Leukemia and mitophagy: a novel perspective for understanding oncogenesis and resistance.

Mitophagy, the selective autophagic process that specifically degrades mitochondria, serves as a vital regulatory mechanism for eliminating damaged mitochondria and maintaining cellular balance. Emerging research underscores the central role of mitophagy in the initiation, advancement, and treatment of cancer. Mitophagy is widely acknowledged to govern mitochondrial homeostasis in hematopoietic stem cells (HSCs), influencing their metabolic dynamics. In this article, we integrate recent data to elucidate the regulatory mechanisms governing mitophagy and its intricate significance in the context of leukemia. An in-depth molecular elucidation of the processes governing mitophagy may serve as a basis for the development of pioneering approaches in targeted therapeutic interventions.

Periosteum coverage versus collagen-membrane coverage in periodontally accelerated osteogenic orthodontics: a randomized controlled clinical trial in Class II and Class III malocclusions.

BACKGROUND: Periodontal accelerated osteogenic orthodontics (PAOO) is a widely-used clinical procedure that combines selective alveolar corticotomy, particulate bone grafting, and the application of orthodontic forces. Different modifications of PAOO such as collagen-membrane coverage can better benefit patients from preventing displacement of grafts. Due to its stability, collagen-membrane coverage gradually gained popularity and became a widely-used procedure in traditional PAOO technique. OBJECTIVES: To quantitatively investigate the radiographic changes of alveolar bone, periodontal soft tissue changes of the mandibular anterior teeth and postoperative complications in periosteum-covered techniques compared with traditional surgical technique in PAOO. METHODS: Orthodontic camouflage for dental Class II or decompensation for skeletal Class III malocclusions were included; Patients with bone defects on the buccal aspects of the anterior mandible regions confirmed by clinical and radiographic examination were randomly divided into the periosteum coverage group or traditional technique group for PAOO. Cone-beam computerized tomography (CBCT) scans were obtained before treatment (T0) and 1 week (T1) and 12 months (T2) after operation. The primary outcome variable was the vertical alveolar bone level (VBL), the secondary evaluation parameters included labial horizontal bone thickness at the midpoint of the middle third (MHBT) or apical third (AHBT) to the limit of the labial cortical surface during a 12-month follow-up. Postoperative sequelae were evaluated after 2 days and 7 days in both the groups. Periodontal parameters were analyzed at T0 and T2. RESULTS: Thirty-six adult subjects were eligible and recruited in the present study. Although experimental group exhibited more severe infection, no significant differences of the postoperative symptoms or periodontal parameters was found between the 2 groups (P > 0.05). All patients were examined respectively using CBCT at baseline (T0), postoperative 1 week (T1) and 12 months (T2). Both alveolar bone height and width increased from T0 to T1 (P < 0.001) and then reduced from T1 to T2 (P < 0.001) in both groups. However, significant bone augmentation was achieved in each group from T0 to T2 (P < 0.001). Furthermore, the vertical alveolar bone augmentation in the experimental group increased significantly than that in the traditional surgery (P < 0.05). CONCLUSIONS: Compared with traditional PAOO surgery, the periosteum-covered technique provides superior graft stabilization and satisfactory vertical bone augmentation in the labial mandibular anterior area.

Timing of force application on buccal tooth movement into bone-grafted alveolar defects: A pilot study in dogs.

INTRODUCTION: The aim of this pilot study was to evaluate the effect of the timing of postoperative orthodontic force application on bone remodeling during tooth movement into surgical alveolar defects with bone grafts in beagle dogs. METHODS: Six beagle dogs underwent surgery for buccal dehiscence-type defects (width, 5 mm; height, 6 mm) on the distal root of maxillary second premolars bilaterally for 12 defects. After 1-month healing, bone-augmentation procedures were undertaken at the dehiscence defects. The second premolars were protracted buccally for 6 weeks into the surgical sites immediately (F-0), at 4 weeks (F-4), or 8 weeks (F-8) after grafting. Orthodontic tooth movement was monitored using digital models. Remodeling of alveolar bone was evaluated by histology, histomorphometry, immunohistochemistry, microcomputed tomography, and fluorescence microscopy. RESULTS: Group F-0 showed significant expansion (mean, 2.42 mm) and tipping (mean, 9.03°) after completing orthodontic tooth treatment. The vertical bone defect was significantly lower in groups F-4 and F-8 than that in group F-0 (mean, 2.1, 2.7, and 4.5 mm, respectively). In group F-4, the formation of new bone and mineralization were significantly greater than those in groups F-0 and F-8 (P <0.05). Group F-4 showed a minimal amount of bone-material remnants. Immunohistochemistry showed the highest expression of collagen-1 and osteopontin in group F-4, followed by group F-8 and group F-0, which demonstrated high osteoblast activity and enhanced bone remodeling in group F-4. CONCLUSIONS: Orthodontic force application at 4 weeks after an augmentation procedure provided the best functional stimulation for an alveolar bone graft. This strategy enhanced new-bone regeneration and degradation of bone substitutes and, eventually, promoted bone remodeling in the bone-grafted area.

Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo.

Bone resorption, initiated by osteoclasts (OCs), plays an essential role in bone homeostasis. The abnormalities of bone resorption may induce a series of diseases, including osteoarthritis, osteoporosis and aseptic peri-implant loosening. Nirogacestat (PF-03084014, PF), a novel gamma-secretase inhibitor, has been used in phase II clinical trial for treatment of desmoid tumor. However, whether it has the therapeutic effect on abnormal bone resorption remains to be evaluated. In this study, we investigated the role of PF in the regulation of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis in vitro, and the lipopolysaccharide (LPS)-induced bone resorption in vivo. It was found that PF could suppress the formation of osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, inhibit bone resorption and downregulate the mRNA level of osteoclast-specific markers, including calcitonin receptor (CTR), tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), dendritic cell-specific transmembrane protein (Dc-stamp), Atp6v0d2 (V-ATPase d2) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Furthermore, Notch2 signaling, as well as RANKL-induced AKT signaling was significantly inhibited in BMMs. Consistent with in vitro observation, we found that PF greatly ameliorated LPS-induced bone resorption. Taken together, our study demonstrated that PF has a great potential to be used in management of osteolytic diseases.

Membrane fixation for osseous graft stabilization in periodontally accelerated osteogenic orthodontics: a comparative study.

BACKGROUND: Periodontally accelerated osteogenic orthodontics (PAOO) is a treatment for bone defects associated with a lack of bone graft stability, especially in coronal locations. This study aimed to compare a modified technique of membrane fixation that utilizes periosteal sutures (using a pouch design) with the traditional approach, which does not use membrane fixation. METHODS: Twenty-eight patients with a total of 168 teeth treated were divided into two groups: 1-A, in which patients were treated using the modified technique (with membrane fixation), and group 2-B, in which patients were treated using the traditional technique (without membrane fixation). The postoperative bone thickness was evaluated via radiographic examination. RESULTS: Postoperative improvements in bone augmentation were detected in both groups. At 12 months, the values of the CHBT (measured from the midpoint of the coronal third to the labial cortical surface, 0.84 ± 0.33 mm) and the values of VBL (measured from the alveolar crest to the cemento-enamel junction, - 2.35 ± 0.80 mm)were significantly greater in the modified technique group than those in the traditional technique group (CHBT:0.12 ± 0.21 mm and VBL:-1.39 ± 0.99 mm; P = 0.00 and P = 0.01). CONCLUSIONS: This study shows that compared to the traditional technique, the modified PAOO technique with membrane fixation using periosteal sutures provides improved graft stabilization, superior coronal augmentation and satisfactory vertical volume.

A Novel Surgical Technique for Augmented Corticotomy-Assisted Orthodontics: Bone Grafting With Periosteum.

PURPOSE: To introduce grafting fixed with the periosteum (dumpling technique) as an alternative surgical technique for augmented corticotomy-assisted orthodontics in the lower anterior region and evaluate the preliminary outcomes. MATERIALS AND METHODS: Eleven patients (9 women, 2 men; mean age, 21.4 yr) with a thin alveolus or alveolar defect in the lower anterior region by clinical and radiographic examination underwent an augmented corticotomy using the new dumpling technique. Cone-beam computerized tomography was used to evaluate morphologic changes of the lower anterior ridge before treatment (T0) and 1 week (T1) and 6 months (T2) after the bone-augmentation procedure. Repeated-measures analysis of variance with Bonferroni multiple-comparison test was used to compare variables at each time point. RESULTS: No severe postsurgical complications occurred in any patient. The mean alveolar bone thickness of the labial plate increased from T0 to T1 (P < .001) and decreased from T1 to T2 (P < .001). However, compared with T0, there was still a significant increase in horizontal bone thickness at T2 (P < .05). The vertical alveolar bone level increased from T0 to T1 (P < .001) and was maintained from T1 to T2 (P > .05). No significant differences were found in root length of the lower anterior teeth at these 3 time points (P > .05). CONCLUSIONS: In this preliminary study, the dumpling technique for augmented corticotomy-assisted surgical orthodontics showed alveolar bone augmentation by increasing the vertical alveolar height and the horizontal bone thickness in the labial aspect of the anterior mandibular area. However, long-term follow-up is necessary.

Targeting mTOR/p70S6K/glycolysis signaling pathway restores glucocorticoid sensitivity to 4E-BP1 null Burkitt Lymphoma.

BACKGROUND: Increasing evidence indicates that rapamycin could be used as a potential glucocorticoid (GC) sensitizer in lymphoblastic malignancies via genetic prevention of 4E-BP1 phosphorylation. Interestingly, we found that combined rapamycin with dexamethasone can effectively reverse GC resistance in 4E-BP1 null lymphoma cells. In this study, we investigated the potential link between mTOR/p70S6K signaling pathway, glycolysis, autophagy and GC resistance. METHODS: Antitumor effects of the combination of rapamycin and dexamethasone were evaluated on cell viability by MTT assay and in vivo studies, on cell cycle and apoptosis by flow cytometry, on autophagy by western blot, MDC staining and transmission electron microscopy and on cell signaling by western blot. Moreover, to test whether inhibiting glycolysis is the core mechanism in rapamycin restoring GC sensitivity, we took glycolysis inhibitor 2-deoxyglucose to replace rapamycin and then evaluated the antitumor effects in vitro. RESULTS: Raji cells are resistant to rapamycin (IC50 > 1000 nM) or dexamethasone (IC50 > 100 µM) treatment alone. The combination of rapamycin and dexamethasone synergistically inhibited the viability of Raji cells in vitro and in vivo by inducing caspase-dependent and -independent cell death and G0/G1 cell cycle arrest. These effects were achieved by the inhibition of mTOR/p70S6K signaling pathway, which led to the inhibition of glycolysis and the induction of autophagy. Pretreatment with pan-caspase inhibitor z-VAD-fmk or autophagy inhibitor 3-MA failed to protect the cells from combined treatment-induced death. Glycolysis inhibitor combined with dexamethasone produced a similar antitumor effects in vitro. CONCLUSIONS: Inhibition of mTOR/p70S6K/glycolysis signaling pathway is the key point of therapy in reversing GC resistant in Burkitt lymphoma patients.

Changes in the temporomandibular joint space after functional treatment of disk displacement with reduction.

This study aimed to evaluate the changes of temporomandibularjoint (TMJ) space in the treatment of disk displacement with reduction (DDWR) for class II cases. Forty-two adolescent patients with unilateral DDWR, who were successfully treated by functional appliance, were selected in this study. Magnetic resonance imaging scans were used before treatment (T1), at the start of treatment (T2), and after functional treatment (T3). Compared with the normal joint, the change of joint space index was calculated. The anterior, posterior, and superior joint spaces were analyzed on the largest sagittal plane among T1, T2, and T3. Student's t-test was used for statistical analysis. The mean treatment period was 10 months (6-16 mo). Functional appliance was effective in eliminating pain and clicking. During the phase of T1, the value of the joint space index of DDWR was significantly higher than that of the control (P < 0.05). There was a significant decrease in the anterior space and an increase in the postsuperior space at T2 (P < 0.01), and then the contrary changes occurred at T3. However, there was a significant increase in the postsuperior space and no significant decrease in the anterior space when T1 and T3 were compared. This study indicates that the TMJ space is well distributed after disk repositioning with functional treatment of DDWR. It is also suggested that the adaptive remodeling in TMJ occurs via functional treatment.

Microgel Encapsulated Mesoporous Silica Nanoparticles for Releasing Wnt16 to Synergistically Treat Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a commonly encountered degenerative joint disease in oral and maxillofacial surgery. Recent studies have shown that the excessive unbalanced activation of Wnt/ß-catenin signaling is connected with the pathogenesis of TMJOA and due to the inability to inhibit the over-activated Wnt pathway, while Wnt16-deficient mice has a more severe Knee OA. However, the efficacy of direct intra-TMJ injection of Wnt16 for the relief of TMJOA is still not directly confirmed. Moreover, small-molecule drugs such as Wnt16 usually exhibit short-lived efficacy and poor treatment adherence. Therefore, in order to obtain a stable release of Wnt16 both in the short and long term, this study fabricates a double-layer slow-release Wnt16 carrier based on mesoporous silica nanospheres (MSNs) encased within hyaluronic acid (HA) hydrogels. The biofunctional hydrogel HA/Wnt16@MSN is analyzed both in vitro and in vivo to evaluate the treatment of TMJOA. As a result, it shows superior pro-cartilage matrix restoration and inhibition of osteoclastogenesis ability, and effectively inhibits the over-activation of the Wnt/ß-catenin pathway. Taken together, biofunctional hydrogel HA/Wnt16@MSN is a promising candidate for the treatment of TMJOA.

Feasibility of simultaneous TMJ arthroscopy in ADDwoR patients undergoing orthognathic surgery for jaw deformity.

This study evaluated the feasibility of simultaneous temporomandibular joint (TMJ) arthroscopy and orthognathic surgery as a new treatment strategy for anterior disc displacement without reduction (ADDwoR) patients with severe jaw deformities. Twelve ADDwoR patients with facial deformities who underwent arthroscopy and orthognathic surgery between September 2015 and December 2019 were retrospectively evaluated. Pre- and postoperative maximum incisal opening (MIO) and joint pain were recorded. Computed tomography (CT) and three-dimensional cephalometric analysis were performed at 3 (T1) and ≥6 (T2) months postoperatively. Magnetic resonance imaging (MRI) of the TMJ was performed before, ≤7 days after and ≥6 months after surgery. The lateral profile radiological findings, the symmetry of the maxilla and mandible, and the MRI measurements were compared. Anterior disc displacement did not recur, and the maximum incisal opening (MIO) increased from 27.4 mm to 32.7 mm after surgery (p < 0.05). No significant differences were found in the lateral profile, symmetry indices or condylar height via MRI between T1 and T2. Joint morphology and the position of both the maxilla and mandible remained stable during postoperative follow-up, while joint symptoms were markedly relieved and facial appearance was noticeably improved. Combined arthroscopy and orthognathic surgery is effective and recommended for ADDwoR patients with jaw deformities.

Association between bilateral condylar resorption and reduced volumes of the craniofacial skeleton and masticatory muscles in adult patients: A retrospective study.

Objectives: This retrospective cohort study aimed to analyze volumes of craniomaxillofacial bone and masticatory muscles of young adults with bilateral idiopathic condylar resorption. Methods: This was a retrospective cohort study of 84 adults with bilateral idiopathic condylar resorption (BCR) and 48 adults with normal temporal-mandibular joint (TMJ) matched for age and sex (mean age, 23.2 ± 3.6 years). The volumes of craniomaxillofacial bone and masticatory muscles, as well as intercondylar angle were measured. Unpaired t-tests and Pearson correlation tests were applied to analyze the data. Multivariable linear regression models were used to estimate the association between bilateral condylar volume and volumes of craniomaxillofacial bone and masticatory muscles adjusted for age, sex, and disc status. Results: Compared to the control group, the BCR group displayed significant decreased volumes of craniomaxillofacial bone (p < 0.001), craniomaxillofacial bone without mandible (p < 0.001), mandible (p < 0.001), mandible without mandibular condylar process (p < 0.001), bilateral masseter muscle (p < 0.001) and bilateral temporalis muscle (p < 0.001), as well as the intercondylar angle (p < 0.001). These variables were significantly correlated to the volume of mandibular condylar process (0.5< r < 0.8; p < 0.001). By linear regression analyses, significant associations were found for the bilateral condylar volume with craniomaxillofacial bone volume and mandible bone volume. Conclusions: Young adults with BCR displayed smaller volumes of craniomaxillofacial skeleton and masticatory muscles, and smaller intercondylar angle than the normal patients. The craniofacial musculoskeletal volume and intercondylar angle are associated with mandibular condylar process volume.

Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma.

BACKGROUND: Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. METHODS: A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells. RESULTS: ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK. CONCLUSIONS: Overexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.

GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis.

BACKGROUND: Growth differentiation factor 15 (GDF15), a divergent TGFß superfamily, has recently been implicated in the modulation of iron homeostasis, acting as an upstream negative regulator of hepcidin, the key iron regulatory hormone produced primarily by hepatocytes. However, little is known about possible roles that GDF15 might play in the regulation of iron homeostasis and development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis (HLH). PROCEDURES: We compared serum GDF15 level and mRNA expressions of GDF15 and key molecules of iron metabolism, and made correlations between their expressions in children with HLH and control children. RESULTS: Serum GDF15 level was remarkably higher in HLH group than that in controls, with median serum concentration of 1,700 and 260 pg/ml, respectively (P < 0.001). In addition, GDF15 mRNA was significantly upregulated but independent of hypoxia-inducible factor-mediated oxygen signaling pathway. More importantly, GDF15 induction was positively correlated to upregulation of ferroportin, the only cellular iron exporter, and to upregulation of ferritin heavy chain. CONCLUSIONS: Our study suggests that GDF15 induction helps suppress further activation of macrophages in stressful physiologic states as HLH, and is intimately implicated in the development of hyperferritinemia by modulating the hepcidin-ferroportin axis, resulting in enhanced ferroportin-mediated iron efflux.

Marsupialization facilitates eruption of dentigerous cyst-associated mandibular premolars in preadolescent patients.

PURPOSE: The purpose of the present study was to investigate the eruption of dentigerous cyst (DC)-associated mandibular premolars after marsupialization in preadolescents. PATIENTS AND METHODS: The present study was a retrospective cohort study of preadolescent patients with DCs who were treated as outpatients at the Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. For our study, the data from these patients were collected, and the eruption of the premolar teeth, along with related factors, such as the interval to eruption, cusp depth, angulation, cyst size, and eruption space, were analyzed for the cyst group compared with the noncyst control group. RESULTS: The mean age of the patients was 9.1 years. All teeth associated with DCs erupted successfully after marsupialization. The follow-up panoramic radiograph showed that the cysts had disappeared and had been replaced by regenerated bone. The initial panoramic radiograph showed the angulation of the teeth in the cyst group had a significantly larger inclination angle than did the teeth in the noncyst group (P < .05). However, no significant difference was found for cusp depth, root formation, or space measurement. The gender, age, cusp depth, angulation, and eruption space were not factors influencing the eruption of the DC-associated tooth for preadolescent patients in the present study. In addition, the cyst-associated teeth took less time to erupt than the teeth in the control group. CONCLUSIONS: The results of the present study suggest that DC-associated mandibular premolars can erupt spontaneously after marsupialization in preadolescents.

An orthodontic technique for minimally invasive extraction of impacted lower third molar.

PURPOSE: To present a novel orthodontic approach for minimally invasive extraction of impacted mandibular third molars (M3s) close to the inferior alveolar nerve (IAN). PATIENTS AND METHODS: Eight patients (8 M3s) requiring extraction of M3s were included in this study; there were 2 cases of horizontal impaction, 4 of mesioangular impaction, and 2 of vertical impaction. Cone-beam computed tomogram showed that the roots of impacted M3s in 2 cases interrupted the cortices of the mandibular canal, and those in the other 6 cases were very close to the IAN. Orthodontic treatment was performed in this study. The crowns of 5 impacted teeth were surgically exposed before the application of the orthodontic device, whereas bonding was performed directly to the occlusal surface of the other 3 M3s, which had partially erupted. The opposing maxillary M3s were removed in 3 cases. One-step orthodontic extraction was applied to vertically impacted M3s and 2-step treatment was applied to horizontally or mesioangularly impacted M3s. Success was defined as the separation of the impacted tooth from the IAN as visualized on cone-beam computed tomogram. RESULTS: After orthodontic treatment, all impacted M3s were extruded and separated from the IAN (mean, 6.6 months; range, 4 to 10 months), without any neurologic consequences. The average time of extraction was 5 minutes. In all 8 cases, new bone formation occurred distal to the adjacent second molar. CONCLUSION: This orthodontic technique may be a minimally invasive approach for the extraction of impacted M3s adjacent to the IAN, with a decreased risk of paresthesias and with osteoperiodontal advantages.

Role of periosteum in alveolar bone regeneration comparing with collagen membrane in a buccal dehiscence model of dogs.

To investigate the role of periosteum on the treatment of buccal dehiscence defects comparing with collagen membrane in canine model. Bilateral dehiscence-type defects at the buccal side on the distal root of the lower 3rd/4th premolars were created in six beagle dogs with a total of 24 defects and assigned into three groups: Group A: blood clot in an untreated defect; Group B: deproteinized bovine bone material (DBBM) covered with an absorbable membrane; Group C: DBBM covered with the periosteum. The structural parameters for trabecular architecture and vertical bone regeneration were evaluated. Histological and histomorphometric evaluation were carried out to observe new bone formation and mineralization in the graft site. Immunohistochemical analysis was performed to identify the expression of osteopontin (OPN) and osteocalcin (OCN) at postoperative 3 months. Group C achieved greater vertical alveolar bone gain than that of group A and group B. The periosteum-covered group showed significantly greater new bone formation and accelerated mineralization. The greater immunolabeling for OPN and OCN was observed in group C than in group A. Periosteal coverage has explicit advantages over collagen membranes for the quality and quantity of new bone regeneration in dehiscence defects repairing.

N-MID, P1NP, ß-CTX, and phosphorus in adolescents with condylar resorption.

OBJECTIVE: Condylar resorption (CR) is a temporomandibular joint disease that causes various physical or functional defects. We aimed to find the association between CR and bone metabolism levels. STUDY DESIGN: In this study, we recruited patients visiting the Orthodontic Clinic at Shanghai Ninth People's Hospital from January 2020 to September 2021. Patient characteristics, magnetic resonance imaging examination results, bone mineral density (BMD), Z-score, bone turnover markers, minerals, and hormones were collected and analyzed. RESULTS: The 89 participants were divided into CR (n = 46) and normal (n = 43) groups. Univariate logistic regression showed that N-terminal mid-fragment of osteocalcin (N-MID), procollagen type 1 N-terminal propeptide (P1NP), ß-C-terminal telopeptide of type 1 collagen (ß-CTX), and phosphorus (P < .001 for all) were protective factors, and BMD (P = .047) was a risk factor for CR. Multivariable logistic regression showed that N-MID, P1NP, ß-CTX, and phosphorus (odds ratio <1, P < .05 for all) were protective factors for CR. Receiver operating characteristic curves showed these indicators to effectively predict CR occurrence (area under the curve >0.7; P < .001). CONCLUSION: Adolescents with low serum N-MID, P1NP, ß-CTX, and phosphorus levels were associated with a higher risk of CR. We suggest that these indicators can guide clinicians in the early detection and prevention of CR in adolescents.

Leukemic transformation by the APL fusion protein PRKAR1A-RAR{alpha} critically depends on recruitment of RXR{alpha}.

PRKAR1A (R1A)-retinoic acid receptor-alpha (R1A-RARalpha) is the sixth RARalpha-containing fusion protein in acute promyelocytic leukemia (APL). Using the murine bone-marrow retroviral transduction/transformation assay, we showed that R1A-RARalpha fusion protein could transform bone-marrow progenitor/stem cells. In gel-shift assays, R1A-RARalpha was able to bind to a panel of retinoic acid response elements both as a homodimer and as a heterodimer with RXRalpha, and demonstrated distinct DNA-binding characteristics compared with wild-type RARalpha/RXRalpha or other X-RARalpha chimeric proteins. The ratio of R1A-RARalpha to RXRalpha proteins affected the retinoic acid response element interaction pattern of R1A-RARalpha/RXRalpha complexes. Studies comparing R1A-RARalpha with R1A-RARalpha(DeltaRIIa) demonstrated that the RIIa protein interaction domain located within R1A was responsible for R1A-RARalpha homodimeric DNA binding and interaction with wild-type R1A protein. However, the RIIa domain was not required for R1A-RARalpha-mediated transformation because its deletion in R1A-RARalpha(DeltaRIIa) did not compromise its transformation capability. In contrast, introduction of point mutations within the RARalpha portion of either R1A-RARalpha or R1A-RARalpha(DeltaRIIa), previously demonstrated to eliminate RXRalpha interaction or treatment of transduced cells with RXRalpha shRNA or a RXRalpha agonist, reduced transformation capability. Thus, leukemic transformation by APL fusion protein PRKAR1A-RARalpha is critically dependent on RXRalpha, which suggests RXRalpha is a promising target for APL.

Use of mesoporous polydopamine nanoparticles as a stable drug-release system alleviates inflammation in knee osteoarthritis.

Osteoarthritis drugs are often short-acting; therefore, to enhance their efficacy, long-term, stable-release, drug-delivery systems are urgently needed. Mesoporous polydopamine (MPDA), a natural nanoparticle with excellent biocompatibility and a high loading capacity, synthesized via a self-aggregation-based method, is frequently used in tumor photothermal therapy. Here, we evaluated its efficiency as a sustained and controlled-release drug carrier and investigated its effectiveness in retarding drug clearance. To this end, we used MPDA as a controlled-release vector to design a drug-loaded microsphere system (RCGD423@MPDA) for osteoarthritis treatment, and thereafter, tested the efficacy of the system in a rat model of osteoarthritis. The results indicated that at an intermediate drug-loading dose, MPDA showed high drug retention. Furthermore, the microsphere system maintained controlled drug release for over 28 days. Our in vitro experiments also showed that drug delivery using this microsphere system inhibited apoptosis-related cartilage degeneration, whereas MPDA-only administration did not show obvious cartilage degradation improvement effect. Results from an in vivo osteoarthritis model also confirmed that drug delivery via this microsphere system inhibited cartilage damage and proteoglycan loss more effectively than the non-vectored drug treatment. These findings suggest that MPDA may be effective as a controlled-release carrier for inhibiting the overall progression of osteoarthritis. Moreover, they provide insights into the selection of drug-clearance retarding vectors, highlighting the applicability of MPDA in this regard.