ABSTRACT
Plexiform neurofibroma (pNF) in the head and neck is a characteristic feature in patients with neurofibromatosis type 1 (NF1) and is associated with significant disfigurement and psychological distress. Yes-associated protein (YAP), the key molecule involved in the Hippo pathway, is a vital transductor that regulates the proliferation and remyelinating of Schwann cells. The functional status of YAP and its feasibility as a potential target are still unknown in pNF. A total of 17 pNF tumor tissue specimens from the head and neck were collected at the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Histologically, diagnosis of the Schwann cell region in pNF was achieved with hematoxylin-eosin staining, positive reactions for S100, SOX10, ERK and p-ERK, and low identification of Ki67 and SMA. Compared with normal nerve tissue, obviously increased nuclear YAP was detected in the Schwann cell region of pNF, with a mean nuclear staining rate of 67.11%. Based on the shNF1 Schwann cell model (the RSC96 cell line), with upregulated expression of RAS, ERK and p-ERK, p-YAP (Ser127) and p-YAP (Ser397) were significantly decreased and total YAP and nuclear YAP were increased. According to a confocal assay, the interference of shNF1 substantially promoted YAP nuclear translocation. Compared with control Schwann cells, the YAP inhibitor CA3 might have a more sensitive effect (IC50: NC=0.96±0.04, shNF1=0.71±0.02, P<0.05) on the shNF1 Schwann cell model than the classic MEK1/2 inhibitor selumetinib (IC50: NC=14.36±0.95, shNF1=24.83±0.98, P>0.05). For in vivo inhibition, the CA3 group and the selumetinib group displayed a similar inhibition effect with no significant difference. Increased nuclear translation and the functional state of YAP implies that the YAP-Hippo pathway might play an important role in the formation and remyelination of pNF. Compared with selumetinib, the YAP inhibitor can exhibit a similar but more sensitive effect on NF1-/- Schwann cells. These observations imply that YAP as a novel or adjuvant therapy target in the treatment of pNF.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/pharmacology , Neurofibroma, Plexiform/genetics , Neurofibromatosis 1/complications , Schwann Cells/pathology , Transcription Factors/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adolescent , Adult , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Proliferation/drug effects , Child , Child, Preschool , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Molecular Targeted Therapy/methods , Neurofibroma, Plexiform/drug therapy , Neurofibroma, Plexiform/pathology , Neurofibromatosis 1/drug therapy , Neurofibromatosis 1/genetics , Transcription Factors/antagonists & inhibitors , Xenograft Model Antitumor Assays , YAP-Signaling Proteins , Young AdultABSTRACT
The article is withdrawn by the authors request.
ABSTRACT
PURPOSE: The aim of this study was to explore the effect of Choukroun platelet-rich fibrin (PRF) combined with autologous micro-morselized bone on the repair of mandibular defects in rabbits. MATERIALS AND METHODS: Thirty-six healthy New Zealand rabbits were selected for the present study. After models of mandibular defects were established, rabbits were randomly divided into Choukroun PRF, autologous micro-morselized bone (autologous), Choukroun PRF combined with autologous bone (combined) and model groups. After the rabbits were sacrificed at 2, 8, and 12 weeks postoperatively, their bone formation was assessed by x-ray and scanning electron microscopy, and the histologic changes of the mandibular defect area were detected by hematoxylin and eosin staining. Cone-beam computed tomography was used to observe the size of the change of the mandibular defect area. Bone mineral density (BMD) was analyzed by dual-energy x-ray absorptiometry. RESULTS: The bone defect in the combined group showed better repair, increased bone mineral content, and denser callus than the other groups, and the defect area was filled with mature trabecular bone. In the Choukroun PRF and autologous groups, the defect area was smaller and filled with osteoporotic trabecular bone. A clear mandibular defect area was still observed in the model group. Compared with the other groups, the combined group showed more bone regeneration, more fibrous tissue regeneration, and greater bone maturity at all time points. The combined group had the highest BMD, there was no relevant difference in BMD between the Choukroun PRF and autologous groups, and the model group had the lowest BMD. BMD in all 4 groups increased with time. CONCLUSION: These findings indicate that Choukroun PRF combined with autologous micro-morselized bone can substantially improve the repair of mandibular defects in rabbits, and the effect is superior to Choukroun PRF or autologous micro-morselized bone alone.
Subject(s)
Bone Transplantation/methods , Mandible/surgery , Platelet-Rich Fibrin , Animals , Bone Density , Bone Regeneration , Cone-Beam Computed Tomography , Microscopy, Electron, Scanning , Rabbits , Transplantation, AutologousABSTRACT
BACKGROUND This study explored the effects of nano-hydroxyapatite/polyetheretherketone (n-HA/PEEK)- coated sandblasted, large-grit, and acid-etched (SLA) implants on inflammatory cytokines and osseointegration in peri-implantitis model beagle dogs. MATERIAL AND METHODS Peri-implantitis models were established. Eight beagle dogs were randomly and evenly assigned into SLA tied, SLA + n-HA/PEEK tied, SLA untied, or SLA + n-HA/PEEK untied groups. A special periodontal probe was used to detect the plaque index (PLI), probing depth (PD), and modified Sulcus Bleeding Index (mSBI). Gingival crevicular fluid was collected and an ELISA kit was utilized to detect IL-1, IL-6, and IL-17 levels. The colony-forming units were counted and the maximum shear strength of implants was tested using the axial pullout test. HE staining was used to detect the inflammation of peri-implant bone tissues. Osseointegration was observed through toluidine blue staining. Bone-to-implant contact (BIC) was obtained through histological observation and the mineral apposition rate (MAR) was calculated after immune fluorescent double staining. RESULTS The SLA tied group demonstrated higher levels of PLI, PD, mSBI, IL-1, IL-6, and IL-17 and a higher degree of inflammation than the SLA + n-HA/PEEK tied group. The tied groups also displayed similar results over the untied groups at the same time point. The maximum shear strength, BIC, and MAR in the SLA tied group were significantly lower than in the SLA + n-HA/PEEK tied group. CONCLUSIONS Our findings demonstrate that SLA + n-HA/PEEK implants can promote osseointegration and relieve the inflammation response of peri-implantitis in beagle dogs.
