeneration. Keywords: Osteoarthritis, Chondrocyte sheet, Transplantation, Monoiodoacetic acid (MIA), OARSI score
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- 2018
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5. Spontaneous remission in adult patients with IgA nephropathy treated with conservative therapy.
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Hirotaka Sato, Daisuke Ichikawa, Eri Okada, Tomo Suzuki, Shiika Watanabe, Sayuri Shirai, and Yugo Shibagaki
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Medicine ,Science - Abstract
BackgroundThere are few studies describing the clinical course and spontaneous remission of IgA nephropathy (IgAN) in adult patients receiving conservative treatment.MethodData from 62 adult patients with biopsy-diagnosed IgAN, who received conservative treatment at least 5 years prior, were retrospectively investigated. No patients received corticosteroids, other immunosuppressants, or tonsillectomy. Remission of proteinuria and hematuria were defined as proteinuria ResultThirty-eight (61.3%) patients had remission of hematuria, 24 (38.7%) had remission of proteinuria, and 19 (30.6%) had remission of both. Remission rates increased in patients with proteinuria ConclusionsRelatively high rates of spontaneous remission were observed. Remission of both hematuria and proteinuria were frequent within 3 years after diagnosis, and renal function was well preserved during this period. These data indicate that it is rational to use conservative treatment for 3 years after the diagnosis instead of aggressive treatments.
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- 2021
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6. Characterization of polydactyly-derived chondrocyte sheets versus adult chondrocyte sheets for articular cartilage repair
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Miki Maehara, Masato Sato, Eriko Toyoda, Takumi Takahashi, Eri Okada, Tomomi Kotoku, and Masahiko Watanabe
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Cartilage regeneration ,Cell sheet technology ,Chondrocyte sheet ,Osteoarthritis ,Polydactyly-derived chondrocyte ,Pathology ,RB1-214 - Abstract
Abstract Background We previously conducted a first-in-human clinical study of articular cartilage repair using autologous chondrocyte sheets and confirmed the regeneration of hyaline-like cartilage in all eight patients. However, regenerative medicine with autologous chondrocyte sheets requires the harvesting of tissue from healthy regions, and the quality of this tissue varies between individuals. To overcome such limitations, allogeneic transplantation is a promising treatment method, particularly for articular cartilage repair. In this study, we investigated the characteristics of polydactyly-derived chondrocyte sheets fabricated from the chondrocytes of young polydactyly donors. Methods Polydactyly-derived chondrocyte (PD) sheets were fabricated from the tissue obtained from eight polydactyly donors (average age = 13.4 months). To create these PD sheets, chondrocytes at passage 2 or 3 were seeded on temperature-responsive culture inserts and cultured for 2 weeks. For comparison, adult chondrocyte sheets were fabricated from tissue obtained from 11 patients who underwent total knee arthroplasty (TKA; average age = 74 years). To create these TKA sheets, chondrocytes and synovial cells were cocultured, and the chondrocyte sheets were triple-layered according to the protocol from our previous clinical study. Cell count, cell viability, cell surface markers, cell histology, and humoral factors secreted by the sheets were characterized and compared between the PD sheets and TKA sheets. Results Polydactyly-derived chondrocytes proliferated rapidly to establish a layered structure with sufficient extracellular matrix and formed sheets that could be easily manipulated without tearing. Similar to TKA sheets, PD sheets expressed aggrecan and fibronectin at the protein level and the surface markers CD44, CD81, and CD90, which are characteristic of mesenchymal cells. PD sheets also produced significantly higher levels of transforming growth factor beta-1 and lower levels of matrix metalloproteinase-3 than those produced by TKA sheets, suggesting that young polydactyly-derived chondrocytes have advantages as a potential cell source. Conclusions PD sheets exhibited characteristics thought to be important to chondrocyte sheets as well as proliferative capacity that may facilitate provision of a stable supply in the future.
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- 2017
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7. Development of Injectable Polydactyly-Derived Chondrocyte Sheets
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Shiho Wasai, Eriko Toyoda, Takumi Takahashi, Miki Maehara, Eri Okada, Ryoka Uchiyama, Tadashi Akamatsu, Masahiko Watanabe, and Masato Sato
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cartilage regeneration ,cell sheet ,osteoarthritis ,minimally invasive treatment ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
We are conducting a clinical study of the use of allogeneic polydactyly-derived chondrocyte sheets (PD sheets) for the repair of articular cartilage damage caused by osteoarthritis. However, the transplantation of PD sheets requires highly invasive surgery. To establish a less invasive treatment, we are currently developing injectable fragments of PD sheets (PD sheets-mini). Polydactyly-derived chondrocytes were seeded in RepCell™ or conventional temperature-responsive inserts and cultured. Cell counts and viability, histology, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR), and flow cytometry were used to characterize PD sheets-mini and PD sheets collected from each culture. To examine the effects of injection on cell viability, PD sheets-mini were tested in four experimental conditions: non-injection control, 18 gauge (G) needle, 23G needle, and syringe only. PD sheets-mini produced similar amounts of humoral factors as PD sheets. No histological differences were observed between PD sheets and PD sheets-mini. Except for COL2A1, expression of cartilage-related genes did not differ between the two types of PD sheet. No significant differences were observed between injection conditions. PD sheets-mini have characteristics that resemble PD sheets. The cell viability of PD sheets-mini was not significantly affected by needle gauge size. Intra-articular injection may be a feasible, less invasive method to transplant PD sheets-mini.
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- 2021
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8. Transcriptomic and Proteomic Analyses Reveal the Potential Mode of Action of Chondrocyte Sheets in Hyaline Cartilage Regeneration
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Eriko Toyoda, Masato Sato, Takumi Takahashi, Miki Maehara, Eri Okada, Shiho Wasai, Hiroshi Iijima, Ken Nonaka, Yuka Kawaguchi, and Masahiko Watanabe
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cartilage regeneration ,cell sheet ,xenogeneic transplantation model ,efficacy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Chondrocyte sheet transplantation is a novel and promising approach to treating patients who have cartilage defects associated with osteoarthritis. Hyaline cartilage regeneration by autologous chondrocyte sheets has already been demonstrated in clinical research. In this study, the efficacy of polydactyly-derived chondrocyte sheets (PD sheets) as an allogeneic alternative to standard chondrocyte sheets was examined using an orthotopic xenogeneic transplantation model. In addition, the expression of genes and the secreted proteins in the PD sheets was analyzed using a microarray and a DNA aptamer array. The efficacy of PD sheets with respect to cartilage defects was assessed using histological scores, after which the expressions of genes and proteins exhibiting a correlation to efficacy were identified. Enrichment analysis of efficacy-correlated genes and proteins showed that they were associated with extracellular matrices, skeletal development, and angiogenesis. Eight genes (ESM1, GREM1, SERPINA3, DKK1, MIA, NTN4, FABP3, and PDGFA) exhibited a positive correlation with the efficacy of PD sheets, and three genes (RARRES2, APOE, and PGF) showed a negative correlation for both transcriptomic and proteomic analyses. Among these, MIA, DKK1, and GREM1 involved in skeletal development pathways and ESM1 involved in the angiogenesis pathway exhibited a correlation between the amount of secretion and efficacy. These results suggest that these secreted factors may prove useful for predicting PD sheet efficacy and may therefore contribute to hyaline cartilage regeneration via PD sheets.
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- 2019
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9. Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease
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Eri Okada, Naoya Morisada, Tomoko Horinouchi, Hideki Fujii, Takayuki Tsuji, Masayoshi Miura, Hideyuki Katori, Masashi Kitagawa, Kunio Morozumi, Takanobu Toriyama, Yuki Nakamura, Ryuta Nishikomori, Sadayuki Nagai, Atsushi Kondo, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Nana Sakakibara, China Nagano, Tomohiko Yamamura, Shingo Ishimori, Joichi Usui, Kunihiro Yamagata, Kazumoto Iijima, Toshiyuki Imasawa, and Kandai Nozu
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ADTKD ,Nephrology ,NGS ,long-read sequencing ,SMRT sequencing ,ADTKD-MUC1 ,MCKD - Abstract
Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD)-MUC1 is predominantly caused by frameshift mutations owing to a single-base insertion into the variable number tandem repeat (VNTR) region in MUC1. Because of the complexity of the variant hotspot, identification using short-read sequencers (SRSs) is challenging. Although recent studies have revealed the usefulness of long-read sequencers (LRSs), the prevalence of MUC1 variants in patients with clinically suspected ADTKD remains unknown. We aimed to clarify this prevalence and the genetic characteristics and clinical manifestations of ADTKD-MUC1 in a Japanese population using an SRS and an LRS. Methods: From January 2015 to December 2019, genetic analysis was performed using an SRS in 48 patients with clinically suspected ADTKD. Additional analyses were conducted using an LRS in patients with negative SRS results. Results: Short-read sequencing results revealed MUC1 variants in 1 patient harboring a cytosine insertion in the second repeat unit of the VNTR region; however, deeper VNTR regions could not be read by the SRS. Therefore, we conducted long-read sequencing analysis of 39 cases and detected MUC1 VNTR variants in 8 patients (in total, 9 patients from unrelated families). With the inclusion of family-affected patients (n = 31), the median age at the development of end-stage kidney disease (ESKD) was 45 years (95% CI: 40–40 years). Conclusion: In Japan, the detection rate of MUC1 variants in patients with clinically suspected ADTKD was 18.8%. More than 20% of patients with negative SRS results had MUC1 variants detected by an LRS.
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- 2022
10. Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes
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China Nagano, Koichi Nakanishi, Tomohiko Yamamura, Takeshi Ninchoji, Hiroshi Kaito, Rini Rossanti, Masafumi Matsuo, Yuko Shima, Sadayuki Nagai, Kazumoto Iijima, Riku Hamada, Yuya Aoto, Naoya Morisada, Nana Sakakibara, Shinya Ishiko, Eri Okada, Tomoko Horinouchi, Atsushi Kondo, and Kandai Nozu
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Adult ,medicine.medical_specialty ,Caroli disease ,Physiology ,Receptors, Cell Surface ,PKHD1 ,Gastroenterology ,Exon ,Japan ,Pregnancy ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Missense mutation ,Genetic Testing ,Allele ,Minigene assay ,Autosomal recessive polycystic kidney disease ,Polycystic Kidney, Autosomal Recessive ,business.industry ,medicine.disease ,Autosomal Recessive Polycystic Kidney Disease ,Congenital hypothyroidism ,Phenotype ,Nephrology ,Mutation ,Female ,Original Article ,business ,Hepatic fibrosis ,Kidney disease ,Minigene - Abstract
Background Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population. Methods We conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes. Results PKHD1 pathogenic variants were identified in 32 patients (0–46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1–2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808 + 1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities. Conclusion Clinical manifestations ranged from cases of neonatal demise to those diagnosed in adulthood. The minigene assay results indicate the importance of functional analysis, and call into question the fundamental belief that at least one non-truncating mutation is necessary for perinatal survival.
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- 2022
11. Factors associated with peritoneal dialysis selection in patients who received pre‒dialysis education
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Azumi Fukuta, Takehiko Kawaguchi, Moritoshi Kadomura, Masahiro Tomonari, Kazuyuki Ri, Mizuho Morooka, Masahiro Hyodo, Eri Okada, and Toshiyuki Imasawa
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Computer Networks and Communications ,Hardware and Architecture ,Software - Published
- 2022
12. Last Nucleotide Substitutions of COL4A5 Exons Cause Aberrant Splicing
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China Nagano, Tomoko Horinouchi, Sadayuki Nagai, Hiroyuki Awano, Tomohiko Yamamura, Yuya Aoto, Masafumi Matsuo, Eri Okada, Atsushi Kondo, Kandai Nozu, Hiroaki Nagase, Yuko Shima, Shinya Ishiko, Kazumoto Iijima, Nana Sakakibara, Rini Rossanti, and Koichi Nakanishi
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Genetics ,last nucleotide position ,business.industry ,genotype–phenotype correlation ,Gene mutation ,genotype-phenotype correlation ,medicine.disease ,Phenotype ,single-base substitutions ,Exon ,splicing ,Nephrology ,Clinical Research ,RNA splicing ,missense variants ,Missense mutation ,Medicine ,COL4A5 ,Alport syndrome ,business ,Genotyping ,Minigene - Abstract
Introduction COL4A5 is a causative gene of X-linked Alport syndrome (XLAS). Male patients with XLAS with nonsense variants have the most severe phenotypes of early onset end-stage kidney disease (ESKD); those with splicing variants have middle phenotypes and those with missense variants have the mildest phenotypes. Therefore, genotyping for male patients with XLAS can be used to predict kidney prognosis. Single-base substitutions at the last nucleotide position in each exon are known to affect splicing patterns and could be splicing variants. Nevertheless, in XLAS, these variants are generally considered to be missense variants, without conducting a transcript analysis, which underestimates some patients as having mild phenotypes. This study aimed to investigate whether single-base substitutions at the last nucleotide position of COL4A5 exons cause aberrant splicing. Methods In total, 20 variants were found in the Human Gene Mutation Database (n = 14) and our cohort (n = 6). We performed functional splicing assays using a hybrid minigene analysis and in vivo transcript analyses of patients’ samples when available. Then, we investigated genotype–phenotype correlations for patients with splicing variants detected in this study by comparing data from our previous studies. Results Among the 20 variants, 17 (85%) caused aberrant splicing. Male patients with splicing variants had more severe phenotypes when compared with those with missense variants. Findings from the in vivo analyses for 3 variants were identical to those from the minigene assay. Conclusion Our study revealed that most single-base substitutions at the last nucleotide position of COL4A5 exons result in splicing variants, rather than missense variants, thereby leading to more severe phenotypes., Graphical abstract
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- 2021
13. Genotype-Phenotype Correlation in WT1 Exon 8 to 9 Missense Variants
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Rini Rossanti, Kandai Nozu, Daisuke Ichikawa, Kazuki Tanaka, Tomoko Horinouchi, China Nagano, Hiroaki Nagase, Koichi Kamei, Eri Okada, Yutaka Takaoka, Shinya Ishiko, Riku Hamada, Yurika Tsuji, Kazumoto Iijima, Nana Sakakibara, Yuko Noguchi, Yuya Aoto, Shingo Ishimori, Tomohiko Yamamura, and Takeshi Ninchoji
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Genetics ,Zinc finger ,Mutation ,C2H2 Zinc Finger ,business.industry ,030232 urology & nephrology ,Wilms' tumor ,030204 cardiovascular system & hematology ,medicine.disease_cause ,medicine.disease ,Phenotype ,WT1 ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Nephrology ,Clinical Research ,Genotype ,end-stage kidney disease ,Missense mutation ,Medicine ,DNA binding ,business ,transcriptional activity - Abstract
Introduction WT1 missense mutation in exon 8 or 9 causes infantile nephrotic syndrome with early progression to end-stage kidney disease (ESKD), Wilms tumor, and 46,XY female. However, some patients with missense mutations in exon 8 or 9 progress to ESKD in their teens or later. Therefore, we conducted a systematic review and functional analysis of WT1 transcriptional activity. Methods We conducted a systematic review of 174 cases with WT1 exon 8 or 9 missense variants from our cohort (n=13) and previous reports (n=161). Of these cases, mild and severe genotypes were selected for further in vitro functional analysis using luciferase assay. Results The median age of developing ESKD was 1.17 years. A comparative study was conducted among three WT1 genotype classes: mutations of the DNA-binding site (DBS group), mutations outside the DNA-binding site but at sites important for zinc finger structure formation by 2 cysteines and 2 histidines (C2H2 group), and mutations leading to other amino acid changes (Others group). The DBS group showed the severest phenotype and the C2H2 group was intermediate, whereas the Others group showed the mildest phenotype (developing ESKD at 0.90, 2.00, and 3.92 years, respectively, with significant differences). In vitro functional analysis showed dominant-negative effects for all variants; in addition, the DBS and C2H2 mutations were associated with significantly lower WT1 transcriptional activity than the other mutations. Conclusion Not only the DNA-binding site but also C2H2 zinc finger structure sites are important for maintaining WT1 transcriptional activity, and their mutation causes severe clinical symptoms., Graphical abstract
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- 2021
14. X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay
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Shoichi Maruyama, Kandai Nozu, Tomohiko Yamamura, Tomoko Horinouchi, Takeshi Ninchoji, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Shogo Minamikawa, Eri Okada, Keiji Kono, Atsushi Fukunaga, Noritoshi Kato, China Nagano, Kazumoto Iijima, Hideki Fujii, Nana Sakakibara, and Shinichi Nishi
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Adult ,Nephrology ,Heterozygote ,medicine.medical_specialty ,Physiology ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Severity of Illness Index ,X-inactivation ,03 medical and health sciences ,0302 clinical medicine ,X Chromosome Inactivation ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Allele ,Gene ,Aged ,Genetics ,Chromosomes, Human, X ,Sequence Analysis, RNA ,business.industry ,RNA ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Fabry disease ,Phenotype ,alpha-Galactosidase ,Leukocytes, Mononuclear ,Fabry Disease ,Female ,business - Abstract
Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity. Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%). We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
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- 2021
15. Aberrant splicing caused by exonic single nucleotide variants positioned 2nd or 3rd to the last nucleotide in the COL4A5 gene
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Eri Okada, Yuya Aoto, Tomoko Horinouchi, Tomohiko Yamamura, Yuta Ichikawa, Yu Tanaka, Chika Ueda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, Ryota Suzuki, Joichi Usui, Kunihiro Yamagata, Kazumoto Iijima, and Kandai Nozu
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Nephrology ,Physiology ,Physiology (medical) - Abstract
Background and objectivesThe evident genotype–phenotype correlation shown by the X-linked Alport syndrome warrants the assessment of the impact of identified gene variants on aberrant splicing. We previously reported that single nucleotide variants (SNVs) in the last nucleotide of exons inCOL4A5cause aberrant splicing. It is known that the nucleotides located 2nd and 3rd to the last nucleotides of exons can also play an essential role in the first step of the splicing process. In this study, we aimed to investigate whether SNVs positioned 2nd or 3rd to the last nucleotide of exons inCOL4A5resulted in aberrant splicing.MethodsWe selected eight candidate variants: six from the Human Gene Variant Database Professional and two from our cohort. We performed anin-vitrosplicing assay and reverse transcription-polymerase chain reaction (RT-PCR) for messenger RNA obtained from patients, if available.ResultsThe candidate variants were initially classified into the following groups: three nonsense, two missense, and three synonymous variants. Splicing assays and RT-PCR for messenger RNA revealed that six of the eight variants caused aberrant splicing. Four variants, initially classified as non-truncating variants, were found to be truncating ones, which usually show relatively more severe phenotypes.ConclusionWe revealed that exonic SNVs positioned 2nd or 3rd to the last nucleotide of exons in theCOL4A5were responsible for aberrant splicing. The results of our study suggest that attention should be paid when interpreting the pathogenicity of exonic SNVs near the 5′ splice site.
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- 2022
16. Association of kidney transplantation with mortality on hemodialysis after graft failure
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Ikuto Masakane, Takehiko Kawaguchi, Atsushi Wada, Eri Okada, Toshiyuki Imasawa, Moritoshi Kadomura, and Takayuki Hamano
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Nephrology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Hazard ratio ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Propensity score matching ,Medicine ,Hemodialysis ,business ,Prospective cohort study ,Kidney transplantation ,Dialysis ,Cohort study - Abstract
Although a substantial number of patients return to dialysis after kidney transplant failure, it remains controversial whether transplant-failure patients have a higher mortality risk than transplant-naive patients on dialysis who have never undergone kidney transplantation. We compared outcomes of transplant-failure and transplant-naive patients on hemodialysis. Data from the Japanese National Dialysis Registry (2012–2013) were analyzed, including 220,438 prevalent hemodialysis patients. Multivariable Cox models were used to compare all-cause, cardiovascular, and infection-related mortality during 1-year follow-up between transplant-failure and transplant-naive patients. Multiple imputation and propensity score matching were utilized as sensitivity analyses. During 209,377 patient-years of follow-up, 18,648 all-cause deaths (8.5% of all patients), 7700 cardiovascular deaths (41% of all-cause deaths), and 3806 infection-related deaths (20% of all-cause deaths) were observed. Adjusted hazard ratios [95% confidence intervals] for all-cause, cardiovascular, and infection-related deaths among transplant-failure patients were 0.81 [0.59–1.11], 0.54 [0.30–0.98], and 1.54 [0.92–2.59], respectively. Sensitivity analyses using multiple imputation and propensity score matching yielded similar results. This Japanese cohort study suggested that a cardiovascular mortality risk of transplant-failure patients could be significantly lower than that of transplant-naive patients, while there might be a trend toward a higher infection-related mortality risk in transplant-failure patients. However, this retrospective, single-country study can introduce an immortal time bias in transplant-failure patients, and limit the external validity. Further prospective studies are warranted to improve the comparability of outcomes between transplant-failure and transplant-naive patients, and to examine worldwide the generalizability of the potential cardiovascular benefit of kidney transplantation even after returning to dialysis.
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- 2021
17. All Reported Non-Canonical Splice Site Variants in GLA Cause Aberrant Splicing
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Eri Okada, Tomoko Horinouchi, Tomohiko Yamamura, Yuya Aoto, Ryota Suzuki, Yuta Ichikawa, Yu Tanaka, Chika Masuda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, Shinya Ishiko, China Nagano, Shingo Ishimori, Joichi Usui, Kunihiro Yamagata, Masafumi Matsuo, and Kandai Nozu
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History ,Polymers and Plastics ,Nephrology ,Physiology ,Physiology (medical) ,Business and International Management ,Industrial and Manufacturing Engineering - Abstract
Background Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene. Methods 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants. Results All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner. Conclusions Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes.
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- 2022
18. Polydactyly-derived allogeneic chondrocyte cell-sheet transplantation with high tibial osteotomy as regenerative therapy for knee osteoarthritis
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Kosuke Hamahashi, Eriko Toyoda, Miya Ishihara, Genya Mitani, Tomonori Takagaki, Nagatoshi Kaneshiro, Miki Maehara, Takumi Takahashi, Eri Okada, Ayako Watanabe, Yoshihiko Nakamura, Reiko Kato, Ryo Matoba, Takehiko Takagi, Hidenori Akutsu, Akihiro Umezawa, Hiroyuki Kobayashi, Tadashi Akamatsu, Masayuki Yamato, Teruo Okano, Masahiko Watanabe, and Masato Sato
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Biomedical Engineering ,Medicine (miscellaneous) ,Cell Biology ,Developmental Biology - Abstract
Allogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.
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- 2021
19. ODP279 A Case of Nephrogenic Diabetes Insipidus Diagnosed at an Advanced Age in a Female Patient with an AVPR2 Gene Mutation and Skewed×Inactivation
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Kento Nakata, Hiraku Kameda, Saki Kuwabara, Ayano Yasui, Yuka Takahashi, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Eri Okada, Kandai Nozu, and Tatsuya Atsumi
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Endocrinology, Diabetes and Metabolism - Abstract
Background Arginine vasopressin receptor 2 (AVPR2) gene mutationsare the most common cause of congenital nephrogenic diabetes insipidus (CNDI), and they are inherited in an X-linked recessive manner. Women are generally asymptomatic or mildly affected, but atypically severe cases have been reported. Skewed X inactivation, in which the X chromosome is unevenly active, is a cause of this atypical severe case.×chromosome inactivation is a developmental compensation mechanism that results in equal doses of X-linked genes between XX females and XY males and has been reported to be accentuated by aging. Clinical Case A 69-year-old woman had no family history of diabetes insipidus. Immediately after undergoing a craniotomy for subarachnoid hemorrhage in July, she showed marked polyuria of approximately 8000 mL/day and hypernatremia of 161 mEq/L. The use of desmopressin (15mcg/kg/day) did not improve herpolyuria. She was referred to our department in September for further investigation and treatment. Her urine osmolality remained hypotonic at approximately 60–80 mOsm/kg/H 2 O (50–1300 mOsm/kg/H 2 O) according to a water restriction test. Her urine osmolality increased slightly to 106 mOsm/kg/H 2 O in a desmopressin test. These results indicated that desmopressin was ineffective, and the patient was diagnosed with nephrogenic diabetes. Her urine output decreased to approximately 2500 mL/day with trichlormethiazide treatment. There was no significant anterior pituitary hypofunction. Genetic examination revealed a heterozygous mutation of the AVPR2 gene (c.656T>G, p. Leu219Arg) in her X chromosome, and her X chromosome activity ratio was 79: 21 in a human androgen receptor assay, indicating skewed X inactivation. Conclusion We observed a case of CNDI in an elderly woman with no family history of the disease. In this case, a combination of the skewed X inactivation, presumably accentuated by aging, and the onset of subarachnoid hemorrhage, reduced her drinking water and led to the diagnosis of CNDI. References: (1)K. Kinoshita et al, J. Endocrinol. Invest. 27: 167-170, 2004. (2)Ding C et al, Am J Med Genet Part A. 2020; 182A: 1032–1040. (3)Y. Nomura et al, Journal of Clinical Endocrinology and Metabolism: 3434-3437, 1997. Presentation: No date and time listed
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- 2022
20. Detecting
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Eri, Okada, Naoya, Morisada, Tomoko, Horinouchi, Hideki, Fujii, Takayuki, Tsuji, Masayoshi, Miura, Hideyuki, Katori, Masashi, Kitagawa, Kunio, Morozumi, Takanobu, Toriyama, Yuki, Nakamura, Ryuta, Nishikomori, Sadayuki, Nagai, Atsushi, Kondo, Yuya, Aoto, Shinya, Ishiko, Rini, Rossanti, Nana, Sakakibara, China, Nagano, Tomohiko, Yamamura, Shingo, Ishimori, Joichi, Usui, Kunihiro, Yamagata, Kazumoto, Iijima, Toshiyuki, Imasawa, and Kandai, Nozu
- Abstract
Autosomal dominant tubulointerstitial kidney disease (ADTKD)-From January 2015 to December 2019, genetic analysis was performed using an SRS in 48 patients with clinically suspected ADTKD. Additional analyses were conducted using an LRS in patients with negative SRS results.Short-read sequencing results revealedIn Japan, the detection rate of
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- 2021
21. Evaluation of Suspected Autosomal Alport Syndrome Synonymous Variants
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Koichi Nakanishi, Masafumi Matsuo, Takeshi Ninchoji, Eri Okada, Masahiko Nagahama, Tomohiko Yamamura, Yuya Aoto, Kazumoto Iijima, Kandai Nozu, Nana Sakakibara, Rini Rossanti, Sadayuki Nagai, Tomoko Horinouchi, Yuko Shima, Shinya Ishiko, Keiichi Tamagaki, Hiroaki Nagase, Satoshi Matsui, China Nagano, Yoshifumi Ubara, Shingo Ishimori, and Atsushi Kondo
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Genetics ,Collagen Type IV ,Messenger RNA ,business.industry ,In silico ,Nephritis, Hereditary ,General Medicine ,Exons ,medicine.disease ,Autoantigens ,Exon skipping ,RNA splicing ,medicine ,Humans ,Alport syndrome ,Synonymous substitution ,business ,Gene ,Silent Mutation ,Minigene ,Original Investigation - Abstract
BACKGROUND: Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many pathogenic variants in COL4A3 and COL4A4 have been identified in patients with autosomal Alport syndrome, synonymous mutations in these genes have rarely been identified. METHODS: We conducted in silico splicing analysis using Human Splicing Finder (HSF) and Alamut to predict splicing domain strength and disruption of the sites. Furthermore, we performed in vitro splicing assays using minigene constructs and mRNA analysis of patient samples to determine the pathogenicity of four synonymous variants detected in four patients with suspected autosomal dominant Alport syndrome (COL4A3 [c.693G>A (p.Val231=)] and COL4A4 [c.1353C>T (p.Gly451=), c.735G>A (p.Pro245=), and c.870G>A (p.Lys290=)]). RESULTS: Both in vivo and in vitro splicing assays showed exon skipping in two out of the four synonymous variants identified (c.735G>A and c.870G>A in COL4A4). Prediction analysis of wild-type and mutated COL4A4 sequences using HSF and Alamut suggested these two variants may lead to the loss of binding sites for several splicing factors, e.g., in acceptor sites and exonic splicing enhancers. The other two variants did not induce aberrant splicing. CONCLUSIONS: This study highlights the pitfalls of classifying the functional consequences of variants by a simple approach. Certain synonymous variants, although they do not alter the amino acid sequence of the encoded protein, can dramatically affect pre-mRNA splicing, as shown in two of our patients. Our findings indicate that transcript analysis should be carried out to evaluate synonymous variants detected in patients with autosomal dominant Alport syndrome.
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- 2021
22. Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases
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Takeshi Ninchoji, Yuya Aoto, Tomohiko Yamamura, Hiroshi Kaito, Sadayuki Nagai, Eri Okada, Naoya Morisada, Hiroaki Nagase, Koichi Nakanishi, Yuko Shima, Shinya Ishiko, Rini Rossanti, China Nagano, Hiroki Takeda, Atsushi Kondo, Kandai Nozu, Tomoko Horinouchi, Kazumoto Iijima, Nana Sakakibara, and Takashi Omori
- Subjects
Adult ,Male ,Heterozygote ,Adolescent ,Science ,Ethnic group ,Prevalence ,computer.software_genre ,Genome ,Article ,Young Adult ,Medical research ,Tubulopathy ,Asian People ,Gene Frequency ,Genetics ,Ethnicity ,Missense mutation ,Medicine ,Humans ,Solute Carrier Family 12, Member 3 ,Allele ,Allele frequency ,Alleles ,Multidisciplinary ,Database ,business.industry ,Genome, Human ,Genetic Variation ,Gitelman syndrome ,medicine.disease ,Phenotype ,Nephrology ,Female ,business ,computer ,Gitelman Syndrome - Abstract
Gitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy–Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.
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- 2021
23. Identification of novel OCRL isoforms associated with phenotypic differences between Dent disease-2 and Lowe syndrome
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Hiroaki Nagase, Hikaru Kitahara, Takeshi Ninchoji, Yoshinori Araki, Ryojiro Tanaka, Toru Igarashi, Shinya Ishiko, Kazumoto Iijima, Kandai Nozu, Eri Okada, Koji Nagatani, Naoya Morisada, Kumiko Jinnouchi, Nana Sakakibara, Takeshi Ijuin, Shogo Minamikawa, Taro Okada, China Nagano, Toju Tanaka, Mari S Harada, Takeshi Matsuyama, Tomoko Horinouchi, Rini Rossanti, Yasufumi Ohtsuka, Koichi Kamei, Yuya Aoto, Shun-ichi Nakamura, Hiroyuki Awano, Masafumi Oka, and Tomohiko Yamamura
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Gene isoform ,Dent Disease ,Transplantation ,Messenger RNA ,business.industry ,Transfection ,Phenotype ,Molecular biology ,In vitro ,Phosphoric Monoester Hydrolases ,Exon ,Oculocerebrorenal Syndrome ,Nephrology ,Mutation ,Medicine ,Humans ,Protein Isoforms ,OCRL ,business ,HeLa Cells - Abstract
Background Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1–7 lead to Dent disease-2, whereas those in exons 8–24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms. Methods Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5′ end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells. Results We successfully cloned the novel isoform transcripts from OCRL exons 6–24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained Conclusions We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.
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- 2021
24. Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome
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Masafumi Matsuo, Yuko Shima, Eriko Tanaka, Koichi Nakanishi, Yurika Tsuji, Tomohiko Yamamura, China Nagano, Kandai Nozu, Kazumoto Iijima, Yoshinori Araki, Takayuki Okamoto, Hiroaki Nagase, Nana Sakakibara, Yuya Aoto, Eri Okada, Toshihiro Sawai, Shinya Ishiko, Koji Tsugawa, Tomoko Horinouchi, and Rini Rossanti
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Genetics ,business.industry ,minigene assay ,Intron ,Chromosome ,transcript analysis ,genotype-phenotype correlation ,medicine.disease ,Phenotype ,Frasier syndrome ,systematic review ,Nephrology ,Clinical Research ,RNA splicing ,Genotype ,medicine ,Allele ,business ,Minigene - Abstract
Introduction Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1. For wild-type WT1, 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or −KTS]), and imbalance of the +KTS/−KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated. Methods We conducted an in vitro minigene splicing assay for 6 reported causative variants and in vivo RNA sequencing to determine the +KTS/−KTS ratio using patients’ samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype. Results The in vitro assay revealed that although all mutant alleles produced −KTS transcripts only, the wild-type allele produced both +KTS and −KTS transcripts at a 1:1 ratio. In vivo RNA sequencing showed that patients’ samples with all heterozygous variants produced similar ratios of +KTS to −KTS (1:3.2−1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period. Conclusion Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS., Graphical abstract
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- 2021
25. Tubulointerstitial Nephritis Associated with Enteritis and Sacroiliitis
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Daisuke Ichikawa, Masahiko Yazawa, Junki Koike, Eri Okada, Tomo Suzuki, Yugo Shibagaki, and Shu Ushimaru
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Adult ,Male ,medicine.medical_specialty ,Case Report ,030204 cardiovascular system & hematology ,Gastroenterology ,Enteritis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Humans ,tubulointerstitial nephritis ,Sacroiliitis ,enteritis ,Pathological ,Kidney ,Granuloma ,medicine.diagnostic_test ,business.industry ,General Medicine ,medicine.disease ,Tubulointerstitial Nephritis ,Ulcerative colitis ,medicine.anatomical_structure ,Nephritis, Interstitial ,030211 gastroenterology & hepatology ,Renal biopsy ,business - Abstract
The association between sacroiliitis and tubulointerstitial nephritis has not been reported. A 28-year-old man with a history of clinically diagnosed ulcerative colitis (4 years earlier) and sacroiliitis (6 months earlier) developed renal dysfunction 9 months ago, which progressed thereafter. We diagnosed him with tubulointerstitial nephritis by a renal biopsy, for which we started steroid therapy. Subsequently, his renal dysfunction, sacroiliitis, and enteritis partially improved. A pathological analysis of the kidney and intestine revealed lymphocyte infiltration and non-caseating granuloma in both organs. The similarities in the pathological findings and treatment response suggested a pathogenetic association between tubulointerstitial nephritis, enteritis, and sacroiliitis.
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- 2019
26. Development of Injectable Polydactyly-Derived Chondrocyte Sheets
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Takumi Takahashi, Masahiko Watanabe, Eri Okada, Miki Maehara, Eriko Toyoda, Masato Sato, Shiho Wasai, Ryoka Uchiyama, and Tadashi Akamatsu
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Cartilage, Articular ,Pathology ,medicine.medical_specialty ,Cell Survival ,Cell ,Gene Expression ,cell sheet ,Cell Count ,Osteoarthritis ,Catalysis ,Chondrocyte ,Article ,Flow cytometry ,Immunophenotyping ,minimally invasive treatment ,Inorganic Chemistry ,lcsh:Chemistry ,Chondrocytes ,medicine ,Animals ,Humans ,Regeneration ,Viability assay ,Physical and Theoretical Chemistry ,cartilage regeneration ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,medicine.diagnostic_test ,Tissue Scaffolds ,Chemistry ,Organic Chemistry ,Histology ,General Medicine ,Articular cartilage damage ,medicine.disease ,Immunohistochemistry ,Computer Science Applications ,Transplantation ,Polydactyly ,osteoarthritis ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,Biomarkers - Abstract
We are conducting a clinical study of the use of allogeneic polydactyly-derived chondrocyte sheets (PD sheets) for the repair of articular cartilage damage caused by osteoarthritis. However, the transplantation of PD sheets requires highly invasive surgery. To establish a less invasive treatment, we are currently developing injectable fragments of PD sheets (PD sheets-mini). Polydactyly-derived chondrocytes were seeded in RepCell™ or conventional temperature-responsive inserts and cultured. Cell counts and viability, histology, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR), and flow cytometry were used to characterize PD sheets-mini and PD sheets collected from each culture. To examine the effects of injection on cell viability, PD sheets-mini were tested in four experimental conditions: non-injection control, 18 gauge (G) needle, 23G needle, and syringe only. PD sheets-mini produced similar amounts of humoral factors as PD sheets. No histological differences were observed between PD sheets and PD sheets-mini. Except for COL2A1, expression of cartilage-related genes did not differ between the two types of PD sheet. No significant differences were observed between injection conditions. PD sheets-mini have characteristics that resemble PD sheets. The cell viability of PD sheets-mini was not significantly affected by needle gauge size. Intra-articular injection may be a feasible, less invasive method to transplant PD sheets-mini.
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- 2021
27. X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay
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Rini Rossanti, Kandai Nozu, Atsushi Fukunaga, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Nana Sakakibara, Shogo Minamikawa, Shinya Ishiko, Yuya Aoto, Eri Okada, Takeshi Ninchoji, Noritoshi Kato, Shoichi Maruyama, Shinichi Nishi, Kazumoto Iijima, and Hideki Fujii
- Abstract
Background: Fabry disease is an X-linked inherited lysosomal storage disorder related to GLA mutations, gene encoding α-galactosidase A. In general, males has severe phenotype, while females has a wide spectrum of sign and symptoms, from asymptomatic to a more classical profile including cardiac, renal, and cerebrovascular manifestations. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Some previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to determine the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. Methods: We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing, the latter being a method that we recently developed. Results: Among all cases, skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with a severe phenotype. In the other eight cases, no skewing was observed, even among cases with severe phenotypes. Conclusions: We conclude that skewed XCI could explain the severity of Fabry disease in only a limited number of female cases and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
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- 2020
28. Association of kidney transplantation with mortality on hemodialysis after graft failure
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Takehiko, Kawaguchi, Takayuki, Hamano, Ikuto, Masakane, Atsushi, Wada, Eri, Okada, Moritoshi, Kadomura, and Toshiyuki, Imasawa
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Cohort Studies ,Renal Dialysis ,Humans ,Kidney Failure, Chronic ,Kidney Diseases ,Kidney Transplantation ,Retrospective Studies - Abstract
Although a substantial number of patients return to dialysis after kidney transplant failure, it remains controversial whether transplant-failure patients have a higher mortality risk than transplant-naïve patients on dialysis who have never undergone kidney transplantation. We compared outcomes of transplant-failure and transplant-naïve patients on hemodialysis.Data from the Japanese National Dialysis Registry (2012-2013) were analyzed, including 220,438 prevalent hemodialysis patients. Multivariable Cox models were used to compare all-cause, cardiovascular, and infection-related mortality during 1-year follow-up between transplant-failure and transplant-naïve patients. Multiple imputation and propensity score matching were utilized as sensitivity analyses.During 209,377 patient-years of follow-up, 18,648 all-cause deaths (8.5% of all patients), 7700 cardiovascular deaths (41% of all-cause deaths), and 3806 infection-related deaths (20% of all-cause deaths) were observed. Adjusted hazard ratios [95% confidence intervals] for all-cause, cardiovascular, and infection-related deaths among transplant-failure patients were 0.81 [0.59-1.11], 0.54 [0.30-0.98], and 1.54 [0.92-2.59], respectively. Sensitivity analyses using multiple imputation and propensity score matching yielded similar results.This Japanese cohort study suggested that a cardiovascular mortality risk of transplant-failure patients could be significantly lower than that of transplant-naïve patients, while there might be a trend toward a higher infection-related mortality risk in transplant-failure patients. However, this retrospective, single-country study can introduce an immortal time bias in transplant-failure patients, and limit the external validity. Further prospective studies are warranted to improve the comparability of outcomes between transplant-failure and transplant-naïve patients, and to examine worldwide the generalizability of the potential cardiovascular benefit of kidney transplantation even after returning to dialysis.
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- 2020
29. Regenerative effects of human chondrocyte sheets in a xenogeneic transplantation model using immune‐deficient rats
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Masahiko Watanabe, Yasuyuki Sogo, Miki Maehara, Eri Okada, Masato Sato, Ayako Tominaga, Takumi Takahashi, Daichi Takizawa, and Eriko Toyoda
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Pathology ,medicine.medical_specialty ,Allogeneic transplantation ,Transplantation, Heterologous ,0206 medical engineering ,chondrocytes ,Biomedical Engineering ,Pain ,Medicine (miscellaneous) ,02 engineering and technology ,articular ,Regenerative medicine ,Chondrocyte ,Biomaterials ,03 medical and health sciences ,preclinical ,medicine ,Animals ,Humans ,Regeneration ,cartilage ,Research Articles ,Aged ,030304 developmental biology ,allogeneic ,Wound Healing ,0303 health sciences ,business.industry ,Hyaline cartilage ,Cartilage ,Regeneration (biology) ,Synoviocytes ,020601 biomedical engineering ,Rats ,Transplantation ,Disease Models, Animal ,surgical procedures, operative ,medicine.anatomical_structure ,xenogeneic transplantation ,Fibrocartilage ,business ,Research Article ,transplantation - Abstract
Although cell transplantation has attracted much attention in regenerative medicine, animal models continue to be used in translational research to evaluate safety and efficacy because cell sources and transplantation modalities are so diverse. In the present study, we investigated the regenerative effects of human chondrocyte sheets on articular cartilage in a xenogeneic transplantation model using immune‐deficient rats. Osteochondral defects were created in the knee joints of immune‐deficient rats that were treated as Group A, untreated (without transplantation); Group B, transplantation of a layered chondrocyte sheet containing 5.0 × 105 cells (layered chondrocyte sheet transplantation); Group C, transplantation of a synoviocyte sheet containing 5.0 × 105 cells (synoviocyte sheet transplantation); or Group D, transplantation of both a synoviocyte sheet plus a layered chondrocyte sheet, each containing 5.0 × 105 cells (synoviocyte sheet plus layered chondrocyte sheet transplantation). Histological evaluation demonstrated that Group B showed cartilage regeneration with hyaline cartilage and fibrocartilage. In Groups C and D, the defect was filled with fibrous tissue but no hyaline cartilage. Transplanted cells were detected at 4 and 12 weeks after transplantation, but the number of cells had decreased at 12 weeks. Our results indicate that layered chondrocyte sheet transplantation contributes to articular cartilage regeneration; this model proved useful for evaluating these regenerative effects.
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- 2020
30. Characteristics of autologous protein solution and leucocyte-poor platelet-rich plasma for the treatment of osteoarthritis of the knee
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Masahiko Watanabe, Satoko Suzuki, Takumi Takahashi, Eriko Toyoda, Miki Maehara, Eri Okada, Yoshiko Iwasaki, Shiho Wasai, Ryoka Uchiyama, and Masato Sato
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Male ,0301 basic medicine ,Necrosis ,medicine.medical_treatment ,Interleukin-1beta ,Anti-Inflammatory Agents ,lcsh:Medicine ,Osteoarthritis ,Fibroblast growth factor ,0302 clinical medicine ,Japan ,Leukocytes ,lcsh:Science ,Aged, 80 and over ,Platelet-Derived Growth Factor ,030222 orthopedics ,Multidisciplinary ,Platelet-Rich Plasma ,Middle Aged ,Osteoarthritis, Knee ,Receptor antagonist ,Leukocyte Transfusion ,Cytokines ,Female ,Tumor necrosis factor alpha ,medicine.symptom ,Adult ,medicine.medical_specialty ,medicine.drug_class ,Predictive markers ,Article ,Proinflammatory cytokine ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Medical research ,Asian People ,Internal medicine ,medicine ,Humans ,Aged ,Tumor Necrosis Factor-alpha ,business.industry ,Growth factor ,lcsh:R ,medicine.disease ,030104 developmental biology ,Endocrinology ,Risk factors ,Platelet-rich plasma ,lcsh:Q ,business - Abstract
Recently, platelet-rich plasma (PRP) has received attention as a treatment for patients with osteoarthritis of the knee (OAK), a chronic degenerative disease, to bridge the gap between conservative and surgical treatments. Here, we investigated the differences in the humoral factors present in two types of PRP purified using the Autologous Protein Solution (APS) kit (group Z; leucocyte-rich PRP) or the Cellaid Serum Collection Set P type (group J; leucocyte-poor [LP]-PRP). Differences in humoral factors between healthy subjects (n = 10) and OAK patients (n = 12; group Z = 6, group J = 6), and the relationship between humoral factors and clinical outcome scores were investigated. Both anti-inflammatory and inflammatory cytokines were highly enriched in APS. The concentrations of tumour necrosis factor (TNF)-α, platelet-derived growth factor, fibroblast growth factor, soluble TNF-receptor 2, soluble Fas and transforming growth factor-β1 were higher in group Z, while the total amounts were higher in group J. The concentration of interleukin-1 receptor antagonist was positively correlated with the magnitude of change in the clinical outcome score and may contribute to improving knee-joint function. This is the first description of the humoral factors in APS and LP-PRP prepared from healthy subjects or OAK patients of Asian descent.
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- 2020
31. P0370RELATIONSHIP BETWEEN ATTENUATION OF C3 GLOMERULAR DEPOSITION AND CLINICAL PROGNOSIS IN IGA NEPHROPATHY: REPEAT-BIOPSY BASED OBSERVATION
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Azumi Fukuta, Mizuho Morooka, Kazuyuki Ri, Eri Okada, Akane Miura, Takehiko Kawaguchi, Masahiro Hyodo, Hiroshi Kitamura, Toshiyuki Imasawa, and Moritoshi Kadomura
- Subjects
Immunoglobulin A ,Transplantation ,Pathology ,medicine.medical_specialty ,Creatinine ,Repeat biopsy ,biology ,medicine.diagnostic_test ,business.industry ,Urinary system ,medicine.disease ,Nephropathy ,chemistry.chemical_compound ,Clinical prognosis ,chemistry ,Nephrology ,Biopsy ,biology.protein ,Medicine ,business ,Survival analysis - Abstract
Background and Aims In IgA nephropathy (IgAN), mesangial IgA deposition activates the complement systems and amplifies the local inflammation, resulting in renal injuries. Although previous studies based on repeat biopsies suggested that the change of MEST-C scores of Oxford classification might be related to the prognosis, there have been few reports about immunofluorescence (IF) changes in repeat biopsies. In this study, we aimed to elucidate the relationship between the changes in the degree of glomerular IgA and C3 depositions and clinical prognosis of IgAN based on repeat biopsy observation. Method Fifty-five patients with IgAN who underwent repeat biopsies at our hospital between 2000 and 2019 were analyzed retrospectively. IF staining in each case was graded with a semiquantitative scale from 0 to 3 (0, negative; 1, weak; 2, moderate; 3, strong staining). MEST-C scores of the Oxford classification were also evaluated. When each score of IF staining or MEST-C in second biopsy was less compared with that in the first biopsy, it was regarded as “improved”. The primary outcome was the time to achieve complete remission (CR), which is defined as disappearance of both urinary protein (UP) ( Results Twenty-seven patients (48%) were male. At the first biopsy, median age and eGFR were 38.5 years (Interquartile ratio (IQR) 17-49) and 92 mL/min/1.73 m2 (IQR 63-108). Median urinary protein creatinine ratio was 0.6 g/gCr (IQR 0.3-1.7) and 45 patients (80%) had microhematuria. Thirty-three patients (59%) were treated by renin angiotensin system inhibitors and forty-three patients (78%) were treated by immunosuppressive therapy. Median period between the two biopsies was 36 months (IQR 25-55). Median IF scores of glomerular IgA and C3 were 2 (IQR 2-3) and 2 (IQR 1-2) in the first biopsies and 2 (IQR 1-2) and 1 (IQR 1-2) in the second biopsies, respectively. During the median 55 months (IQR 17-99) follow up period, disappearance of UP and microhematuria were observed in 47 (84%) and 36 (64%). Thirty-three (59%) patients reached CR. Improvement of the degree of C3 deposition between two biopsies was significantly associated with CR (Hazard ratio (HR) 0.37; 95% confidential interval (CI) 0.17-0.80, p=0.012), while that of IgA deposition had no association (HR 057; CI 0.27-1.19, p=0.125). Improvement of the degree of C3 deposition was also significantly associated with disappearance of microhematuria (HR 0.45; 95%CI 0.24-0.86, p=0.016), but not with disappearance of UP (HR 0.60; 95%CI 0.34-1.2, p=0.15). Multivariate linear regression revealed that the rate of eGFR decline was not related to IF scores. Any of the Oxford classification scores were not associated with these outcomes. Conclusion Attenuation of glomerular C3 deposition is associated with CR. This suggest that C3 deposition, rather than IgA deposition, may be related with the clinical prognosis of IgAN.
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- 2020
32. Intra-articular administration of EP2 enhances the articular cartilage repair in a rabbit model
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Yoshiki Tani, Shinsei Fujimura, Masayuki Yamato, Teruo Okano, Eri Okada, Munetaka Yokoyama, Miyuki Yokoyama, Hideyuki Maruki, Eriko Toyoda, Takumi Takahashi, Masato Sato, Joji Mochida, and Yoshiharu Kato
- Subjects
Cartilage, Articular ,0301 basic medicine ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Biomedical Engineering ,Medicine (miscellaneous) ,Knee Injuries ,Group A ,Chondrocyte ,Group B ,Biomaterials ,03 medical and health sciences ,Chondrocytes ,Internal medicine ,Articular cartilage repair ,Animals ,Urea ,Medicine ,business.industry ,Antagonist ,Histology ,Receptors, Prostaglandin E, EP2 Subtype ,Allografts ,Pyridazines ,Transplantation ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Models, Animal ,Rabbits ,business ,Signal Transduction - Abstract
We have reported the usefulness of chondrocyte sheets on articular cartilage repair in animal experiments. Here, we investigated the regenerative effects of EP2 signalling with or without chondrocyte sheets. Forty-five rabbits were used, with six rabbits in each of the six groups and nine rabbits for chondrocytes and synovial cells harvesting to fabricate triple-layered chondrocyte sheets: osteochondral defect only (control, Group A), EP2 agonist (Group B), EP2 antagonist (Group C), chondrocyte sheets (Group D), EP2 agonist and chondrocyte sheets (Group E), and EP2 antagonist and chondrocyte sheets (Group F). After surgery, the weight distribution ratio was measured as an indicator of pain alleviation. Injections of the EP2 agonist or EP2 antagonist were given from 4 weeks after surgery. The rabbits were sacrificed at 12 weeks, and the repaired tissues were evaluated for histology. The weight distribution ratio and International Cartilage Repair Society grading were as follows: Group A: 40.5% ± 0.2%, 14.8 ± 0.5; Group B: 43.4% ± 0.7%, 25.4 ± 0.8; Group C: 38.7% ± 0.7%, 13.7 ± 0.3; Group D: 48.6% ± 0.6%, 40.2 ± 0.5; Group E: 49.1% ± 0.3%, 40.5 ± 0.4; and Group F; 46.8% ± 0.4%, 38.7 ± 0.5. Significant differences in histology and pain alleviation were observed between groups except between Groups A and C, between Groups D and E, and between Groups D and F. These findings show that the intra-articular administration of an EP2 agonist achieved pain alleviation and tissue repair. However, no synergistic effect with chondrocyte sheets was observed.
- Published
- 2018
33. Transcriptomic and Proteomic Analyses Reveal the Potential Mode of Action of Chondrocyte Sheets in Hyaline Cartilage Regeneration
- Author
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Ken Nonaka, Takumi Takahashi, Masahiko Watanabe, Masato Sato, Eri Okada, Shiho Wasai, Miki Maehara, Eriko Toyoda, Hiroshi Iijima, and Yuka Kawaguchi
- Subjects
0301 basic medicine ,Adult ,Cartilage, Articular ,Male ,Proteomics ,Adolescent ,Angiogenesis ,efficacy ,Angiogenesis Pathway ,cell sheet ,Enzyme-Linked Immunosorbent Assay ,02 engineering and technology ,Catalysis ,Chondrocyte ,Article ,Inorganic Chemistry ,Transcriptome ,lcsh:Chemistry ,03 medical and health sciences ,Young Adult ,Chondrocytes ,medicine ,Humans ,Physical and Theoretical Chemistry ,Child ,cartilage regeneration ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Cells, Cultured ,Chemistry ,Hyaline cartilage ,Cartilage ,Regeneration (biology) ,Organic Chemistry ,General Medicine ,021001 nanoscience & nanotechnology ,Computer Science Applications ,Cell biology ,Transplantation ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,xenogeneic transplantation model ,Female ,0210 nano-technology - Abstract
Chondrocyte sheet transplantation is a novel and promising approach to treating patients who have cartilage defects associated with osteoarthritis. Hyaline cartilage regeneration by autologous chondrocyte sheets has already been demonstrated in clinical research. In this study, the efficacy of polydactyly-derived chondrocyte sheets (PD sheets) as an allogeneic alternative to standard chondrocyte sheets was examined using an orthotopic xenogeneic transplantation model. In addition, the expression of genes and the secreted proteins in the PD sheets was analyzed using a microarray and a DNA aptamer array. The efficacy of PD sheets with respect to cartilage defects was assessed using histological scores, after which the expressions of genes and proteins exhibiting a correlation to efficacy were identified. Enrichment analysis of efficacy-correlated genes and proteins showed that they were associated with extracellular matrices, skeletal development, and angiogenesis. Eight genes (ESM1, GREM1, SERPINA3, DKK1, MIA, NTN4, FABP3, and PDGFA) exhibited a positive correlation with the efficacy of PD sheets, and three genes (RARRES2, APOE, and PGF) showed a negative correlation for both transcriptomic and proteomic analyses. Among these, MIA, DKK1, and GREM1 involved in skeletal development pathways and ESM1 involved in the angiogenesis pathway exhibited a correlation between the amount of secretion and efficacy. These results suggest that these secreted factors may prove useful for predicting PD sheet efficacy and may therefore contribute to hyaline cartilage regeneration via PD sheets.
- Published
- 2019
34. Spontaneous remission in adult patients with IgA nephropathy treated with conservative therapy
- Author
-
Eri Okada, Sayuri Shirai, Shiika Watanabe, Yugo Shibagaki, Tomo Suzuki, Daisuke Ichikawa, and Hirotaka Sato
- Subjects
Male ,Physiology ,Biopsy ,medicine.medical_treatment ,Remission, Spontaneous ,030232 urology & nephrology ,Spontaneous remission ,Urine ,030204 cardiovascular system & hematology ,Antiplatelet Therapy ,Conservative Treatment ,Kidney ,urologic and male genital diseases ,Steroid Therapy ,0302 clinical medicine ,Chronic Kidney Disease ,Medicine and Health Sciences ,Multidisciplinary ,Proteinuria ,Pharmaceutics ,Glomerulonephritis ,Prognosis ,female genital diseases and pregnancy complications ,Body Fluids ,Treatment Outcome ,Nephrology ,Medicine ,Female ,Anatomy ,medicine.symptom ,Immunosuppressive Agents ,Research Article ,Glomerular Filtration Rate ,Adult ,medicine.medical_specialty ,Science ,Corticosteroid Therapy ,Urology ,Renal function ,Surgical and Invasive Medical Procedures ,Nephropathy ,03 medical and health sciences ,Signs and Symptoms ,Drug Therapy ,Diagnostic Medicine ,Renal Diseases ,medicine ,Humans ,Hematuria ,Retrospective Studies ,High-power field ,urogenital system ,business.industry ,Biology and Life Sciences ,Glomerulonephritis, IGA ,Retrospective cohort study ,Renal System ,medicine.disease ,Tonsillectomy ,Clinical Medicine ,business - Abstract
Background There are few studies describing the clinical course and spontaneous remission of IgA nephropathy (IgAN) in adult patients receiving conservative treatment. Method Data from 62 adult patients with biopsy-diagnosed IgAN, who received conservative treatment at least 5 years prior, were retrospectively investigated. No patients received corticosteroids, other immunosuppressants, or tonsillectomy. Remission of proteinuria and hematuria were defined as proteinuria Result Thirty-eight (61.3%) patients had remission of hematuria, 24 (38.7%) had remission of proteinuria, and 19 (30.6%) had remission of both. Remission rates increased in patients with proteinuria Conclusions Relatively high rates of spontaneous remission were observed. Remission of both hematuria and proteinuria were frequent within 3 years after diagnosis, and renal function was well preserved during this period. These data indicate that it is rational to use conservative treatment for 3 years after the diagnosis instead of aggressive treatments.
- Published
- 2021
35. Diagnosis of Legionella pneumonia based on Legionella urinary antigen testing of serum instead of urine in a hemodialysis patient
- Author
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Mari Okajima, Maiko Kimura, Eri Okada, Moritoshi Kadomura, Masaki Uehara, Motonobu Nishimura, Satoshi Kumakura, Takafumi Yamakawa, Takehiko Kawaguchi, Satoshi Ishikawa, and Toshiyuki Imasawa
- Subjects
0301 basic medicine ,medicine.medical_specialty ,biology ,Legionella ,business.industry ,Urinary system ,medicine.medical_treatment ,030106 microbiology ,Legionella Pneumonia ,Urine ,biology.organism_classification ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,Hemodialysis ,business ,Antigen testing - Published
- 2017
36. FP357The glomerular hyperfiltration theory may not be applied to the progression of benign nephrosclerosis
- Author
-
Takehiko Kawaguchi, Masaki Uehara, Ikuro Mori, Moritoshi Kadomura, Azumi Fukuta, Eri Okada, Hiroshi Kitamura, Toshiyuki Imasawa, and Kazuyuki Ri
- Subjects
Transplantation ,medicine.medical_specialty ,Nephrology ,business.industry ,Benign nephrosclerosis ,Urology ,medicine ,business ,medicine.disease ,Glomerular hyperfiltration - Published
- 2019
37. Effects of a cell-free method using collagen vitrigel incorporating TGF-β1 on articular cartilage repair in a rabbit osteochondral defect model
- Author
-
Masato Sato, Shigehisa Aoki, Yoshiki Tani, Eriko Toyoda, Joji Mochida, Munetaka Yokoyama, Takumi Takahashi, Yoshiharu Kato, Eri Okada, Toshiaki Takezawa, and Hideyuki Maruki
- Subjects
0301 basic medicine ,Materials science ,0206 medical engineering ,Biomedical Engineering ,02 engineering and technology ,Cell free ,Anatomy ,020601 biomedical engineering ,Controlled release ,Group A ,In vitro ,Biomaterials ,Andrology ,03 medical and health sciences ,030104 developmental biology ,In vivo ,Articular cartilage repair ,Cartilage repair ,Transforming growth factor - Abstract
We studied the ability of collagen vitrigel material to repair cartilage in vivo when used alone or with transforming growth factor-β (TGF-β). We measured the time course and quantity of TGF-β1 released from the collagen vitrigel in vitro to quantify the controlled release of TGF-β1. Over 14 days, 0.91 ng of TGF-β was released from the collagen vitrigel. Osteochondral defects were made in the femoral trochlear groove in 36 Japanese white rabbits, which were divided into three groups: untreated group (group A), collagen vitrigel-implanted group (group B), and TGF-β1-incorporated collagen vitrigel-implanted group (group C). The weight distribution ratio between the affected and unaffected limbs served as an indicator of pain. Animals were sacrificed at 4 and 12 weeks after surgery, and their tissues were assessed histologically. The weight distribution ratio increased in all groups and did not differ significantly between groups at 12 weeks. Group A needed 6 weeks to attain maximum improvement, and groups B and C showed near-maximum improvement at 4 and 2 weeks, respectively. The International Cartilage Repair Society II score improved significantly in group C relative to the other groups. These findings suggest that sustained, slow release of TGF-β caused early pain mitigation and cartilage repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2592-2602, 2017.
- Published
- 2016
38. Rabbit xenogeneic transplantation model for evaluating human chondrocyte sheets used in articular cartilage repair
- Author
-
Masahiko Watanabe, Hideyuki Maruki, Ayako Tominaga, Masato Sato, Miki Maehara, Eriko Toyoda, Eri Okada, Daichi Takizawa, Takumi Takahashi, and Ken Okazaki
- Subjects
Cartilage, Articular ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Transplantation, Heterologous ,chondrocytes ,Biomedical Engineering ,Medicine (miscellaneous) ,articular ,Models, Biological ,Tacrolimus ,Chondrocyte ,Biomaterials ,03 medical and health sciences ,preclinical ,medicine ,Articular cartilage repair ,Animals ,Humans ,Regeneration ,cartilage ,Research Articles ,Aged ,Pain Measurement ,Aged, 80 and over ,Wound Healing ,business.industry ,Hyaline cartilage ,Regeneration (biology) ,Cartilage ,Immunosuppression ,Middle Aged ,allogeneic transplantation ,Transplantation ,030104 developmental biology ,medicine.anatomical_structure ,xenogeneic transplantation ,Fibrocartilage ,Rabbits ,business ,Biomarkers ,Research Article ,transplantation - Abstract
Research on cartilage regeneration has developed novel sources for human chondrocytes and new regenerative therapies, but appropriate animal models for translational research are needed. Although rabbit models are frequently used in such studies, the availability of immunocompromised rabbits is limited. Here, we investigated the usefulness of an immunosuppressed rabbit model to evaluate directly the efficacy of human chondrocyte sheets through xenogeneic transplantation. Human chondrocyte sheets were transplanted into knee osteochondral defects in Japanese white rabbits administered with immunosuppressant tacrolimus at a dosage of 0.8 or 1.6 mg/kg/day for 4 weeks. Histological evaluation at 4 weeks after transplantation in rabbits administered 1.6 mg/kg/day showed successful engraftment of human chondrocytes and cartilage regeneration involving a mixture of hyaline cartilage and fibrocartilage. No human chondrocytes were detected in rabbits administered 0.8 mg/kg/day, although regeneration of hyaline cartilage was confirmed. Histological evaluation at 12 weeks after transplantation (i.e., 8 weeks after termination of immunosuppression) showed strong immune rejection of human chondrocytes, which indicated that, even after engraftment, articular cartilage is not particularly immune privileged in xenogeneic transplantation. Our results suggest that Japanese white rabbits administered tacrolimus at 1.6 mg/kg/day and evaluated at 4 weeks may be useful as a preclinical model for the direct evaluation of human cell‐based therapies.
- Published
- 2018
39. Cartilage repair and inhibition of the progression of cartilage degeneration after transplantation of allogeneic chondrocyte sheets in a nontraumatic early arthritis model
- Author
-
Eriko Toyoda, Miki Maehara, Takumi Takahashi, Masahiko Watanabe, Eri Okada, Naoki Takatori, and Masato Sato
- Subjects
0301 basic medicine ,Pathology ,OA, Osteoarthritis ,endocrine system diseases ,PVDF, Polyvinylidene difluoride ,Osteoarthritis ,Group A ,Group B ,0302 clinical medicine ,IFP, Infrapatellar fat pad ,Medicine ,DPBS, Dulbecco's phosphate-buffered saline ,Cartilage degeneration ,Col2A1, Collagen type Ⅱalpha 1 ,lcsh:R5-920 ,DMEM, Dulbecco's modified Eagle's medium ,lcsh:Cytology ,EDTA, Ethylenediaminetetraacetic acid ,Col1A1, Collagen type Ⅰalpha 1 ,OARSI, Osteoarthritis research society international ,medicine.anatomical_structure ,Original Article ,lcsh:Medicine (General) ,Chondrocyte sheet ,Early arthritis ,Monoiodoacetic acid (MIA) ,OARSI score ,medicine.medical_specialty ,Biomedical Engineering ,Chondrocyte ,Biomaterials ,03 medical and health sciences ,lcsh:QH573-671 ,Cartilage repair ,030203 arthritis & rheumatology ,Transplantation ,AB, Antibiotic-antimycotic solution ,business.industry ,qPCR, Quantitative real-time polymerase chain reaction ,medicine.disease ,030104 developmental biology ,MIA, Monoiodoacetic acid ,FBS, Fetal bovine serum ,Mmp13, Matrix metalloproteinase-13 ,Comp, Cartilage oligomeric matrix protein ,business ,ITGa10, Integrin alpha-10 ,Acan, Aggrecan ,Developmental Biology - Abstract
Introduction Using a rat model of nontraumatic early arthritis induced by intra-articular administration of low-dose monoiodoacetic acid (MIA), we transplanted allogeneic chondrocyte sheets and examined the effects on tissue repair. Methods MIA (0.2 mg/50 μl) was injected into the right knee of 20 male Wistar rats. Four weeks later, rats were randomly allocated into three groups: Group A was examined 4 weeks after administration of MIA; Group B, 8 weeks after MIA injection and chondrocyte sheet transplantation, and Group C, 8 weeks after MIA injection but without chondrocyte sheet transplantation. Allogeneic chondrocyte sheets were transplanted into the right knee of Group B rats. Pain was assessed as the weight distribution ratio of the damaged to undamaged limb. The OARSI score was used for histological scoring. Results The limb weight distribution ratio indicated significantly less pain in Group B. Histological scoring showed significant differences in cartilage repair and inhibition of the progression of cartilage degeneration between Groups B and C, but not between Groups A and B, or Groups A and C. Conclusions These findings suggest that, in this rat model of nontraumatic early arthritis induced by low-dose MIA injection, allogeneic chondrocyte sheet transplantation induces cartilage repair and suppresses cartilage degeneration., Highlights • Therapeutic effects of allogeneic chondrocyte sheets were examined using an arthritis model of rat induced by low-dose MIA. • Chondrocyte sheets exhibited sufficient expression of genes important to maintaining a stable cartilage matrix. • Transplantation of chondrocyte sheets alleviated pain and induced cartilage repair and suppressed cartilage degeneration.
- Published
- 2018
40. TMEM55a localizes to macrophage phagosomes to down-regulate phagocytosis
- Author
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Yoshihiro Kasuu, Miho Yamada, Kiyomi Nigorikawa, Yoshimasa Tanaka, Satoshi Kofuji, Kaoru Hazeki, Shin Morioka, Shunsuke Takasuga, Takehiko Sasaki, Hiroki Nakanishi, and Eri Okada
- Subjects
Phosphatidylinositol 4,5-Diphosphate ,0301 basic medicine ,Phagocytic cup ,Phagocytosis ,Phosphatase ,Vesicular Transport Proteins ,Biology ,Phosphatidylinositols ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Phagosomes ,Animals ,Macrophage ,Phosphatidylinositol ,Phagosome ,Macrophages ,Cell Membrane ,Cell Biology ,Transfection ,In vitro ,Cell biology ,Phosphotransferases (Alcohol Group Acceptor) ,RAW 264.7 Cells ,030104 developmental biology ,chemistry ,Phosphoinositide Phosphatases ,030217 neurology & neurosurgery ,Protein Binding - Abstract
TMEM55a (also known as PIP4P2) is an enzyme that dephosphorylates the phosphatidylinositol (PtdIns) PtdIns(4,5)P2 to form PtdIns(5)P in vitro However, the in vivo conversion of the polyphosphoinositide into PtdIns(5)P by the phosphatase has not yet been demonstrated, and the role of TMEM55a remains poorly understood. Here, we found that mouse macrophages (Raw264.7) deficient in TMEM55a showed an increased engulfment of large particles without affecting the phagocytosis of Escherichia coli Transfection of a bacterial phosphatase with similar substrate specificity to TMEM55a, namely IpgD, into Raw264.7 cells inhibited the engulfment of IgG-erythrocytes in a manner dependent on its phosphatase activity. In contrast, cells transfected with PIP4K2a, which catalyzes PtdIns(4,5)P2 production from PtdIns(5)P, increased phagocytosis. Fluorescent TMEM55a transfected into Raw264.7 cells was found to mostly localize to the phagosome. The accumulation of PtdIns(4,5)P2, PtdIns(3,4,5)P3 and F-actin on the phagocytic cup was increased in TMEM55a-deficient cells, as monitored by live-cell imaging. Phagosomal PtdIns(5)P was decreased in the knockdown cells, but the augmentation of phagocytosis in these cells was unaffected by the exogenous addition of PtdIns(5)P. Taken together, these results suggest that TMEM55a negatively regulates the phagocytosis of large particles by reducing phagosomal PtdIns(4,5)P2 accumulation during cup formation.
- Published
- 2018
41. SP419ASSOCIATION BETWEEN GLOMERULAR CLASS AND RENAL PROGNOSIS IN DIABETIC NEPHROPATHY
- Author
-
Takafumi Yamakawa, Ikuro Mori, Azumi Yamada, Moritoshi Kadomura, Eri Okada, Masaki Uehara, Hiroshi Kitamura, Takehiko Kawaguchi, and Toshiyuki Imasawa
- Subjects
Diabetic nephropathy ,Transplantation ,Class (computer programming) ,Kidney ,medicine.medical_specialty ,medicine.anatomical_structure ,Nephrology ,business.industry ,Urology ,Medicine ,business ,medicine.disease - Published
- 2018
42. SP041GLOMERULAR SIZES SHOULD DEPEND ON THE TYPE OF GLOMERULAR DISEASE OR THE RENAL FUNCTION
- Author
-
Hiroshi Kitamura, Toshiyuki Imasawa, Azumi Yamada, Moritoshi Kadomura, Takehiko Kawaguchi, Eri Okada, Masaki Uehara, and Ikuro Mori
- Subjects
Transplantation ,medicine.medical_specialty ,Nephrology ,business.industry ,Urology ,Medicine ,Renal function ,Glomerular disease ,business - Published
- 2018
43. Effects of a cell-free method using collagen vitrigel incorporating TGF-β1 on articular cartilage repair in a rabbit osteochondral defect model
- Author
-
Hideyuki, Maruki, Masato, Sato, Toshiaki, Takezawa, Yoshiki, Tani, Munetaka, Yokoyama, Takumi, Takahashi, Eriko, Toyoda, Eri, Okada, Shigehisa, Aoki, Joji, Mochida, and Yoshiharu, Kato
- Subjects
Cartilage, Articular ,Drug Implants ,Transforming Growth Factor beta1 ,Animals ,Female ,Collagen ,Femur ,Rabbits - Abstract
We studied the ability of collagen vitrigel material to repair cartilage in vivo when used alone or with transforming growth factor-β (TGF-β). We measured the time course and quantity of TGF-β1 released from the collagen vitrigel in vitro to quantify the controlled release of TGF-β1. Over 14 days, 0.91 ng of TGF-β was released from the collagen vitrigel. Osteochondral defects were made in the femoral trochlear groove in 36 Japanese white rabbits, which were divided into three groups: untreated group (group A), collagen vitrigel-implanted group (group B), and TGF-β1-incorporated collagen vitrigel-implanted group (group C). The weight distribution ratio between the affected and unaffected limbs served as an indicator of pain. Animals were sacrificed at 4 and 12 weeks after surgery, and their tissues were assessed histologically. The weight distribution ratio increased in all groups and did not differ significantly between groups at 12 weeks. Group A needed 6 weeks to attain maximum improvement, and groups B and C showed near-maximum improvement at 4 and 2 weeks, respectively. The International Cartilage Repair Society II score improved significantly in group C relative to the other groups. These findings suggest that sustained, slow release of TGF-β caused early pain mitigation and cartilage repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2592-2602, 2017.
- Published
- 2016
44. A Comparison Study of Glucose Fluctuation During Automated Peritoneal Dialysis and Continuous Ambulatory Peritoneal Dialysis
- Author
-
Eri, Okada, Daisuke, Oishi, Tsutomu, Sakurada, Takashi, Yasuda, and Yugo, Shibagaki
- Subjects
Blood Glucose ,Glycated Hemoglobin ,Male ,Diabetes Mellitus, Type 1 ,Diabetes Mellitus, Type 2 ,Peritoneal Dialysis, Continuous Ambulatory ,Humans ,Hypoglycemic Agents ,Kidney Failure, Chronic ,Female ,Middle Aged ,Aged ,Retrospective Studies - Abstract
In recent years, it has become possible to examine an individual's daily glucose profile with a continuous glucose monitoring system (CGMS). The aim of the present study was to use a CGMS to evaluate the difference in glucose fluctuation between diabetic patients on automated peritoneal dialysis (APD) and those on continuous ambulatory peritoneal dialysis (CAPD). We retrospectively studied 20 diabetic patients on peritoneal dialysis (16 men, 4 women; mean age: 55 ± 10 years) who used a CGMS a total of 23 times (12 times by APD users, 11 times by CAPD users). The difference in the maximum and minimum blood glucose over 72 hours (ABG) and the standard deviation of blood glucose were used as indicators of glucose fluctuation. Average blood glucose levels as evaluated by CGMS and by glycosylated hemoglobin were not significantly different between the APD and CAPD patients. However, the ABG (181 ± 64 mg/dL vs. 238 ± 67 mg/dL, p = 0.02) and the standard deviation of blood glucose (36.3 ± 14.5 mg/dL vs. 49.2 ± 14.1 mg/dL, p = 0.03) were significantly lower in the APD patients than in the CAPD patients. The present study indicates that, compared with CAPD, APD might reduce glucose fluctuation in diabetic peritoneal dialysis patients.
- Published
- 2015
45. Assessment of the Safety of Chondrocyte Sheet Implantation for Cartilage Regeneration
- Author
-
Miyuki Yokoyama, Masato Sato, Akihiro Umezawa, Genya Mitani, Tomonori Takagaki, Munetaka Yokoyama, Tomoko Kawake, Eri Okada, Mami Kokubo, Noriko Ito, Yuko Takaku, Kunihiko Murai, Ryo Matoba, Hidenori Akutsu, Masayuki Yamato, Teruo Okano, and Joji Mochida
- Subjects
0301 basic medicine ,Cartilage, Articular ,Male ,Cell ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Osteoarthritis ,Mice, SCID ,Biology ,Chondrocyte ,03 medical and health sciences ,Chondrocytes ,In vivo ,medicine ,Bioluminescence imaging ,Animals ,Regeneration ,Cells, Cultured ,Tissue Scaffolds ,Guided Tissue Regeneration ,Cartilage ,Regeneration (biology) ,Equipment Design ,medicine.disease ,Cell biology ,Rats ,Equipment Failure Analysis ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Rats, Inbred Lew ,Stem cell ,Biomedical engineering - Abstract
We have previously studied the effects of chondrocyte sheets on the repair and regeneration of articular cartilage by using temperature-responsive culture inserts. On the basis of this work, we succeeded in rapid fabrication of chondrocyte sheets with the use of a coculture method in which inserts were placed between synoviocytes and chondrocytes. Treatment of cartilage defects using layered chondrocyte sheets promotes repair and regeneration; this method is compatible with in vivo osteoarthritis models that reproduce partial-thickness defects. In human stem cell clinical research guidelines, the Ministry of Health, Labour and Welfare (MHLW) approved several applications related to this technology. Indeed, its translation to a clinical setting is already yielding favorable results. In this study, we evaluated the risk of tumorigenesis associated with this treatment and characterized the dynamics of biological processes associated with the posttransplantation cell sheets in vivo. Furthermore, we also confirmed the safety of the procedure by using array comparative genomic hybridization (array CGH) and G-band staining to screen for deleterious genetic aberrations during prolonged subculture of cells. The safety of chondrocytes that were cultured for longer than normal was confirmed by the array CGH and G-band staining results. In addition, tumorigenicity testing confirmed that culture chondrocyte sheets are not tumorigenic. Furthermore, from the evaluation of bioluminescence imaging following implantation of the cell sheets, it was confirmed that the transplanted chondrocytes and synoviocytes remained in the knee joint and did not transfer elsewhere over time. We believe that the technique used in this study is a highly useful method for evaluating the safety of not only chondrocytes but also extensive subculturing in general.
- Published
- 2015
46. MP058ASSOCIATION BETWEEN PATHOLOGY AND CLINICAL PARAMETERS IN IGA NEPHROPATHY
- Author
-
Satoshi Kumakura, Takafumi Yamakawa, Takehiko Kawaguchi, Toshiyuki Imasawa, Mari Okajima, Moritoshi Kadomura, Hiroshi Kitamura, Eri Okada, and Masaki Uehara
- Subjects
Transplantation ,Pathology ,medicine.medical_specialty ,Nephrology ,business.industry ,medicine ,Glomerulonephritis iga ,medicine.disease ,business ,Nephropathy - Published
- 2017
47. SP133RELATIONS BETWEEN URINARY PROTEIN AND RENAL TUBULAR INJURY MARKERS IN MINIMAL CHANGE NEPHROTIC SYNDROME AND PRIMARY MEMBRANOUS NEPHROPATY; A CROSS-SECTIONAL STUDY
- Author
-
Masaki Uehara, Mari Okajima, Moritoshi Kadomura, Takehiko Kawaguchi, Toshiyuki Imasawa, Hiroshi Kitamura, Eri Okada, Satoshi Kumakura, and Takafumi Yamakawa
- Subjects
Urinary protein ,Transplantation ,medicine.medical_specialty ,Nephrology ,Cross-sectional study ,business.industry ,Urology ,Minimal change nephrotic syndrome ,Medicine ,business - Published
- 2017
48. SuO005SPOT URINE SODIUM MEASUREMENTS IN THE FIRST MORNING VOID DO NOT ACCURATELY ESTIMATE DIETARY SODIUM INTAKE IN CHRONIC KIDNEY DISEASE
- Author
-
Ikuro Mori, Moritoshi Kadomura, Toshiyuki Imasawa, Masaki Uehara, Azumi Yamada, Takehiko Kawaguchi, and Eri Okada
- Subjects
Transplantation ,Nephrology ,business.industry ,medicine ,Dietary sodium intake ,Physiology ,medicine.disease ,First morning void ,business ,Urine sodium ,Kidney disease - Published
- 2018
49. Analysis of differentially expressed genes through sheet formation of polydactyly -derived chondrocytes
- Author
-
A. Umezawa, K. Nonaka, Masahiro Sato, H. Iijima, Takumi Takahashi, Miki Maehara, Eri Okada, H. Akutsu, Eriko Toyoda, Masahiko Watanabe, R. Matoba, Tadashi Akamatsu, and T. Takagi
- Subjects
Genetics ,Differentially expressed genes ,Rheumatology ,Polydactyly ,Biomedical Engineering ,medicine ,Orthopedics and Sports Medicine ,Biology ,medicine.disease - Published
- 2018
50. Australian Multiculturalism : the achievement and the subjects through the current affairs of Queensland(Abstracts of the Master's Theses)
- Author
-
Eri, OKADA
- Published
- 2005
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