FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2979973845> ?p ?o ?g. }

• W2979973845 endingPage "3150" @default.
• W2979973845 startingPage "3150" @default.
• W2979973845 abstract "Abstract Background: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by no efficient hematopoiesis and frequent progression to acute myeloid leukemia (AML). Even in low risk MDS, clonal hematopoiesis already dominates at diagnosis, and clones found in secondary AML originate from the MDS stage of disease, highlighting the need to specifically target the MDS-initiating clone. PF-0449913 is a potent and selective hedgehog pathway inhibitor that act by binding Smoothened (SMO) and blocking signal transduction. PF-04449913 demonstrated preliminary antitumor activity in a phase I trial, when given as monotherapy in patients with several hematopoietic malignancy. Jak1 tyrosine kinase plays an important role in cytokine signaling. Jak1 functions to phosphorylate STAT3 transcription factor, which triggers their dimerization and nuclear translocation. In the present study, we investigated the combining effects of PF-04449913 and Jak1 inhibitor, PF-6667291 in terminal differentiation of MDS-derived induced potent stem cells (iPSC). Methods: We generated iPSCs from bone marrow mononuclear cells of two MDS patients (RAEB1 and RAEB2 by WHO classification) with chromosome 5 deletion and complex karyotypic abnormalities, respectively. Karyotyping analysis revealed that MDS-derived iPSCs have identical abnormalities to primary MDS cells. We also generated iPSCs from bone marrow mononuclear cells of normal volunteer as control. To investigate the effects of PF-04449913 on self-renewal and the relevance as a therapeutic target in MDS initiating cells, we examined the activity of PF-04449913 against MDS-derived iPSCs transferred NOD/SCID mice in vivo. NOD/SCID mice were injected subcutaneously with MDS-derived iPSCs or normal iPSCs then treated with PF-04449913 (100 mg/kg; p.o.) from day 10 for 28 days. We also used MDS-L, a myelodysplastic cell line established from MDS patient with del (5q) and complex karyotypic abnormalities for in vitro studies. In vitro re-differentiation of MDS-iPSCs was performed with differentiation media (30 ng/ml VEGF, 30 ng/ml BMP-4, 40 ng/ml SCF, 50 ng/ml Activin) for 4 days. At day 14, a single cell suspension expressing CD34+CD38- was achieved with hematopoietic cytokines (300 ng/ml Flt-3 ligand, 10 ng/ml IL-3, 10 ng/ml IL-6, 50 ng/ml G-CSF, 25 ng/ml BMP-4). Results: Both MDS-derived iPSCs transferred NOD/SCID mice and normal iPSCs transferred NOD/SCID mice demonstrated the engraftment of CD34+CD38- positive cells by flow cytometry. However, the treatment with PF-04449913 reduced the population of CD34+CD38- positive cells in MDS-derived iPSCs transferred NOD/SCID mice. We isolated human CD45+ cells from the spleen of mice from each treatment group and injected equivalent numbers of CD45+ cells into secondary recipients. Following 50 days, all mice treated with vehicle engrafted with CD34+CD38- positive cells. In contrast, CD34+CD38- positive cells engraftment was not detected in recipient mice (n=3) from PF-04449913-treated donors. These results demonstrate the persistent effects of PF-0449913 on long term self-renewing MDS-initiating cells. Next we performed in vitro re-differentiation of MDS-iPSCs, which express CD34+CD38- population. CD34+CD38- cells from MDS-derived iPSCs were cultured with 2 μM of PF-04449913 and 1 μM of PF-6667291 in STEMdiff APEL medium for 14 days for CFC activities. Treatments with PF-04449913 and PF-6667291 significantly reduced the colony formations of mature erythroid, granulocyte-macrophage, and mixed of these hematopoietic cells. To identify the mechanisms that limit the terminal differentiation of MDS-derived iPSC by PF-04449913 and PF-6667291, MDS-L cells were cultured with PF-04449913 and PF-6667291 for 72 hrs. The treatments with PF-04449913 and PF-6667291 induced the expressions of p21Cip1, cleaved PARP and reduced the expression of BMI-1, c-Myc, Nanog, and phospho-Stat3. Conclusion: Our preclinical results indicate that the combination with PF-04449913 and PF-6667291 have potential as an important option for controlling the terminal differentiation of MDS-initiating cells. It is expected that the combination with PF-04449913 and PF-6667291 may become extremely useful therapeutic interventions in a number of hematological neoplasms, including MDS. Disclosures Tauchi: Pfizer Inc.: Research Funding. Ohyashiki:Bristol-Myers Squibb: Research Funding; Novartis International AG,: Honoraria, Research Funding." @default.
• W2979973845 created "2019-10-18" @default.
• W2979973845 creator A5016402296 @default.
• W2979973845 creator A5019513106 @default.
• W2979973845 creator A5053689963 @default.
• W2979973845 creator A5054243155 @default.
• W2979973845 creator A5083522292 @default.
• W2979973845 date "2016-12-02" @default.
• W2979973845 modified "2023-09-27" @default.
• W2979973845 title "Combining Effects of the SMO Inhibitor and Jak1 Inhibitor in Terminal Differentiation of MDS-Derived Induced Potent Stem Cells (iPSC)" @default.
• W2979973845 doi "https://doi.org/10.1182/blood.v128.22.3150.3150" @default.
• W2979973845 hasPublicationYear "2016" @default.
• W2979973845 type Work @default.
• W2979973845 sameAs 2979973845 @default.
• W2979973845 citedByCount "0" @default.
• W2979973845 crossrefType "journal-article" @default.
• W2979973845 hasAuthorship W2979973845A5016402296 @default.
• W2979973845 hasAuthorship W2979973845A5019513106 @default.
• W2979973845 hasAuthorship W2979973845A5053689963 @default.
• W2979973845 hasAuthorship W2979973845A5054243155 @default.
• W2979973845 hasAuthorship W2979973845A5083522292 @default.
• W2979973845 hasConcept C104317684 @default.
• W2979973845 hasConcept C107459253 @default.
• W2979973845 hasConcept C109159458 @default.
• W2979973845 hasConcept C145103041 @default.
• W2979973845 hasConcept C145837895 @default.
• W2979973845 hasConcept C203014093 @default.
• W2979973845 hasConcept C2778539099 @default.
• W2979973845 hasConcept C2779282312 @default.
• W2979973845 hasConcept C2780007613 @default.
• W2979973845 hasConcept C28328180 @default.
• W2979973845 hasConcept C502942594 @default.
• W2979973845 hasConcept C54355233 @default.
• W2979973845 hasConcept C62478195 @default.
• W2979973845 hasConcept C86803240 @default.
• W2979973845 hasConcept C95444343 @default.
• W2979973845 hasConceptScore W2979973845C104317684 @default.
• W2979973845 hasConceptScore W2979973845C107459253 @default.
• W2979973845 hasConceptScore W2979973845C109159458 @default.
• W2979973845 hasConceptScore W2979973845C145103041 @default.
• W2979973845 hasConceptScore W2979973845C145837895 @default.
• W2979973845 hasConceptScore W2979973845C203014093 @default.
• W2979973845 hasConceptScore W2979973845C2778539099 @default.
• W2979973845 hasConceptScore W2979973845C2779282312 @default.
• W2979973845 hasConceptScore W2979973845C2780007613 @default.
• W2979973845 hasConceptScore W2979973845C28328180 @default.
• W2979973845 hasConceptScore W2979973845C502942594 @default.
• W2979973845 hasConceptScore W2979973845C54355233 @default.
• W2979973845 hasConceptScore W2979973845C62478195 @default.
• W2979973845 hasConceptScore W2979973845C86803240 @default.
• W2979973845 hasConceptScore W2979973845C95444343 @default.
• W2979973845 hasIssue "22" @default.
• W2979973845 hasLocation W29799738451 @default.
• W2979973845 hasOpenAccess W2979973845 @default.
• W2979973845 hasPrimaryLocation W29799738451 @default.
• W2979973845 hasRelatedWork W2007136279 @default.
• W2979973845 hasRelatedWork W2156234019 @default.
• W2979973845 hasRelatedWork W2252742661 @default.
• W2979973845 hasRelatedWork W2405320342 @default.
• W2979973845 hasRelatedWork W2462874031 @default.
• W2979973845 hasRelatedWork W2503912067 @default.
• W2979973845 hasRelatedWork W2549889297 @default.
• W2979973845 hasRelatedWork W2560013383 @default.
• W2979973845 hasRelatedWork W2570387335 @default.
• W2979973845 hasRelatedWork W2581552906 @default.
• W2979973845 hasRelatedWork W2588788961 @default.
• W2979973845 hasRelatedWork W2594213988 @default.
• W2979973845 hasRelatedWork W2594893174 @default.
• W2979973845 hasRelatedWork W2606219893 @default.
• W2979973845 hasRelatedWork W2915022322 @default.
• W2979973845 hasRelatedWork W2975553029 @default.
• W2979973845 hasRelatedWork W2979344655 @default.
• W2979973845 hasRelatedWork W2979962080 @default.
• W2979973845 hasRelatedWork W2980215458 @default.
• W2979973845 hasRelatedWork W2983677619 @default.
• W2979973845 hasVolume "128" @default.
• W2979973845 isParatext "false" @default.
• W2979973845 isRetracted "false" @default.
• W2979973845 magId "2979973845" @default.
• W2979973845 workType "article" @default.