1,723,167 research outputs found
Comparative analysis of mRNA expression between control- and miR-7977-transduced MSCs.
No full text(A) Transfection of control or miR-7977 mimic into MSCs. 5 nM of miR-7977 mimic was used for transfection. After 72 hrs, total RNA was prepared for transcriptome analysis. (B) The mRNA was analyzed by Human Gene 2.0ST Array and compared. Scattered plot demonstrates the total RNA level in control MSCs and miR-7977-transduced MSCs. (C) Cluster analysis of mRNA expression in MSCs. The gene symbols that have the target sites predicted by miRDB are indicated by red ink. CEL data were normalized by the rma method provided by Bioconductor (R commander 3.4.1). Dendrogram and heatmap were made by using the amap and gplots package. The genes shown were selected when the expression level significantly differed between control and miR-7977-transduced MSCs [control (n = 3) vs. miR-7977 (n = 3), P = 0.023]. The gene expression level in the heatmap was expressed by intensity-based Z-score.</p
RMC-7977: A PROMISING INHIBITOR FOR THE TREATMENT OF NF1-RELATED TUMORS
Get PDFNeurofibromatosis type 1 (NF1) is a common genetic disorder characterized by mutations in the NF1 gene, leading to the loss of neurofibromin, a RAS GTPase-activating protein, which results in the persistent activation of the RAS-MAPK signaling pathway, facilitating tumorigenesis, such as cutaneous and plexiform neurofibromas, malignant peripheral nerve sheath tumors (MPNSTs), and gliomas. Despite advances in our understanding of NF1-associated tumor biology, current treatment options remain limited, especially for MPNSTs and high-grade gliomas. RMC-7977, a novel tri-complex pan-RAS inhibitor, selectively targets the active GTP-bound form of RAS by forming a stable complex with cyclophilin A (CYPA) and RAS, offering a new therapeutic approach.
Here, we evaluated the efficacy of RMC-7977 in NF1 -mutated tumor models. IC50 assays were performed on multiple NF1 cell lines, identifying sensitive lines for in vivo investigation. Xenograft mouse models were then established via orthotopic implantation of luciferase-tagged cells into the sciatic nerve, brain, or subcutaneously of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We found that RMC-7977 significantly suppressed tumor progression in ST8814, S462, and JH-2-002 models, and improved survival in intracranial LN229 tumor-bearing mice, with delayed but statistically significant tumor growth inhibition and prolonged survival. Interestingly, despite its high molecular weight of 865.1 Da, RMC-7977 demonstrated the ability to penetrate the Blood-Brain Tumor Barrier (BBTB) and exert antitumor activity within the central nervous system. Overall, these findings provide foundational evidence for RMC-7977 as a promising therapeutic strategy for targeting RAS-driven NF1 malignancies
miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells
No full textWe and others have demonstrated that various abnormalities of the bone marrow (BM) mesenchymal stromal cells (MSCs) such as aberrant cytokine expression, abnormal hedgehog signaling, and impaired miRNA biogenesis are observed in patients with acute myeloid leukemia (AML). However, underlying mechanisms to induce the dysfunction of BM MSCs have not yet been clarified. We previously showed that AML cells release abundant exosomal miR-7977, which, in turn, enters BM mesenchymal stromal cells (MSCs). However, the precise function of miR-7977 is not known. In this study, we performed transduction of a miR-7977 mimic into MSCs, compared transcriptomes between control-transduced (n = 3) and miR-7977-transduced MSCs (n = 3), and conducted pathway analysis. The array data revealed that the expression of 0.05% of genes was reduced 2-fold and the expression of 0.01% of genes was increased 2-fold. Interestingly, approximately half of these genes possessed a miR-7977 target site, while the other genes did not, suggesting that miR-7977 regulates the gene expression level directly and indirectly. Gene set enrichment analysis showed that the gene sets of Yes-associated protein 1 (YAP1) _up were significantly enriched (p</div
RMC-7977: A PROMISING INHIBITOR FOR THE TREATMENT OF NF1-RELATED TUMORS
Get PDFNeurofibromatosis type 1 (NF1) is a common genetic disorder characterized by mutations in the NF1 gene, leading to the loss of neurofibromin, a RAS GTPase-activating protein, which results in the persistent activation of the RAS-MAPK signaling pathway, facilitating tumorigenesis, such as cutaneous and plexiform neurofibromas, malignant peripheral nerve sheath tumors (MPNSTs), and gliomas. Despite advances in our understanding of NF1-associated tumor biology, current treatment options remain limited, especially for MPNSTs and high-grade gliomas. RMC-7977, a novel tri-complex pan-RAS inhibitor, selectively targets the active GTP-bound form of RAS by forming a stable complex with cyclophilin A (CYPA) and RAS, offering a new therapeutic approach.
Here, we evaluated the efficacy of RMC-7977 in NF1 -mutated tumor models. IC50 assays were performed on multiple NF1 cell lines, identifying sensitive lines for in vivo investigation. Xenograft mouse models were then established via orthotopic implantation of luciferase-tagged cells into the sciatic nerve, brain, or subcutaneously of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We found that RMC-7977 significantly suppressed tumor progression in ST8814, S462, and JH-2-002 models, and improved survival in intracranial LN229 tumor-bearing mice, with delayed but statistically significant tumor growth inhibition and prolonged survival. Interestingly, despite its high molecular weight of 865.1 Da, RMC-7977 demonstrated the ability to penetrate the Blood-Brain Tumor Barrier (BBTB) and exert antitumor activity within the central nervous system. Overall, these findings provide foundational evidence for RMC-7977 as a promising therapeutic strategy for targeting RAS-driven NF1 malignancies
Alteration of cell function after miR-7977 transfer.
No full text(A) pCMV-MIR- or pCMV-7977-transduced HTS-5 cells were visualized under a fluorescence microscope. Cell membrane was stained with WGA594 and nucleus was stained with Hoechst33342. Scale bar = 50 μm. (B) Saturation density was evaluated when HTS-5 reached confluence. pCMV-MIR-transduced HTS-5 vs. pCMV-7977-transduced HTS-5, *p = 0.00265. Transduced cells were selected with 175 μm Geneticin (G418) before analysis. (C) Annexin V/PI assay. The X-axis indicates Annexin V-FITC and Y-axis indicates PI. (D) Cell cycle analysis. G1 84.2±2.46 vs. 61.4±1.10, p<0.0018 (n = 3); S 10.0±2.07 vs. 14.0±0.94, p<0.0035; G2M 5.63±0.60 vs. 24.5±1.26, p = 0.00042.</p
Transduction of miR-7977 induce nuclear localization of YAP1 and inactivated Hippo-YAP signaling via transcription factor TEAD.
No full text(A) Nuclear localization of GFP-tagged YAP1 after transduction of YAP1 (GFP-tagged)—pCMV6-AC-GFP into HTS-5. Subsequently, control or 20 nM miR-7977 mimic was transfected, and the cells were visualized. Left panel: control siRNA transfer. Right panel: miR-7977 transfer. Scale = 10 μm. (B) Schematic diagram of luciferase assay to evaluate the interaction of TEAD and YAP1. (C) Transduction of pCMV-MIR-7977 and 8xGTIIC-luciferase into the HTS-5 stromal cell line and analysis of luciferase activity 2 days after transduction. Luciferase activity was normalized to the activity of an internal control (renilla luciferase). *P t-test). Data represent three independent experiments, each done in octuplicate.</p
HD 7977 and its possible influence on Solar System bodies
Get PDFContext. In the latest Gaia third data release, one can find extremely small proper motion components for the star HD 7977. This, together with the radial velocity measurement lead to the conclusion that this star passed very close to the Sun in the recent past.
Aims. Such a very close approach of a one solar mass star must have resulted in noticeable changes in the motion of all Solar System bodies, especially those on less tight orbits, namely long-period comets (LPCs) and transneptunian objects (TNOs). We estimate and discuss these effects.
Methods. Our current knowledge on the solar neighbourhood found in the latest Gaia catalogues allowed us to perform numerical integrations and prepare a list of potential stellar perturbers of LPCs. We used this list, made available in the StePPeD database. To study the past motion of LPCs under the simultaneous action of the Galactic potential and passing stars, we used precise original cometary orbits taken from the current CODE catalogue.
Results. We examined the reliability of the extremely small proper motion of HD 7977 and conclude that this star can be an unresolved binary; however, according to the astrometry covering more than a century, the current Gaia data cannot be ruled out. We present the parameters of a very close passage of this star near the Sun. We also show examples of the strong influence of this passage on the past motion of some LPCs. We also discuss the possible influence of this perturber on other Solar System bodies.
Conclusions. It is possible that 2.47 Myr ago the one solar mass star HD 7977 passed as close as 1000 au from the Sun. Such an event constitutes a kind of dynamical horizon for all studies of the past Solar System bodies’ dynamics
Transduction of miR-7977 reduced the level of STK4 and YAP1.
No full text(A) qRT-PCR for STK4 was conducted after transduction of control or miR-7977 for primary MSCs (5 nM) and HTS-5 (20 nM). The left panel shows the results in MSC (n = 5), and the right panel shows the results in the HTS-5 mesenchymal cell line (n = 3). (B) Immunoblot analysis of Hippo signaling pathway after transfer of control siRNA or miR-7977 into HTS-5. Anti-STK4 Ab, anti-YAP1 and anti- phospho-YAP1 Ser127 were used. As internal standard, anti-β-actin was used.</p
- …
