6 results on '"Sasa, K"'
Search Results
2. Expression of Kielin/chordin-like protein is regulated by BMP-2 in osteoblasts.
- Author
-
Toba K, Yamada A, Sasa K, Shirota T, and Kamijo R
- Abstract
Bone morphogenetic protein (BMP), an osteoinductive factor, is a cytokine that induces osteoblast differentiation and mineralization, and expected to be applicable for hard tissue reconstruction. Kielin/chordin-like protein (Kcp), a member of the family of cysteine-rich proteins, enhances BMP signaling. The present study found that expression of Kcp in osteoblasts was induced by BMP-2 in a concentration- and time-dependent manner. Up-regulation of Kcp by BMP-2 was inhibited by Dorsomorphin, a SMAD signaling inhibitor. The involvement of up-regulation of Kcp by BMP-2 in induction of osteoblast differentiation by BMP-2 was also examined, which showed that suppression of Kcp expression by si Kcp partially inhibited induction of osteoblast differentiation and mineralization by BMP-2. Together, these results suggest that Kcp induced by BMP-2 functions to provide positive feedback for promotion of osteoblastic differentiation and mineralization by BMP-2 in osteoblasts., Competing Interests: None of the authors have conflicts of interest to declare regarding the contents of this article., (© 2024 The Authors. Published by Elsevier Inc.)
- Published
- 2024
- Full Text
- View/download PDF
3. Detection of Novel Tyrosine Kinase Fusion Genes as Potential Therapeutic Targets in Bone and Soft Tissue Sarcomas Using DNA/RNA-based Clinical Sequencing.
- Author
-
Hasegawa N, Hayashi T, Niizuma H, Kikuta K, Imanishi J, Endo M, Ikeuchi H, Sasa K, Sano K, Hirabayashi K, Takagi T, Ishijima M, Kato S, Kohsaka S, Saito T, and Suehara Y
- Subjects
- Animals, Mice, Humans, Adult, Child, Protein-Tyrosine Kinases genetics, DNA Copy Number Variations, Tyrosine Kinase Inhibitors, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Receptor Protein-Tyrosine Kinases genetics, RNA, Autoantigens, Calmodulin-Binding Proteins genetics, Leiomyosarcoma pathology, Sarcoma drug therapy, Sarcoma genetics, Sarcoma pathology, Bone Neoplasms drug therapy, Bone Neoplasms genetics, Soft Tissue Neoplasms drug therapy, Soft Tissue Neoplasms genetics
- Abstract
Background: Approximately 1% of clinically treatable tyrosine kinase fusions, including anaplastic lymphoma kinase, neurotrophic tyrosine receptor kinase, RET proto-oncogene, and ROS proto-oncogene 1, have been identified in soft tissue sarcomas via comprehensive genome profiling based on DNA sequencing. Histologic tumor-specific fusion genes have been reported in approximately 20% of soft tissue sarcomas; however, unlike tyrosine kinase fusion genes, these fusions cannot be directly targeted in therapy. Approximately 80% of tumor-specific fusion-negative sarcomas, including myxofibrosarcoma and leiomyosarcoma, that are defined in complex karyotype sarcomas remain genetically uncharacterized; this mutually exclusive pattern of mutations suggests that other mutually exclusive driver oncogenes are yet to be discovered. Tumor-specific, fusion-negative sarcomas may be associated with unique translocations, and oncogenic fusion genes, including tyrosine kinase fusions, may have been overlooked in these sarcomas., Questions/purposes: (1) Can DNA- or RNA-based analysis reveal any characteristic gene alterations in bone and soft tissue sarcomas? (2) Can useful and potential tyrosine kinase fusions in tumors from tumor-specific, fusion-negative sarcomas be detected using an RNA-based screening system? (3) Do the identified potential fusion tumors, especially in neurotrophic tyrosine receptor kinase gene fusions in bone sarcoma, transform cells and respond to targeted drug treatment in in vitro assays? (4) Can the identified tyrosine kinase fusion genes in sarcomas be useful therapeutic targets?, Methods: Between 2017 and 2020, we treated 100 patients for bone and soft tissue sarcomas at five institutions. Any biopsy or surgery from which a specimen could be obtained was included as potentially eligible. Ninety percent (90 patients) of patients were eligible; a further 8% (8 patients) were excluded because they were either lost to follow-up or their diagnosis was changed, leaving 82% (82 patients) for analysis here. To answer our first and second questions regarding gene alterations and potential tyrosine kinase fusions in eight bone and 74 soft tissue sarcomas, we used the TruSight Tumor 170 assay to detect mutations, copy number variations, and gene fusions in the samples. To answer our third question, we performed functional analyses involving in vitro assays to determine whether the identified tyrosine kinase fusions were associated with oncogenic abilities and drug responses. Finally, to determine usefulness as therapeutic targets, two pediatric patients harboring an NTRK fusion and an ALK fusion were treated with tyrosine kinase inhibitors in clinical trials., Results: DNA/RNA-based analysis demonstrated characteristic alterations in bone and soft tissue sarcomas; DNA-based analyses detected TP53 and copy number alterations of MDM2 and CDK4 . These single-nucleotide variants and copy number variations were enriched in specific fusion-negative sarcomas. RNA-based screening detected fusion genes in 24% (20 of 82) of patients. Useful potential fusions were detected in 19% (11 of 58) of tumor-specific fusion-negative sarcomas, with nine of these patients harboring tyrosine kinase fusion genes; five of these patients had in-frame tyrosine kinase fusion genes ( STRN3-NTRK3, VWC2-EGFR, ICK-KDR, FOXP2-MET , and CEP290-MET ) with unknown pathologic significance. The functional analysis revealed that STRN3-NTRK3 rearrangement that was identified in bone had a strong transforming potential in 3T3 cells, and that STRN3-NTRK3 -positive cells were sensitive to larotrectinib in vitro. To confirm the usefulness of identified tyrosine kinase fusion genes as therapeutic targets, patients with well-characterized LMNA-NTRK1 and CLTC-ALK fusions were treated with tyrosine kinase inhibitors in clinical trials, and a complete response was achieved., Conclusion: We identified useful potential therapeutic targets for tyrosine kinase fusions in bone and soft tissue sarcomas using RNA-based analysis. We successfully identified STRN3-NTRK3 fusion in a patient with leiomyosarcoma of bone and determined the malignant potential of this fusion gene via functional analyses and drug effects. In light of these discoveries, comprehensive genome profiling should be considered even if the sarcoma is a bone sarcoma. There seem to be some limitations regarding current DNA-based comprehensive genome profiling tests, and it is important to use RNA testing for proper diagnosis and accurate identification of fusion genes. Studies on more patients, validation of results, and further functional analysis of unknown tyrosine kinase fusion genes are required to establish future treatments., Clinical Relevance: DNA- and RNA-based screening systems may be useful for detecting tyrosine kinase fusion genes in specific fusion-negative sarcomas and identifying key therapeutic targets, leading to possible breakthroughs in the treatment of bone and soft tissue sarcomas. Given that current DNA sequencing misses fusion genes, RNA-based screening systems should be widely considered as a worldwide test for sarcoma. If standard treatments such as chemotherapy are not effective, or even if the sarcoma is of bone, RNA sequencing should be considered to identify as many therapeutic targets as possible., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of Bone and Joint Surgeons.)
- Published
- 2024
- Full Text
- View/download PDF
4. Supersulfides support bone growth by promoting chondrocyte proliferation in the growth plates.
- Author
-
Sasama Y, Yoshimura K, Hoshino M, Sasa K, Akaike T, Morita M, Baba K, Shirota T, and Miyamoto Y
- Subjects
- Mice, Animals, Cystine pharmacology, Cell Proliferation, Bone Development, Sulfur pharmacology, Growth Plate, Chondrocytes
- Abstract
Objectives: While chondrocytes have mitochondria, they receive little O
2 from the bloodstream. Sulfur respiration, an essential energy production system in mitochondria, uses supersulfides instead of O2 . Supersulfides are inorganic and organic sulfides with catenated sulfur atoms and are primarily produced by cysteinyl tRNA synthetase-2 (CARS2). Here, we investigated the role of supersulfides in chondrocyte proliferation and bone growth driven by growth plate chondrocyte proliferation., Methods: We examined the effects of NaHS, an HS- /H2 S donor, and cystine, the cellular source of cysteine, on the proliferation of mouse primary chondrocytes and growth of embryonic mouse tibia in vitro. We also examined the effect of RNA interference acting on the Cars2 gene on chondrocyte proliferation in the presence of cystine., Results: NaHS (30 μmol/L) enhanced tibia longitudinal growth in vitro with expansion of the proliferating zone of their growth plates. While NaHS (30 μmol/L) also promoted chondrocyte proliferation only under normoxic conditions (20 % O2 ), cystine (0.5 mmol/L) promoted it under both normoxic and hypoxic (2 % O2 ) conditions. Cars2 gene knockdown abrogated the ability of cystine (0.5 mmol/L) to promote chondrocyte proliferation under normoxic conditions, indicating that supersulfides produced by CARS2 were responsible for the cystine-dependent promotion of bone growth., Conclusions: The presented results indicate that supersulfides play a vital role in bone growth achieved by chondrocyte proliferation in the growth plates driven by sulfur respiration., Competing Interests: Declaration of competing interest All authors declare that the research was conducted without financial interest and that they have no conflict of interest., (Copyright © 2023 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
5. NTRK2 expression in gastrointestinal stromal tumors with a special emphasis on the clinicopathological and prognostic impacts.
- Author
-
Sasa K, Son R, Oguchi A, Ashizawa K, Hasegawa N, Kubota D, Suehara Y, Takagi T, Okubo T, Akaike K, Sugimoto K, Takahashi M, Sakamoto K, Hashimoto T, Mine S, Fukunaga T, Ishijima M, Hayashi T, Yao T, Murakawa Y, and Saito T
- Subjects
- Humans, Prognosis, Receptor Protein-Tyrosine Kinases, Proto-Oncogenes, Proto-Oncogene Proteins c-kit, Gastrointestinal Stromal Tumors genetics
- Abstract
Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
6. Novel epigenetic roles of lactylation in osteogenesis.
- Author
-
Sasa K, Kato T, and Yamada A
- Subjects
- Humans, Animals, Epigenesis, Genetic, Osteogenesis genetics
- Published
- 2024
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.