FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4282965764> ?p ?o ?g. }

• W4282965764 endingPage "3779" @default.
• W4282965764 startingPage "3779" @default.
• W4282965764 abstract "Abstract Background: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by a rash that progresses to poikiloderma; small stature; skeletal anomalies; sparse hair, eyelashes, and/or eyebrows, juvenile cataracts, and an increased risk to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have a significantly increased incidence of osteosarcoma. However, there is currently no available RTS model that recapitulates the bone malignancy phenotype in this disease, severely limiting the ability of researchers to explore new treatment avenues. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. Methods: iPSCs were reprogrammed from fibroblasts of four individuals from two RTS families, each with one affected RTS proband with RECQL4 mutations and one unaffected parent. These patient iPSCs were differentiated to mesenchymal stem cells (MSCs) and then to osteoblasts, the cell-of-origin of osteosarcoma. All of these MSCs and osteoblasts were subjected to transcriptome analysis by RNA-seq. Based on enriched mitochondrial respiratory gene signatures, we also systematically analyzed the enzymatic activities of the major mitochondrial respiratory protein complexes including complex I/II/III and citrate synthase enzyme activity in RTS osteoblasts by Seahorse assay. Finally, we tested the potential therapeutic effect of clinical oxidative phosphorylation complex I inhibitor IACS-010759 to treat RTS cells and dissect the pharmacological mechanisms involved. Results: RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and a gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts revealed decreased bone morphogenesis gene expression but aberrantly upregulated mitochondrial complex I gene expression. Metabolic assays of RTS osteoblasts demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation, but decreased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell viability of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes to RTS osteoblasts suggested that inhibition of mitochondrial complex I in RTS osteoblasts leads to enhanced cell senescence, decreased MAPK signaling and cell cycle associated genes. Conclusion: In summary, we established an RTS iPSC disease platform to dissect the pathological mechanisms involved in RTS-associated osteosarcoma. Our data suggested that mitochondrial complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies. Citation Format: An Xu, Brittany E. Jewell, Dandan Zhu, Mo-Fan Huang, Yi-Hung Chen, Linchao Lu, Ruiying Zhao, Lisa L. Wang, Dung-Fang Lee. Patient-derived iPSCs reveal pharmacologic targeting mitochondrial respiratory complex I for treating Rothmund-Thomson syndrome associated osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3779." @default.
• W4282965764 created "2022-06-17" @default.
• W4282965764 creator A5017438781 @default.
• W4282965764 creator A5026375867 @default.
• W4282965764 creator A5027307547 @default.
• W4282965764 creator A5040112024 @default.
• W4282965764 creator A5045649756 @default.
• W4282965764 creator A5058062993 @default.
• W4282965764 creator A5067810544 @default.
• W4282965764 creator A5082152043 @default.
• W4282965764 creator A5083380528 @default.
• W4282965764 date "2022-06-15" @default.
• W4282965764 modified "2023-10-17" @default.
• W4282965764 title "Abstract 3779: Patient-derived iPSCs reveal pharmacologic targeting mitochondrial respiratory complex I for treating Rothmund-Thomson syndrome associated osteosarcoma" @default.
• W4282965764 doi "https://doi.org/10.1158/1538-7445.am2022-3779" @default.
• W4282965764 hasPublicationYear "2022" @default.
• W4282965764 type Work @default.
• W4282965764 citedByCount "0" @default.
• W4282965764 crossrefType "journal-article" @default.
• W4282965764 hasAuthorship W4282965764A5017438781 @default.
• W4282965764 hasAuthorship W4282965764A5026375867 @default.
• W4282965764 hasAuthorship W4282965764A5027307547 @default.
• W4282965764 hasAuthorship W4282965764A5040112024 @default.
• W4282965764 hasAuthorship W4282965764A5045649756 @default.
• W4282965764 hasAuthorship W4282965764A5058062993 @default.
• W4282965764 hasAuthorship W4282965764A5067810544 @default.
• W4282965764 hasAuthorship W4282965764A5082152043 @default.
• W4282965764 hasAuthorship W4282965764A5083380528 @default.
• W4282965764 hasConcept C104317684 @default.
• W4282965764 hasConcept C107459253 @default.
• W4282965764 hasConcept C145103041 @default.
• W4282965764 hasConcept C150194340 @default.
• W4282965764 hasConcept C162317418 @default.
• W4282965764 hasConcept C198826908 @default.
• W4282965764 hasConcept C2777760704 @default.
• W4282965764 hasConcept C502942594 @default.
• W4282965764 hasConcept C54355233 @default.
• W4282965764 hasConcept C60644358 @default.
• W4282965764 hasConcept C71924100 @default.
• W4282965764 hasConcept C86803240 @default.
• W4282965764 hasConcept C95444343 @default.
• W4282965764 hasConceptScore W4282965764C104317684 @default.
• W4282965764 hasConceptScore W4282965764C107459253 @default.
• W4282965764 hasConceptScore W4282965764C145103041 @default.
• W4282965764 hasConceptScore W4282965764C150194340 @default.
• W4282965764 hasConceptScore W4282965764C162317418 @default.
• W4282965764 hasConceptScore W4282965764C198826908 @default.
• W4282965764 hasConceptScore W4282965764C2777760704 @default.
• W4282965764 hasConceptScore W4282965764C502942594 @default.
• W4282965764 hasConceptScore W4282965764C54355233 @default.
• W4282965764 hasConceptScore W4282965764C60644358 @default.
• W4282965764 hasConceptScore W4282965764C71924100 @default.
• W4282965764 hasConceptScore W4282965764C86803240 @default.
• W4282965764 hasConceptScore W4282965764C95444343 @default.
• W4282965764 hasIssue "12_Supplement" @default.
• W4282965764 hasLocation W42829657641 @default.
• W4282965764 hasOpenAccess W4282965764 @default.
• W4282965764 hasPrimaryLocation W42829657641 @default.
• W4282965764 hasRelatedWork W1764863744 @default.
• W4282965764 hasRelatedWork W2608045240 @default.
• W4282965764 hasRelatedWork W2919381586 @default.
• W4282965764 hasRelatedWork W2992622905 @default.
• W4282965764 hasRelatedWork W3000738194 @default.
• W4282965764 hasRelatedWork W3005743378 @default.
• W4282965764 hasRelatedWork W3029979236 @default.
• W4282965764 hasRelatedWork W4200602986 @default.
• W4282965764 hasRelatedWork W4220937601 @default.
• W4282965764 hasRelatedWork W4284881450 @default.
• W4282965764 hasVolume "82" @default.
• W4282965764 isParatext "false" @default.
• W4282965764 isRetracted "false" @default.
• W4282965764 workType "article" @default.