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Dangerous alliance
Lady Victoria Aston, obsessed with Jane Austen and content to stay home, is suddenly expected to enter society and find a husband, preferably one who cares for her more than her dowry.
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Treatment decision in adult patients with class III malocclusion: surgery versus orthodontics
BackgroundOne of the most controversial issues in treatment planning of class III malocclusion patients is the choice between orthodontic camouflage and orthognathic surgery. Our aim was to delineate diagnostic measures in borderline class III cases for choosing proper treatment.MethodsThe pretreatment lateral cephalograms of 65 patients exhibiting moderate skeletal class III were analyzed. The camouflage group comprised of 36 patients with the mean age of 23.5 (SD 4.8), and the surgery group comprised of 29 patients with the mean age of 24.8 years (SD 3.1). The camouflage treatment consisted of flaring of the upper incisors and retraction of the lower incisors, and the surgical group was corrected by setback of the mandible, maxillary advancement, or bimaxillary surgery. Mann-Whitney U test was used to compare the variables between the two groups. Stepwise discriminant analysis was applied to identify the dentoskeletal variables that best separate the groups.ResultsHoldaway H angle and Wits appraisal were able to differentiate between the patients suitable for orthodontic camouflage or surgical treatment. Cases with a Holdaway angle greater than 10.3° and Wits appraisal greater than − 5.8 mm would be treated successfully by camouflage, while those with a Holdaway angle of less than 10.3° and with Wits appraisal less than − 5.8 mm can be treated surgically. Based on this model, 81.5% of our patients were properly classified.ConclusionsHoldaway H angle and Wits appraisal can be used as a critical diagnostic parameter for determining the treatment modality in class III borderline cases.
Journal Article
Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2
The kinase Mst1, which acts in the Hippo pathway, controls cell proliferation, differentiation and apoptosis. Junichi Sadoshima and his colleagues show that Mst1 in cardiomyocytes phosphorylates the protein Beclin1 to coordinately suppress autophagy and promote apoptosis, thereby having deleterious effects on the heart.
Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax.
Journal Article
Three-Dimensional Evaluation of the Effects of Different Treatment Methods on Pharyngeal Airways in Patients with Skeletal Class III Malocclusion
Background and Objectives: The aim of this prospective study was to assess the effects of rapid maxillary expansion (RME) and/or face mask (FM) treatments on the pharyngeal airway in patients with skeletal Class III malocclusion caused by maxillary deficiency. This study utilized cone beam computed tomography (CIBT) for a three-dimensional (3D) analysis of airway changes, comparing the results with those of a control group consisting of untreated skeletal Class III patients. Materials and Methods: The study included 60 participants (34 boys, 26 girls) aged 9 to 14 years, all diagnosed with skeletal Class III malocclusion due to maxillary underdevelopment. The participants were divided into four treatment groups, each consisting of 15 individuals: Group 1—RME; Group 2—RME/FM; Group 3—FM; Group 4—Control group. The pharyngeal airway measurements were evaluated using CBCT and analyzed with Dolphin 3D software (version 11.9). Volumetric parameters and minimal axial area (MAA) were measured in the nasopharyngeal, retropalatal, retroglossal, and total airway regions. The collected data were statistically analyzed using SPSS 20.0 software. Results: The results indicated significant changes in pharyngeal airway volumes across all treatment groups compared to the control group. A statistically significant increase in nasopharyngeal, retropalatal, and total airway volume were observed in all treatment groups. Only the RME group demonstrated a significant increase in retroglossal volume. Significant increases in MAA were found in the RME/FM and FM groups in the nasopharyngeal and retropalatal regions. However, minimal changes were observed in the retroglossal region across all treatment groups. The control group showed no significant changes in any of the measured parameters, underscoring the effects of the treatments. Conclusions: The findings of this study suggest that both RME and/or FM treatments result in significant positive changes in the pharyngeal airways, particularly in the nasopharyngeal and retropalatal regions. The retroglossal region showed more limited response to the treatments. The combined RME/FM therapy was found to be particularly effective in improving airway dimensions in the anterior and mid-pharyngeal regions. These results highlight that early orthodontic interventions, such as RME and FM, can improve both airway patency and overall respiratory function, in addition to addressing skeletal Class III malocclusion.
Journal Article
Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes
The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a–GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations.
The phosphatidylinositol-3-phosphate (PI3P) is generated by the lipid kinase VPS34, in the context of VPS34 complex I on autophagosomes or complex II on endosomes. Biochemical and structural analyses provide insights into the mechanism of both VPS34 complexes recruitment to and activation on membranes by specific Rab GTPases.
Journal Article
A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy
A small-molecule inhibitor of the type III phosphatidylinositol 3-kinase, Vps34, binds the ATP binding pocket and prevents vesicle trafficking and autophagy.
Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (
K
D
1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration–approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer.
Journal Article
Dentoskeletal changes and anteroposterior improvements in skeletal class III malocclusion treated with MEAW: A retrospective study
Skeletal Class III malocclusion is a severe dentofacial deformity that often requires surgical correction, but the associated risks have increased interest in non-surgical alternatives. The multiloop edgewise archwire (MEAW) technique has been used as a conservative option. The aim of this study was to investigate the dentoskeletal changes associated with the MEAW technique in treating skeletal Class III malocclusion, with a particular focus on improvements in anteroposterior bimaxillary relationships and comparison with surgical outcomes.
This retrospective study included 60 patients with skeletal Class III malocclusion, comprising 30 treated with the MEAW technique and 30 matched patients who underwent orthognathic surgery. Dentoskeletal parameters were assessed on pre- and post-treatment lateral cephalograms. Pearson's correlation analysis and multiple linear regression were performed to identify factors associated with improvements in anteroposterior relationships.
Significant dental and skeletal changes were observed, including alterations in incisor inclination and bimaxillary measurements (p < 0.05). Post-treatment, anteroposterior relationships improved significantly, with changes strongly associated with increases in the BaNA angle and decreases in the SNB angle. However, compared to the surgical group, the MEAW group demonstrated less pronounced improvements in anteroposterior bimaxillary relationships. Regression analysis identified the BaNA angle and incisor inclination as key contributors.
Although the effect is less pronounced than in the case of surgical intervention, the MEAW technique effectively improves anteroposterior bimaxillary relationships in skeletal Class III malocclusion. These findings suggest that MEAW is a valuable non-surgical alternative for selected skeletal Class III patients.
Journal Article
Upper airway changes in Class III patients using miniscrew-anchored maxillary protraction with hybrid and hyrax expanders: a randomized controlled trial
ObjectivesThe aim of this study was to compare the upper airway space changes after miniscrew-anchored maxillary protraction with hybrid (HH) and conventional hyrax (CH) expanders.Material and methodsThe sample comprised Class III malocclusion growing patients that were randomized into two groups of miniscrew-anchored maxillary protraction. The group HH was treated with a hybrid hyrax appliance in the maxilla and two miniscrews distally to the canines in the mandible. Class III elastics were used from the maxillary first molar to the mandibular miniscrews until anterior crossbite correction. The group CH was treated with a similar protocol except for the conventional hyrax expander in the maxilla. Cone-beam computed tomography was obtained before (T1) and after 12 months of therapy (T2). The shape and size of upper airway were assessed. Intergroup comparisons were performed using Mann-Whitney U test (p < 0.05).ResultsThe group HH was composed of 20 patients (8 female, 12 male) with a mean age of 10.76 years. The group CH was composed of 15 patients (6 female, 9 male) with a mean age of 11.52 years. Anteroposterior and transverse increases of the upper airway were found for both groups. The oropharynx and the most constricted area increased similarly in both groups.ConclusionsNo differences in upper airway changes were observed using protraction anchored on hybrid or conventional hyrax expanders.Clinical relevanceMaxillary protraction anchored on hybrid or conventional hyrax expanders may benefit patients with breathing disorders due to the increase of the upper airway volume and most constricted area. Registration: ClinicalTrials.gov (NCT03712007).
Journal Article
Long-term three-dimensional skeletal effects of hybrid hyrax with facemask versus mentoplate in growing Class III patients: a randomized controlled trial
Background
Early intervention in Class III malocclusion aims to prevent the need for surgery in adulthood by enhancing upper jaw growth while limiting lower jaw development. Although traditional facemask treatment remain common, bone-anchored devices are increasingly used, claiming better skeletal control and patient compliance. However, strong evidence supporting these advantages is limited.
Methods
Single-center, parallel-group, randomized controlled trial with 1:1 allocation ratio.
Participants:
28 growing Class III patients (mean age 9.7 ± 1.3 years) in mixed dentition with skeletal class III malocclusion.
Interventions:
Patients were randomly assigned to either hybrid hyrax with facemask (HH + FM, n = 14) or hybrid hyrax with mentoplate (HH + MP, n = 14). All received Alt-RAMEC protocol expansion. FM group used 360–400 g/side elastic traction 12–14 h daily; MP group used 185 g/side continuous traction.
Objective:
To compare 5-year three-dimensional (3D) skeletal effects between HH + FM and HH + MP protocols.
Outcome:
Primary outcome was 3D volumetric changes of upper and lower jaw at 1 year (T1) and 5 years (T2) post-treatment, measured using low-dose CT scans. Randomization: 28 patients were allocated to either treatment-protocols using sequentially numbered opaque, sealed envelopes. The randomization sequence was generated with a 1:1 allocation ratio.
Blinding:
Due to the nature of the trial, the operator and children could not be blinded to the treatment allocation. However, blinding was used when assessing the outcomes.
Results
Follow-up: one patient was lost at the one-year follow-up and an additional three patients were lost at the 5-year-follow-up. Outcomes: At T2 (5 years), maxillary advancement was identical between both groups (0.85 mm ± 0.5). Mandibular growth control showed minimal difference (FM: − 0.01 mm ± 0.24; MP: 0.10 mm ± 0.33). No significant differences were found between groups for any skeletal measurements (
p
> 0.05). Male patients showed lager mandibular changes both signed (
p
< 0.03) and unsigned (
p
< 0.01). Harms: minor harms were encountered with the anchor hooks (fracture or mucosal irritation), however none led to treatment cessation.
Conclusions
Both protocols demonstrated comparable long-term skeletal effects in Class III correction. Treatment choice should be based on individual patient factors rather than assumed mechanical advantages.
Journal Article
Impact of tonsillectomy on the efficacy of Alt-RAMEC/PFM treatment protocols in children with class III malocclusion and tonsillar hypertrophy: protocol for a cluster randomised controlled trial
IntroductionOrthodontic treatment using face mask protraction combined with an alternate rapid maxillary expansion and constriction/protraction face mask (Alt-RAMEC/PFM) protocol is effective in the early treatment of patients with class III malocclusion, but the stability of treatment outcomes represents a major concern. Previous studies have suggested that tonsillar hypertrophy can be a risk factor for class III malocclusion and tonsillectomy may prompt the normalisation of dentofacial growth. However, these studies had a low-to-moderate level of evidence. This study was designed to identify the impact of tonsillectomy before orthodontic treatment on the efficacy and stability of Alt-RAMEC/PFM protocols and the sleep quality and oral health in children with anterior crossbite and tonsillar hypertrophy.Methods and analysisThis is a two-arm, parallel-group, superiority cluster randomised controlled trial, with four clinics randomly assigned to the surgery-first arm and the orthodontic-first arm in a 1:1 ratio. The Alt-RAMEC protocol involves alternate activation and deactivation of the expander’s jet screw over 6 weeks to stimulate maxillary suture distraction. Patients will be instructed to wear the PFM for a minimum of 14 hours per day. The primary outcomes are changes in Wits appraisal and the degree of maxillary advancement from baseline to the end of orthodontic treatment. Lateral cephalometric radiographs, polysomnography, Obstructive Sleep Apnoea-18 questionnaire and Oral Health Impact Profile-14 questionnaire will be traced, collected and measured. We will recruit 96 patients intofor the study. To assess differences, repeated multilevel linear mixed modelling analyses will be used.Ethics and disseminationThis study has been granted ethical approval by the Ethics Committee of the School & Hospital of Stomatology, Wuhan University (approval No. 2023-D10). Written informed consent will be obtained from the participants and their guardians. The results of the trial will be disseminated through academic conferences and journal publications.Trial registration numberChiCTR2300078833.
Journal Article