18 results on '"Yutaka Nezu"'
Search Results
2. Clinical Outcome of Low-Grade Myofibroblastic Sarcoma in Japan: A Multicenter Study from the Japanese Musculoskeletal Oncology Group
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Munehisa Kito, Keisuke Ae, Masanori Okamoto, Makoto Endo, Kunihiro Ikuta, Akihiko Takeuchi, Naohiro Yasuda, Taketoshi Yasuda, Yoshinori Imura, Takeshi Morii, Kazutaka Kikuta, Teruya Kawamoto, Yutaka Nezu, Ichiro Baba, Shusa Ohshika, Takeshi Uehara, Takafumi Ueda, Jun Takahashi, and Hirotaka Kawano
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Cancer Research ,Oncology ,low-grade myofibroblastic sarcoma ,rare sarcoma ,wide excision ,radiotherapy ,local relapse ,prognosis - Abstract
This retrospective multicenter study aimed to analyze the clinical features and prognosis of 24 patients diagnosed with LGMS between 2002 and 2019 in the Japanese sarcoma network. Twenty-two cases were surgically treated and two cases were treated with radical radiotherapy (RT). The pathological margin was R0 in 14 cases, R1 in 7 cases, and R2 in 1 case. The best overall response in the two patients who underwent radical RT was one complete response and one partial response. Local relapse occurred in 20.8% of patients. Local relapse-free survival (LRFS) was 91.3% at 2 years and 75.4% at 5 years. In univariate analysis, tumors of 5 cm or more were significantly more likely to cause local relapse (p < 0.01). In terms of the treatment of relapsed tumors, surgery was performed in two cases and radical RT was performed in three cases. None of the patients experienced a second local relapse. Disease-specific survival was 100% at 5 years. A wide excision aimed at the microscopically R0 margin is considered the standard treatment for LGMS. However, RT may be a viable option in unresectable cases or in cases where surgery is expected to cause significant functional impairment.
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- 2023
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3. Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib
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Makoto Endo, Tomoko Kataoka, Toshifumi Fujiwara, Satoshi Tsukushi, Masanobu Takahashi, Eisuke Kobayashi, Yoko Yamada, Takaaki Tanaka, Yutaka Nezu, Hiroaki Hiraga, Junji Wasa, Akihito Nagano, Kenji Nakano, Robert Nakayama, Tetsuya Hamada, Masanori Kawano, Tomoaki Torigoe, Akio Sakamoto, Kunihiro Asanuma, Takeshi Morii, Ryunosuke Machida, Yuta Sekino, Haruhiko Fukuda, Yoshinao Oda, Toshifumi Ozaki, and Kazuhiro Tanaka
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Cancer Research ,Oncology ,Genetics - Abstract
Background Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. Methods The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. Discussion This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. Trial registration This study was registered with the Japan Registry of Clinical Trials (jRCTs031190152) on December 5, 2019.
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- 2023
4. Tranilast reduces the frequency of invasive treatment for extra-abdominal desmoid fibromatosis
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Shintaro, Fujita, Masanobu, Takeyama, Shingo, Kato, Yusuke, Kawabata, Yutaka, Nezu, Kenta, Hayashida, Keiju, Saito, Kato, Ikuma, Kota, Washimi, Hyonmin, Choe, Toru, Hiruma, and Yutaka, Inaba
- Abstract
BackgroundThe active surveillance (AS) has been suggested for the initial treatment of extra-abdominal desmoid fibromatosis (EADF), the percentage of patients who shifted to invasive secondary treatments was significant. Tranilast, an anti-keloid medication, is frequently used in Japan, but there is no detailed report on its efficacy.MethodsWe retrospectively analyzed the medical records of EADF patients treated with tranilast between January 2009 and March 2021. Since EADF has been reported to shrink spontaneously, the effects of all drugs should be compared to AS. Therefore, we compared its clinical course with that under AS (determined by a systematic review) to assess the effect of tranilast. A systematic literature review of AS outcomes was conducted on July 22, 2021, according to PRISMA guidelines. The primary endpoint was the rate of conversion to secondary treatment. Secondary endpoints were progression-free survival, objective response rate (ORR), disease control rate (DCR), and adverse events. The rates of conversion to secondary treatment, ORRs, and DCRs were compared between the two groups using the Fisher's exact test.ResultsEighteen patients who received tranilast as the initial treatment for EADF were included. Two patients (11.1%) underwent surgical resection due to tumor growth and continuous pain. Compared to the secondary treatment conversion rate from the pure AS approach (40.1%), tranilast was shown to significantly reduce the rate (p = 0.01). The ORR and DCR did not different between the two groups.ConclusionsAs initial treatment for EADF, tranilast is preferred over AS.
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- 2022
5. Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma
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Yutaka Nezu, Suguru Yokoo, Kunihiko Numoto, Tsukasa Yonemoto, Aki Yoshida, Shintaro Iwata, Joe Hasei, Toshifumi Ozaki, Toshiyuki Kunisada, Tomohiro Fujiwara, Akira Kawai, Takeshi Ishii, Koji Uotani, Masahiro Kiyono, Ken Takeda, Takahiro Ochiya, and Takuya Morita
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0301 basic medicine ,Adult ,Male ,Mice, Nude ,lcsh:Medicine ,Exosomes ,Article ,Diagnosis, Differential ,03 medical and health sciences ,Sarcoma, Synovial ,Young Adult ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Clinical significance ,Circulating MicroRNA ,Liquid biopsy ,Child ,lcsh:Science ,Mice, Inbred BALB C ,Multidisciplinary ,business.industry ,lcsh:R ,Case-control study ,Sarcoma ,Middle Aged ,medicine.disease ,Synovial sarcoma ,Microvesicles ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Case-Control Studies ,Cancer research ,Biomarker (medicine) ,Female ,lcsh:Q ,Sarcoma, Experimental ,business - Abstract
The lack of useful biomarkers is a crucial problem for patients with soft tissue sarcomas (STSs). Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel impact as biomarkers for patients with malignant diseases, but their significance in synovial sarcoma (SS) patients remains unknown. Initial global miRNA screening using SS patient serum and SS cell culture media identified a signature of four upregulated miRNAs. Among these candidates, miR-92b-3p secretion from SS cells was confirmed, which was embedded within tumour-derived exosomes rather than argonaute-2. Animal experiments revealed a close correlation between serum miR-92b-3p levels and tumour dynamics. Clinical relevance was validated in two independent clinical cohorts, and we subsequently identified that serum miR-92b-3p levels were significantly higher in SS patients in comparison to that in healthy individuals. Moreover, serum miR-92b-3p was robust in discriminating patients with SS from the other STS patients and reflected tumour burden in SS patients. Overall, liquid biopsy using serum miR-92b-3p expression levels may represent a novel approach for monitoring tumour dynamics of SS.
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- 2017
6. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy
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Sandro Santagata, Nathanael S. Gray, Theresa D. Manz, Nami Kim, Nobufumi Sekino, Xiao Zhen Zhou, Futoshi Suizu, Giorgio Gaglia, Dipikaa Akshinthala, Shizhong Ke, Benika J. Pinch, Manuel Hidalgo, Babara Wegiel, Kun Ping Lu, Senthil K. Muthuswamy, Yutaka Nezu, Kenoki Ohuchida, Shin Kibe, Gerburg M. Wulf, Chenxi Qiu, Nir London, Tae Ho Lee, Yoshinao Oda, Ana Verma, Kazuhiro Koikawa, John G. Clohessy, and Masafumi Nakamura
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Tumor microenvironment ,Combination therapy ,medicine.medical_treatment ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Gemcitabine ,Targeted therapy ,Cancer immunotherapy ,Pancreatic cancer ,Cancer cell ,medicine ,Cancer research ,Cancer-Associated Fibroblasts ,medicine.drug - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.
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- 2021
7. Inhibition of death-associated protein kinase 1 attenuates cis P-tau and neurodegeneration in traumatic brain injury
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Nami Kim, Xiao Zhen Zhou, Tae Ho Lee, Kazuhiro Koikawa, Chenxi Qiu, Bin Wang, and Yutaka Nezu
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0301 basic medicine ,Traumatic brain injury ,tau Proteins ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Brain Injuries, Traumatic ,Prolyl isomerase ,Animals ,Medicine ,Phosphorylation ,Kinase activity ,Protein kinase A ,business.industry ,General Neuroscience ,Neurodegeneration ,Brain ,medicine.disease ,nervous system diseases ,Death-Associated Protein Kinases ,Chronic traumatic encephalopathy ,030104 developmental biology ,Death-Associated Protein Kinase 1 ,Cancer research ,PIN1 ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Traumatic brain injury (TBI) is the leading cause of mortality and disability in young people and may lead to the development of progressive neurodegeneration, such as that observed in chronic traumatic encephalopathy. We have recently found that the conformation-specific cis phosphorylated form of tau (cis P-tau) is a major early driver of neurodegeneration after TBI. However, not much is known about how cis P-tau is regulated in TBI. In this study, we demonstrated a novel critical role of death-associated protein kinase 1 (DAPK1) in regulating cis P-tau induction after TBI. We found that DAPK1 is significantly upregulated in mouse brains after TBI and subsequently promotes cis P-tau induction. Genetic deletion of DAPK1 in mice not only significantly decreases cis P-tau expression, but also effectively attenuates neuropathology development and rescues behavioral impairments after TBI. Mechanistically, DAPK1-mediated cis P-tau induction is regulated by the phosphorylation of Pin1 at Ser71, a unique prolyl isomerase known to control the conformational status of P-tau. Furthermore, pharmacological suppression of DAPK1 kinase activity dramatically decreases the levels of Pin1 phosphorylated at Ser71 as well as cis P-tau after neuronal stress. Thus, DAPK1 is a novel regulator of TBI that, in combination with its downstream targets, has a major impact on the development and/or outcome of TBI, and targeting DAPK1 might offer a potential therapeutic impact on TBI-related neurodegenerative diseases.
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- 2021
8. The risk assessment of pathological fracture in the proximal femur using a CT-based finite element method
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Yutaka Inaba, Tomoyuki Saito, Yutaka Nezu, Takayuki Kamiishi, Kosuke Matsuo, and Yusuke Kawabata
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Adult ,Male ,Adolescent ,Medial cortex ,Radiography ,Finite Element Analysis ,Osteolysis ,Risk Assessment ,Lesion ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cortex (anatomy) ,medicine ,Humans ,Orthopedics and Sports Medicine ,Pathological ,Aged ,Aged, 80 and over ,030222 orthopedics ,Osteosynthesis ,Hip Fractures ,business.industry ,Anatomy ,Middle Aged ,Fractures, Spontaneous ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Fracture (geology) ,Female ,Hip Joint ,Surgery ,Tomography ,Joint Diseases ,medicine.symptom ,Tomography, X-Ray Computed ,Nuclear medicine ,business - Abstract
Background Patients who have lytic bone lesions in their proximal femurs are at risk for pathological fracture. Lesions with high fracture risk are surgically treated using prophylactic osteosynthesis, whereas low-risk lesions are treated conservatively. However, it is difficult to discriminate between high- and low-risk lesions based on clinical and radiographic findings. The computed tomography (CT)-based finite element (FE) models are useful for predicting the fracture load on proximal femoral lytic lesions. Materials and methods FE models were constructed from the quantitative CT scans of the femurs using software that created individual bone shapes and density distributions. Three independent observers measured the lesion size, Mirels' score, and thickness of the proximal femur along the horizontal plane. The predictive risk values of the proximal femur measured using the CT-based FE analysis were statistically compared. Results The patients were divided into two groups (high and low risk). The mean fracture load was significantly higher in the high-risk group than in the low-risk group (5395 ± 525 N, 2622 ± 364 N, respectively, p = 0.0003). No significant differences in age, body weight, lesion size or Mirels' score were observed between groups. However, the thickness of the medial cortex in the high-risk group according to the FE analysis was significantly thinner than that in the low-risk group. Furthermore, the medial cortex thickness was positively correlated with the predicted fracture load. An optimal cut-off value of 3.67 mm for the thickness of the inner cortex resulted in 100% sensitivity and 75.1% specificity values for classifying the patients based on their fracture risk. Conclusions Our findings indicate that the FE method is useful for the prediction of the pathological fracture. This method shows a versatile potential for the prediction of pathological fracture and might aid in judging the optimal treatment to prevent fracture.
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- 2017
9. Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma
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Akira Kawai, Eisuke Kobayashi, Machiko Kawamura, Aki Yoshida, Tadashi Komatsubara, Koji Uotani, Toshiyuki Kunisada, Akihiko Yoshida, Kazuhisa Sugiu, Toshinori Omori, Tomohiro Fujiwara, Toshifumi Ozaki, Ken Takeda, Takenori Uehara, Yutaka Nezu, Takuya Morita, and Takahiro Ochiya
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Male ,0301 basic medicine ,Oncology ,Pathology ,Kaplan-Meier Estimate ,Exosomes ,Mice ,0302 clinical medicine ,Neoplasm Metastasis ,Child ,Hematology ,microRNA ,Prognosis ,Combined Modality Therapy ,Child, Preschool ,030220 oncology & carcinogenesis ,Cohort ,Heterografts ,biomarker ,Biomarker (medicine) ,Osteosarcoma ,Female ,Research Paper ,Adult ,medicine.medical_specialty ,Adolescent ,Bone Neoplasms ,Young Adult ,03 medical and health sciences ,osteosarcoma ,Internal medicine ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Clinical significance ,Circulating MicroRNA ,Liquid biopsy ,Neoplasm Staging ,Blood Cells ,liquid biopsy ,business.industry ,Gene Expression Profiling ,Infant, Newborn ,Case-control study ,Infant ,Reproducibility of Results ,Cancer ,medicine.disease ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,ROC Curve ,Case-Control Studies ,business - Abstract
// Tomohiro Fujiwara 1, 2, 3 , Koji Uotani 1 , Aki Yoshida 1 , Takuya Morita 1 , Yutaka Nezu 3 , Eisuke Kobayashi 4 , Akihiko Yoshida 5 , Takenori Uehara 1 , Toshinori Omori 1 , Kazuhisa Sugiu 1 , Tadashi Komatsubara 1 , Ken Takeda 6 , Toshiyuki Kunisada 7 , Machiko Kawamura 8 , Akira Kawai 4 , Takahiro Ochiya 3 , Toshifumi Ozaki 1 1 Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 2 Center of Innovative Medicine, Okayama University Hospital, Okayama, Japan 3 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan 4 Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan 6 Department of Intelligent Orthopaedic System, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 7 Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 8 Department of Hematology, Saitama Cancer Center, Saitama, Japan Correspondence to: Tomohiro Fujiwara, email: tomomedvn@gmail.com Keywords: microRNA, liquid biopsy, osteosarcoma, biomarker, prognosis Received: September 24, 2016 Accepted: February 27, 2017 Published: March 23, 2017 ABSTRACT Background: Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. Methods: Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. Results: Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. Conclusions: Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.
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- 2017
10. miR-135b, a key regulator of malignancy, is linked to poor prognosis in human myxoid liposarcoma
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Takahiro Ochiya, Tomoyuki Saito, Yutaka Nezu, Keitaro Hagiwara, Yusuke Yamamoto, Tomohiro Fujiwara, Akira Kawai, Kosuke Matsuo, and Akihiko Yoshida
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,MMP2 ,Regulator ,Biology ,Liposarcoma ,Malignancy ,Molecular oncology ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Gene Silencing ,Neoplasm Metastasis ,3' Untranslated Regions ,Molecular Biology ,Mice, Knockout ,Myxoid liposarcoma ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Cell cycle ,Prognosis ,medicine.disease ,Liposarcoma, Myxoid ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Matrix Metalloproteinase 2 ,Original Article ,RNA Interference ,Thrombospondins - Abstract
Myxoid/round cell (RC) liposarcomas (MLS) were originally classified into two distinct populations based on histological differences; a myxoid component and a RC component. It is notable that, depending on an increase of the RC component, the prognosis significantly differs. Hence, the RC component is associated with metastasis and poor prognosis. However, the molecular mechanisms that contribute to the malignancy of the RC component still remain largely unknown. Here, we report microRNA-135b (miR-135b), a key regulator of the malignancy, highly expressed in the RC component and promoting MLS cell invasion in vitro and metastasis in vivo through the direct suppression of thrombospondin 2 (THBS2). Decreased THBS2 expression by miR-135b increases the total amount of matrix metalloproteinase 2 (MMP2) and influences cellular density and an extracellular matrix structure, thereby resulting in morphological change in tumor. The expression levels of miR-135b and THBS2 significantly correlated with a poor prognosis in MLS patients. Overall, our study reveals that the miR-135b/THBS2/MMP2 axis is tightly related to MLS pathophysiology and has an important clinical implication. This work provides noteworthy evidence for overcoming metastasis and improving patient outcomes, and sheds light on miR-135b and THBS2 as novel molecular targets for diagnosis and therapy in MLS.
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- 2016
11. The Biological Role and Clinical Implication of MicroRNAs in Osteosarcoma
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Akira Kawai, Takahiro Ochiya, Yutaka Nezu, Kosuke Matsuo, and Tomoyuki Saito
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,microRNA ,Cancer research ,medicine ,Osteosarcoma ,Biology ,medicine.disease - Published
- 2017
12. A tissue microRNA signature that predicts the prognosis of breast cancer in young women
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Yusuke Yamamoto, Takahiro Ochiya, Takayuki Kinoshita, Nobuyoshi Hiraoka, Chikako Shimizu, Juntaro Matsuzaki, Ryou U. Takahashi, Kenji Tamura, Masayuki Yoshida, Sho Shiino, Ai Hironaka-Mitsuhashi, Yutaka Nezu, and Toshikazu Ushijima
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0301 basic medicine ,Oncology ,Microarrays ,Total rna ,Cancer Treatment ,lcsh:Medicine ,Disease ,Biochemistry ,0302 clinical medicine ,Breast Tumors ,Medicine and Health Sciences ,Medicine ,lcsh:Science ,Multidisciplinary ,Treatment choices ,Prognosis ,Cancer treatment ,Nucleic acids ,Bioassays and Physiological Analysis ,030220 oncology & carcinogenesis ,Female ,Research Article ,Mirna signature ,Adult ,medicine.medical_specialty ,Surgical and Invasive Medical Procedures ,Breast Neoplasms ,Candidate mirnas ,Research and Analysis Methods ,03 medical and health sciences ,Breast cancer ,Diagnostic Medicine ,Internal medicine ,microRNA ,Breast Cancer ,Genetics ,Cancer Detection and Diagnosis ,Humans ,Non-coding RNA ,Biology and life sciences ,business.industry ,lcsh:R ,Cancers and Neoplasms ,medicine.disease ,Gene regulation ,MicroRNAs ,030104 developmental biology ,Cancer research ,RNA ,lcsh:Q ,Gene expression ,business ,Biomarkers - Abstract
Since breast cancers in young women are generally aggressive, young patients tend to be intensively treated with anti-cancer drugs. To optimize the strategy for treatment, particularly in young women, prognostic biomarkers are urgently required. The objective of this study was to identify a tissue microRNA (miRNA) signature that predicts prognosis in young breast cancer patients. Total RNA from 45 breast cancer patients aged 0.7. Five of the miRNAs were validated by qRT-PCR, and the expression levels of three of those five (miR-183-5p, miR-194-5p, and miR-1285-5p), both alone and in combination, were associated with OS. In conclusion, we identified three candidate miRNAs that could be used separately or in combination as prognostic biomarkers in young breast cancer patients. This miRNA signature may enable selection of better treatment choices for young women with this disease.
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- 2017
13. List of Contributors
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Carolina Abril-Tormo, Sahar Al-Mahdawi, Diogo Almeida-Rios, Sara Anjomani Virmouni, Juan Ausio, Bharati Bapat, Charlotte L. Bevan, Jenefer M. Blackwell, Tiziana Bonaldi, Abdelhalim Boukaba, Eoin Brennan, Enrique J. Busó, F. Javier Carmona Sanz, Raimundo Cervera, Alfredo Ciccodicola, Joan Climent, Valerio Costa, Ana B. Crujeiras, Alessandro Cuomo, Avery DeVries, Angel Diaz-Lagares, Roberta Esposito, Alessandro Fatica, Alfredo Ferro, Claire E. Fletcher, Ana-Maria Florea, Ernest Fraenkel, Yu Fujita, Tomohiro Fujiwara, Miriam Gagliardi, José Luis García-Giménez, Rosalba Giugno, Catherine Godson, Inês Graça, Kirsten Grønbæk, Shinji Hagiwara, Rui Henrique, José Santiago Ibañez Cabellos, Marisa Iborra, Toyotaka Ishibashi, Sarra E. Jamieson, Carmen Jerónimo, Sadhana Joshi, Phillip Kantharidis, Akira Kawai, Vinita Khot, Lasse Sommer Kristensen, Ana Lluch, José Antonio López-Guerrero, Paula Lopez-Serra, Annita Louloupi, Luca Magnani, Jacobo Martínez-Santamaría, Maria R. Matarazzo, Aaron McClelland, Pamela Milani, Yutaka Nezu, Roberta Noberini, Takahiro Ochiya, Toshifumi Ozaki, Federico V. Pallardó, Lorena Peiró-Chova, Marco Pellegrini, Tandy L.D. Petrov, Olga Bahamonde Ponce, Mark A. Pook, Alfredo Pulvirenti, João Ramalho-Carvalho, Alberto Ramos, George Rasti, Nicole C. Riddle, Peter H.J. Riegman, Carlos Romá Mateo, Francesco Russo, Fabian Sanchis-Gomar, Juan Sandoval, Flavia Scoyni, Marta Seco Cervera, Akifumi Shibakawa, Nicolas G. Simonet, Ailsa Sita-Lumsden, Olafur Andri Stefansson, Deepali Sundrani, Genevieve Syn, Trygve O. Tollefsbol, Eneda Toska, Marianne B. Treppendahl, Toshikazu Ushijima, Alejandro Vaquero, Donata Vercelli, Filipa Quintela Vieira, Yinan Zhang, Fang Zhao, and Wilbert Zwart
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- 2016
14. MicroRNAs in Bone and Soft Tissue Sarcomas and Their Value as Biomarkers
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Akira Kawai, Yu Fujita, Toshifumi Ozaki, Takahiro Ochiya, Yutaka Nezu, and Tomohiro Fujiwara
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Pathology ,medicine.medical_specialty ,Diagnostic methods ,Genetic heterogeneity ,Soft tissue sarcoma ,Soft tissue ,Biology ,Tumor response ,medicine.disease ,microRNA ,medicine ,Cancer research ,Biomarker (medicine) ,Sarcoma - Abstract
Bone and soft tissue sarcomas are malignant neoplasms that are histologically and genetically heterogeneous, and various subtypes of them have been identified. Evidence of microRNA (miRNA) dysregulation in bone and soft tissue sarcomas has been recently described. miRNA dysregulation that is associated with genetic abnormalities unique to the specific subtypes of sarcomas, functionally important, or correlated with clinical prognosis has been gradually identified. Furthermore, the discovery of circulating miRNAs in patient blood has accelerated interest in their potential to transform clinical applications. Considering the lack of useful bone and soft tissue sarcoma biomarkers, the discovery of miRNA dysregulation may provide a diagnostic method that can be used at early disease stages to detect tumors, predict tumor response to chemotherapy, or identify prognoses. Such interventions would address some of the most important challenges in sarcoma management. In this review, we summarize the emerging evidence of miRNA dysregulation in bone and soft tissue sarcomas and discuss their potential as novel biomarkers and therapeutics.
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- 2016
15. Circulating MicroRNAs in Sarcoma: Potential Biomarkers for Diagnosis and Targets for Therapy
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Nobuyoshi Kosaka, Takahiro Ochiya, Toshifumi Ozaki, Yutaka Nezu, Yu Fujita, Akira Kawai, and Tomohiro Fujiwara
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Tumor biology ,business.industry ,General Medicine ,Tumor response ,Bioinformatics ,medicine.disease ,Diagnostic classification ,Diagnostic modalities ,Circulating MicroRNA ,Potential biomarkers ,microRNA ,medicine ,Sarcoma ,business - Abstract
The importance of microRNAs (miRNAs) in tumor biology has been recognized over the past several years. Recently, evidence of circulating miRNAs in both healthy and unhealthy individuals has been accumulated, and is accelerating their potential to transform clinical diagnostics and therapeutics. Since there is a lack of useful biomarkers for bone and soft tissue sarcomas, the discovery of novel biomarkers that can be used at early disease stages to detect tumors or predict tumor response to chemotherapy or the chance of survival is one of the most important challenges in sarcoma management. Further more highly, sensitive and specific biomarkers might help diagnostic classification, since some cases are unclassifiable using modern diagnostic modalities. In this review, we summarize the emerging evidence of circulating miRNAs in sarcoma and discuss their potential as novel biomarkers and therapeutics.
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- 2014
16. Abstract 456: Identification of circulating tumor-derived microRNA signatures in osteosarcoma
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Yutaka Nezu, Kazuhisa Sugiu, Hirotaka Kanzaki, Koji Uotani, Takuya Morita, Aki Yoshida, Takahiro Ochiya, Ken Takeda, Toshiyuki Kunisada, Akira Kawai, Tomohiro Fujiwara, Toshinori Omori, Tadashi Komatsubara, and Toshifumi Ozaki
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Mesenchymal stem cell ,Cancer ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Downregulation and upregulation ,Cell culture ,030220 oncology & carcinogenesis ,Internal medicine ,microRNA ,Medicine ,Alkaline phosphatase ,Osteosarcoma ,business - Abstract
Introduction: The lack of useful biomarkers is one of the most important clinical problems of bone and soft tissue sarcomas, although early detection of recurrent or metastatic disease and early decision making according to tumor response to chemotherapy is important to improve patient prognosis. The recent discovery of circulating cell-free microRNAs (miRNAs) in human blood has represented a new approach for the diagnostic screening for malignant diseases. In this study, we investigated whether the serum miRNA levels could be used as novel biomarkers for osteosarcoma (OS) patients. Methods: Global miRNA profiling was performed using the serum samples collected from OS patients, age-matched non-OS patients and healthy volunteers. The expression levels of extracted miRNA were confirmed in human OS cell lines (SaOS2, U2OS, HOS, 143B), human mesenchymal stem cell (hMSC), and their culture media. The miRNA candidates were evaluated using the serum samples of the validation set. Results: The miRNA expression profile of the serum samples of 10 OS patients, 10 age-matched non-OS patients, and 10 healthy controls identified 236 serum miRNAs to be highly expressed in the OS compared to the non-OS patients and healthy controls. Among these miRNAs, 8 miRNAs were overlapped with the secretory miRNAs in the culture medium of 7 osteosarcoma cell lines. Quantitative RT-PCR revealed that two candidates were significantly upregulated in the OS cells and culture medium, compared to MSCs. The expression of these miRNAs in the culture media from all OS cell lines increased along with culture time and tumor cell numbers, indicating that it is an important secretory miRNA derived from OS cells. The serum concentration of these miRNAs in OS patients was significantly higher than those in healthy volunteers and non-OS patients. Our ROC analyses revealed that an AUC value based on the miRNA expression was 0.868 (95% confidence interval = 0.743 to 0.993), which was was higher than that of alkaline phosphatase (ALP). Finally, the detected serum miRNA expression levels markedly decreased at the postoperative status in operative cases, while gradually decreased during neoadjuvant chemotherapy, which revealed that serum miRNA expression levels correlated with the tumor burden and drug sensitivity. Conclusions: We identified circulating tumor-derived miRNA signatures in the serum obtained from the OS patients. Furthermore, the definitive miRNA reflected tumor burden in OS patients. Evaluating the serum miRNA expression may thus have important clinical implications for risk stratification and the planning of post-therapeutic surveillance. Citation Format: Tomohiro Fujiwara, Koji Uotani, Aki Yoshida, Takuya Morita, Tadashi Komatsubara, Kazuhisa Sugiu, Toshinori Omori, Ken Takeda, Toshiyuki Kunisada, Yutaka Nezu, Akira Kawai, Hirotaka Kanzaki, Takahiro Ochiya, Toshifumi Ozaki. Identification of circulating tumor-derived microRNA signatures in osteosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 456.
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- 2016
17. Abstract 969: Circulating cell-free microRNA as a novel biomarker for synovial sarcoma patients
- Author
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Junya Toguchida, Akira Kawai, Takenori Uehara, Kazuhisa Sugiu, Koji Uotani, Tadashi Komatsubara, Takuya Morita, Toshinori Omari, Toshifumi Ozaki, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Yutaka Nezu, and Takahiro Ochiya
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Cancer Research ,Pathology ,medicine.medical_specialty ,Mesenchymal stem cell ,Biology ,medicine.disease ,Synovial sarcoma ,Fusion gene ,Oncology ,In vivo ,Cell culture ,Tumor progression ,microRNA ,medicine ,Biomarker (medicine) - Abstract
INTRODUCTION Synovial sarcoma (SS) is characterized by the SS18-SSX fusion gene, and the presence of this chromosomal translocation is clinically useful as a diagnostic marker. However, SS18-SSX does not reflect disease progression and can be detected only with tumor specimens surgically resected. Therefore, novel non-invasive biomarkers would help clinicians to diagnose or detect tumor progression, which could improve patients’ prognosis. We investigated the expression of the serum microRNA (miRNA) of SS patients, and evaluated its significance using in vitro and in vivo experimental models. METHODS In the screening phase, global analysis by miRNA microarray was performed using extracted RNA derived from patients’ serum and culture medium. The serum samples were collected from SS patients, age-matched non-SS patients, and healthy volunteers. The culture mediums were obtained from human SS cell lines and human mesenchymal stem cells (hMSCs) as controls. In the validation phase, the expression levels of miRNA derived from culture medium were evaluated by quantitative real-time PCR (qRT-PCR) to determine the secretory potential of miRNA candidates. SS cell lines and hMSCs were cultured and the culture medium was collected at 0, 24, and 48 hours. Furthermore, serum miRNA levels of SS-bearing mice were analyzed by qRT-PCR according to the tumor growth and tumor resection. RESULTS A miRNA microarray profiling revealed that four miRNAs were significantly highly expressed (p < 0.05) in SS patients’ serum and cell culture medium, compared to control samples, which were selected as candidates for further analysis. We then identified that one miRNA expression among four candidates in the culture medium from all SS cell lines increased with time and with increasing numbers of tumor cells. These data suggested that the detected miRNA is a secretory miRNA derived from SS cells. Next, we investigated whether the serum expression of the detected miRNA correlates with tumor progression using SS-bearing mice, which demonstrated that the detected miRNA expression in mice serum increased size-dependently (R = 0.78, p < 0.05). Moreover, it significantly reduced after tumor resection (p < 0.05), indicating that the detected serum miRNA level reflects tumor burden in vivo. Furthermore, the expression of the detected miRNA in serum collected from SS patients was significantly higher compared with that in serum collected from other soft tissue sarcoma patients. CONCLUSIONS Our results indicate that the serum expression of the detected miRNA could be useful for tumor monitoring as a non-invasive biomarker for SS. Moreover, the detected miRNA may contribute to SS progression. Citation Format: Koji Uotani, Tomohiro Fujiwara, Aki Yoshida, Takuya Morita, Yutaka Nezu, Tadashi Komatsubara, Kazuhisa Sugiu, Takenori Uehara, Toshinori Omari, Ken Takeda, Toshiyuki Kunisada, Junya Toguchida, Akira Kawai, Takahiro Ochiya, Toshifumi Ozaki. Circulating cell-free microRNA as a novel biomarker for synovial sarcoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 969.
- Published
- 2016
18. RPN2 Gene Confers Osteosarcoma Cell Malignant Phenotypes and Determines Clinical Prognosis
- Author
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Akira Kawai, Nobuyoshi Kosaka, Ryou U. Takahashi, Toshifumi Ozaki, Tomohiro Fujiwara, Yutaka Nezu, and Takahiro Ochiya
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musculoskeletal diseases ,Pathology ,medicine.medical_specialty ,Cell ,drug response ,Transferase complex ,ribophorin II (RPN2) ,Metastasis ,RNA interference ,osteosarcoma ,Drug Discovery ,medicine ,Gene silencing ,metastasis ,Gene knockdown ,business.industry ,lcsh:RM1-950 ,medicine.disease ,medicine.anatomical_structure ,lcsh:Therapeutics. Pharmacology ,Cancer cell ,Cancer research ,Molecular Medicine ,Osteosarcoma ,Original Article ,business - Abstract
Drug resistance and metastasis are lethal characteristics of tumors. We previously demonstrated that silencing of ribophorin II (RPN2), which is part of the N-oligosaccharyl transferase complex, efficiently induced apoptosis and reduced resistance to docetaxel in human breast cancer cells. Here, we report the clinical and functional correlations of RPN2 expression in osteosarcoma. Immunohistochemical evaluation of 35 osteosarcoma patient biopsies revealed that RPN2 was moderately to highly expressed in all specimens, and higher RPN2 mRNA expression was significantly correlated with poor prognosis. To investigate whether lethal phenotypes of osteosarcoma could be reduced by regulating the expression of RPN2, we conducted a study of RNAi-induced RPN2 knockdown in highly metastatic human osteosarcoma cells. The results indicated that RPN2 silencing reduced cell proliferation, sphere formation, cell invasion, and sensitized drug response in vitro. Mice bearing RPN2-silenced highly metastatic osteosarcoma xenografts showed reduced tumor growth and lung metastasis, and survived longer than mice bearing control tumor xenografts. Taken together, our data suggest that RPN2 silencing contributes to regulation of lethal osteosarcoma phenotypes and could be a novel target for RNAi-based therapeutics against osteosarcoma.
- Published
- 2014
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