RIPK2 inhibitors for disease therapy: Current status and perspectives.

Receptor-interacting protein kinase 2 (RIPK2) belongs to the receptor-interacting protein family (RIPs), which is mainly distributed in the cytoplasm. RIPK2 is widely expressed in human tissues, and its mRNA level is highly expressed in the spleen, leukocytes, placenta, testis, and heart. RIPK2 is a dual-specificity kinase with multiple domains, which can interact with tumor necrosis factor receptor (TNFR), and participate in the Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD) signaling pathways. It is considered as a vital adapter molecule involved in the innate immunity, adaptive immunity, and apoptosis. Functionally, RIPK2 and its targeted small molecules are of great significance in inflammatory responses, autoimmune diseases and tumors. The present study reviews the molecule structure and biological functions of RIPK2, and its correlation between human diseases. In addition, we focus on the structure-activity relationship of small molecule inhibitors of RIPK2 and their therapeutic potential in human diseases.

Accuracy in predicting soft tissue changes of orthodontic class III cases using Dolphin® software.

OBJECTIVES: The prediction of posttreatment outcomes is conducive to the final determination of ideal therapeutic options. However, the prediction accuracy in orthodontic class III cases is unclear. Therefore, this study conducted exploration on prediction accuracy in orthodontic class III patients using the Dolphin® software. MATERIALS AND METHODS: In this retrospective study, lateral cephalometric radiographs of pre- and posttreatment were collected from 28 angle class III adults who received completed non-orthognathic orthodontic therapy (8 males, 20 females; mean age = 20.89 ± 4.26 years). The values of 7 posttreatment parameters were recorded and inserted into the Dolphin® Imaging software to generate a predicted outcome, and then the prediction radiograph and actual posttreatment radiograph were superimposed and compared in terms of soft tissue parameters and landmarks. RESULTS: The prediction showed significant differences with the actual outcomes in nasal prominence (the difference between the prediction and the actual value was - 0.78 ± 1.82 mm), the distance from the lower lip to the H line (0.55 ± 1.11 mm), and the distance from the lower lip to the E line (0.77 ± 1.62 mm) (p < 0.05). Point subnasale (Sn) (an accuracy of 92.86% in the horizontal direction and 100% in the vertical direction in 2 mm) and point soft tissue A (ST A) (an accuracy of 92.86% in the horizontal direction and 85.71% in the vertical direction in 2 mm) were proven to be the most accurate landmarks, while the predictions in the chin region were relatively inaccurate. Furthermore, the predictions in the vertical direction were of higher accuracy compared to the horizontal direction except for the points around the chin. CONCLUSIONS: The Dolphin® software demonstrated acceptable prediction accuracy in midfacial changes in class III patients. However, there were still limitations for changes in the chin and lower lip prominence. CLINICAL RELEVANCE: Clarifying the accuracy of Dolphin® software in predicting soft tissue changes of orthodontic class III cases will facilitate physician-patient communication and clinical treatment.

Artificial intelligence system for automated landmark localization and analysis of cephalometry.

OBJECTIVES: Cephalometric analysis is essential for diagnosis, treatment planning and outcome assessment of orthodontics and orthognathic surgery. Utilizing artificial intelligence (AI) to achieve automated landmark localization has proved feasible and convenient. However, current systems remain insufficient for clinical application, as patients exhibit various malocclusions in cephalograms produced by different manufacturers while limited cephalograms were applied to train AI in these systems. METHODS: A robust and clinically applicable AI system was proposed for automatic cephalometric analysis. First, 9870 cephalograms taken by different radiography machines with various malocclusions of patients were collected from 20 medical institutions. Then 30 landmarks of all these cephalogram samples were manually annotated to train an AI system, composed of a two-stage convolutional neural network and a software-as-a-service system. Further, more than 100 orthodontists participated to refine the AI-output landmark localizations and retrain this system. RESULTS: The average landmark prediction error of this system was as low as 0.94 ± 0.74 mm and the system achieved an average classification accuracy of 89.33%. CONCLUSIONS: An automatic cephalometric analysis system based on convolutional neural network was proposed, which can realize automatic landmark location and cephalometric measurements classification. This system showed promise in improving diagnostic efficiency in clinical circumstances.

Enhanced PDGFR/Wnt/ß-catenin activity of mesenchymal stem cells with high migration ability rescue bone loss of osteoporosis.

Osteoporosis is a widespread disease characterized by bone mass loss and microarchitectural deterioration. The side effects of clinical drugs make mesenchymal stem cells (MSCs)-based therapy gain increasing focus in the treatment of osteoporosis. MSCs need to migrate to the site of damage and undergo differentiation in order to participate in the subsequent bone repair process. Therefore, the homing ability of MSCs may be related to the repair ability. Here, we proposed a novel method to screen MSCs with high migration capacity and confirmed that these MSCs exhibited higher osteogenic differentiation ability both in vivo and in vitro. Further results indicated that MSCs with high migration ability could partly rescue the bone loss of ovarectomized (OVX) rats. Higher expression of Platelet-derived growth factors receptor ß- (PDGFRß) and more nuclear transduction of ß-catenin in MSCs with high migration ability may be responsible for biological functions. This article may provide a method to improve the efficacy of MSCs-based therapy in the clinic.

Relationship of matrix stiffness and cell morphology in regulation of osteogenesis and adipogenesis of BMSCs.

BACKGROUNDS: Matrix stiffness has been found to regulate cell morphology, while both cell morphology and matrix stiffness are verified as important factors directing BMSCs (bone marrow mesenchymal stem cells) differentiation. This study aimed to investigate whether matrix stiffness depended on cell morphology to regulate osteogenesis and adipogenesis of BMSCs on 2D substrates. METHODS AND RESULTS: First, we seeded BMSCs on tissue culture plates (TCPs) with different fibronectin (FN) concentrations and cytoskeleton inhibitor cytochalasin D, and FN was found to promote cell spreading and osteogenesis while inhibiting adipogenesis of BMSCs through F-actin reorganization. Based on these, we modulated BMSCs morphology on 0.5 kPa and 32 kPa CytoSoft® substrates through FN. High concentration of FN (300 µg/ml) coated on 0.5 kPa substrates promoted cell spreading to similar levels with 32 kPa substrates coated with 100 µg/ml of FN, and cells in both groups dominantly commit osteogenesis. On the other hand, low FN concentration (30 µg/ml) on 32 kPa substrates induced restricted cell morphology similar with 0.5 kPa substrates coated with 100 µg/ml of FN, and cells in both groups mainly commit adipogenesis. Immunofluorescence indicated nuclear translocation and higher intensity of YAP/TAZ when cells spread to larger areas, regardless of matrix stiffness. However, when cell spreading areas were fixed as similar levels, matrix stiffness didn't significantly affect YAP/TAZ intensity or location. CONCLUSIONS: Matrix stiffness failed to regulate BMSCs differentiation and YAP/TAZ activity without corresponding cell morphology. Cell spreading area could mediate effects of matrix stiffness on osteogenesis and adipogenesis of BMSCs.

Morphological analysis of mandibular anterior alveolar bone in high-angle adult females assessed with cone-beam computed tomography / 口腔疾病防治

Objective@#To investigate the features of alveolar bone morphology of mandibular central incisors in high-angle adult females using cone-beam computed tomography (CBCT) and evaluate the influence of aging in these patients.@*Methods@# CBCT and lateral cephalometric images of 142 untreated adult female patients were selected and grouped by facial growth pattern. The number of high-angle cases was increased to 164 to further explore the difference within high-angle adult females who were divided into two groups according to age. The indexes of alveolar bone height and thickness in the lower incisor region and inclination of the lower incisors were measured by Dolphin software. The data was statistically analyzed.@*Results@#Compared with the average-angle group, the high-angle group had a lower alveolar bone attachment level (P < 0.05) and less bone thickness at the root apex level (P < 0.05). The thickness of lingual alveolar bone decreased with labial inclination of the lower incisors in both the high-angle and average-angle groups (r = -0.251, P = 0.025; r = -0.428, P = 0.001, respectively). In hyperdivergent female patients, the middle-aged group had a lower attachment level of alveolar bone than the young group (P < 0.05), but no significant difference in bone thickness at the root apex level (P > 0.05) was found between the two groups@*Conclusion @# High-angle adult females had thinner mandibular anterior alveolar bone with significantly lower attachment levels. Aging and inclination of lower incisors influenced bone morphology and should be taken into careful consideration.

Orthodontic emergencies and mental state of Chinese orthodontic patients during the COVID-19 pandemic.

BACKGROUND: The ongoing COVID-19 pandemic postponed routine follow-up visits of many orthodontic patients, which compromised their treatment process and mental states. This study was aimed to assess orthodontic emergency occurrence and psychological states of Chinese orthodontic patients during this pandemic. METHODS: Orthodontic patients in China were invited to answer an anonymous online questionnaire from February 20, 2020 to March 5, 2020, when routine dental care was suspended in China. The questionnaire included self-assessment of oral hygiene and compliance, orthodontic emergencies, perceptions and feelings about COVID-19 and anxiety self-rating scale, etc. Collected data was statistically analyzed with Chi-square, independent t test and univariable generalized estimating equations regression analysis. RESULTS: A total of 1078 respondents (292 male; 786 female) from 30 provinces of China were included in this study. About one-third (33.67%) of patients reported that they encountered orthodontic problems during the pandemic. Patients with clear aligners reported fewer orthodontic problems than those with fixed appliances or removable appliances. Female patients, elder patients and patients who encountered orthodontic emergencies were more anxious than other patients. CONCLUSIONS: The compliance and occurrence of orthodontic emergencies differed in patients with different orthodontic appliances. Patients with orthodontic emergencies exhibited higher anxiety states.

Effects of biophysical cues of 3D hydrogels on mesenchymal stem cells differentiation.

For stem cell research, three-dimensional (3D) hydrogels are increasingly recognized as more physiological systems than two-dimensional culture plates due to bidirectional and 3D interaction of stem cells and surrounding matrix. Among various stem cells, mesenchymal stem cells (MSCs) are one of the most widely applied from bench to bedside. In 3D hydrogels, MSCs are allowed to actively remodel the surrounding matrix through proteolytic degradation and cell-exerted force, which highly resembles in vivo situation. Notably, factors affecting hydrogel modifiability including matrix viscoelasticity and matrix degradability have been found to regulate adhesion, morphology, and fate decision of MSCs. In addition, MSCs within 3D hydrogels have been found to employ multiple mechanotransduction mechanisms including not only the classic integrin-actomyosin cytoskeleton system but also ion channels, microtubule cytoskeleton, and self-secreted proteinaceous matrix. This review summarizes the effects of biophysical cues on MSCs differentiation in 3D hydrogels and underlying mechanobiology in a hope to update our readers' understanding of stem cell biology and guide tissue engineering.