Clinical phenotypes of adult-onset Behçet's syndrome: a comprehensive cross-sectional study in China.

Behçet's syndrome (BS) is a variant vasculitis that can involve multiple organs with inflammatory manifestations. This study aimed to provide a more comprehensive analysis of the clinical phenotypes and characteristics of BS patients. We enrolled 2792 BS patients referred from China nationwide to Huadong Hospital Affiliated to Fudan University from October 2012 to December 2022. Detailed assessments of demographic information, clinical manifestations, laboratory results, gastroscopy, and medical imaging were conducted. Cluster analysis was performed based on 13 variables to determine the clinical phenotypes, and each phenotype was characterized according to the features of BS patients. A total of 1834 BS patients were included, while 958 invalid patients were excluded. The median age at onset was 31 years (IQR, 24-40 years), and the median disease duration was 10 years (IQR, 5-15 years). Eight clusters were identified, including mucocutaneous (n = 655, 35.7%), gastrointestinal (n = 363, 19.8%), articular (n = 184, 10%), ocular (n = 223, 12.2%), cardiovascular (n = 119, 6.5%), neurological (n = 118, 6.4%), vascular (n = 114, 6.2%), and hematological phenotype (n = 58, 3.2%). Ocular (RR = 1.672 (95% CI, 1.327-2.106); P < 0.001), gastrointestinal (RR = = 1.194 (95% CI, 1.031-1.383); P = 0.018), cardiovascular (RR = = 2.582 (95% CI, 1.842-3.620); P < 0.001), and vascular (RR = = 2.288 (95% CI, 1.600-3.272); P < 0.001) involvement were more prevalent in male BS patients, while the hematological (RR = 0.528 (95% CI, 0.360-0.776); P = 0.001) involvement was more common among female patients. BS presents significant heterogeneity and gender differences. The eight phenotypes of BS patients we propose hold the potential to assist clinicians in devising more personalized treatment and follow-up strategies. Key Points • This cluster analysis divided adult-onset BS into eight clinical phenotypes. • BS demonstrates a high level of clinical heterogeneity and gender differences. • Hematologic phenotypes of BS present distinctive clinical characteristics.

Comparison of treatment effects between clear aligners and fixed appliances in patients treated with miniscrew-assisted molar distalization.

OBJECTIVES: The biomechanics in achieving molar distalization may differ between fixed appliances and clear aligners in the control of tooth movement. The objective of this study was to compare the treatment effects between clear aligners (CA) and fixed appliances (FA) in patients treated with miniscrew-assisted molar distalization. METHODS: The sample consisted of 46 subjects with mild-to-moderate crowding. A total of 22 patients treated with clear aligners (age, 25.66 ±â€…6.11 years old) and 24 patients treated with fixed appliances (age, 24.04 ±â€…4.95 years old) for miniscrew-assisted molar distalization were included in this study. The dental and skeletal changes were evaluated by the pre- and post-treatment lateral cephalograms. RESULTS: Significant changes were found with the vertical variables SN-OP angle (2.24 ±â€…3.22°, P < .05) and SN-MP angle (0.73 ±â€…1.15°, P < .05) for the FA group when compared with the CA group (SN-OP angle 0.41 ±â€…2.26° and SN-MP angle -0.21 ±â€…1.38°, P > .05). Both treatment groups achieved a 2-3 mm. molar distalization with significant intrusion of the upper molars. The CA group showed significantly less distal tipping of molars (U6^PP angle -2.29 ±â€…3.29° and L6^MP angle -2.92 ±â€…2.49°, P < .05) compared to the FA group (-5.24 ±â€…4.28° and -5.53 ±â€…5.03°, P < .05). In addition, significant retraction and lingual inclination of the upper and lower incisors were found in both groups. LIMITATIONS: The changes of tooth position were evaluated by 2D lateral cephalograms, not 3D measurements. CONCLUSIONS: Compared to fixed appliances, clear aligners seemed to have better control of vertical dimension and distal tipping of molars in patients treated with miniscrew-assisted molar distalization.

TLR4/Rac1/NLRP3 Pathway Mediates Amyloid-ß-Induced Neuroinflammation in Alzheimer's Disease.

Background: Neuroinflammation plays a crucial part in the initial onset and progression of Alzheimer's disease (AD). NLRP3 inflammasome was demonstrated to get involved in amyloid-ß (Aß)-induced neuroinflammation. However, the mechanism of Aß-triggered activation of NLRP3 inflammasome remains poorly understood. Objective: Based on our previous data, the study aimed to identify the downstream signals that bridge the activation of TLR4 and NLRP3 inflammasome associated with Aß. Methods: BV-2 cells were transfected with TLR4siRNA or pretreated with a CLI-095 or NSC23766, followed by Aß1-42 treatment. APP/PS1 mice were injected intraperitoneally with CLI-095 or NSC23766. NLRP3 inflammasome and microglia activation was detected with immunostaining and western blot. G-LISA and Rac1 pull-down activation test were performed to investigate the activation of Rac1. Real-time PCR and ELISA were used to detect the inflammatory cytokines. Aß plaques were assessed by western blotting and immunofluorescence staining. Morris water maze test was conducted to determine the spatial memory in mice. Results: Rac1 and NLRP3 inflammasome were activated by Aß in both in vitro and in vivo experiments. Inhibition of TLR4 reduced the activity of Rac1 and NLRP3 inflammasome induced by Aß1-42. Furthermore, inhibition of Rac1 blocked NLRP3 inflammasome activation mediated by TLR4. Blocking the pathway by CLI095 or NSC23766 suppressed Aß1-42-triggered activation of microglia, reduced the expression of pro-inflammatory mediators and ameliorated the cognition deficits in APP/PS1 mice. Conclusions: Our study demonstrated that TLR4/Rac1/NLRP3 pathway mediated Aß-induced neuroinflammation, which unveiled a novel pathway and key contributors underlying the pathogenic mechanism of Aß.

Puerarin alleviates atherosclerosis via the inhibition of Prevotella copri and its trimethylamine production.

OBJECTIVE: Puerarin (PU) is a natural compound that exhibits limited oral bioavailability but has shown promise in the treatment of atherosclerosis (AS). However, the precise mechanisms underlying its therapeutic effects remain incompletely understood. This study aimed to investigate the effects of PU and its mechanisms in mitigating AS in both mice and humans. DESIGN: The impact of PU on AS was examined in ApoE -/- mice fed a high-fat diet (HFD) and in human patients with carotid artery plaque. To explore the causal link between PU-associated gut microbiota and AS, faecal microbiota transplantation (FMT) and mono-colonisation of mice with Prevotella copri (P. copri) were employed. RESULTS: PU alleviated AS by modulating the gut microbiota, as evidenced by alterations in gut microbiota composition and the amelioration of AS following FMT from PU-treated mice into ApoE-/- mice fed HFD. Specifically, PU reduced the abundance of P. copri, which exacerbated AS by producing trimethylamine (TMA). Prolonged mono-colonisation of P. copri undermines the beneficial effects of PU on AS. In clinical, the plaque scores of AS patients were positively correlated with the abundance of P. copri and plasma trimethylamine-N-oxide (TMAO) levels. A 1-week oral intervention with PU effectively decreased P. copri levels and reduced TMAO concentrations in patients with carotid artery plaque. CONCLUSION: PU may provide therapeutic benefits in combating AS by targeting P. copri and its production of TMA. TRIAL REGISTRATION NUMBER: ChiCTR1900022488.

miR-141-3p attenuates RSL3-induced ferroptosis and intestinal epithelial-mesenchymal transition via directly inhabits ZEB1 in intestinal Behçet's syndrome.

The aims of this study were to investigate whether the ferroptosis is involved in intestinal Behçet's syndrome (IBS), and to identify if miR-141-3p could attenuate RAS-selective lethal 3 (RSL3)-induced ferroptosis and intestinal epithelial to mesenchymal transition (EMT) via directly inhabits zinc fnger E-box binding homeobox 1 (ZEB1). The expressions of ferroptosis-related proteins in the intestinal tissues of patients with IBS were investigated by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Malondialdehyde (MDA) contents of the intestinal tissues and cells were detected. Serum from IBS patients and RSL3 were co-cultured with intestinal epithelial cells in vitro. In order to investigate whether RSL3-induced ferroptosis can be ameliorated by miR-141-3p, the intestinal epithelial cells were firstly stimulated with RSL3 and then incubated with miR-141-3p mimics. Western blot was used to measure the expression of EMT and ferroptosis-related proteins. Expression of GPX4 (22.51% ± 2.05%, 51.75% ± 3.47%, t = - 7.77, p = 0.000) and xCT (17.49% ± 1.57%, 28.73% ± 1.75%, t = - 4.38, p = 0.003) were significantly lower in intestinal mucosal tissues of patients with IBS compared with HC group. Compared with the HC samples, the IBS specimens had significantly higher MDA (t = 4.32, p = 0.01). Moreover, the relative mRNA levels of ferritin light chain (FTL) (t = 4.07, p = 0.02) and ferritin heavy chain (FTH) (t = 8.82, p = 0.001) in the intestinal tissues were significant higher in IBS patients than in HC group. Serum from IBS patients could induce intestinal epithelial cell ferroptosis in vitro. Moreover, miR-141-3p could attenuate intestinal epithelial cell ferroptosis-induced by RSL3 and intestinal EMT via targeting ZEB1 in vitro. Ferroptosis were induced in patients with IBS. Moreover, the serum from IBS patients could induce ferroptosis in vitro. miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1. Therefore, miR-141-3p may open new avenues for the treatment of IBS in the future. Key Points • Ferroptosis in IBS is first reported in this study. • In this study, we explored that the serum from IBS patients could induce ferroptosis in vitro and miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1.

PLK1-activating IFI16-STING-TBK1 pathway induces apoptosis of intestinal epithelial cells in patients with intestinal Behçet's syndrome.

Inflammatory signals from immunological cells may cause damage to intestinal epithelial cells (IECs), resulting in intestinal inflammation and tissue impairment. Interferon-γ-inducible protein 16 (IFI16) was reported to be involved in the pathogenesis of Behçet's syndrome (BS). This study aimed to investigate how inflammatory cytokines released by immunological cells and IFI16 participate in the pathogenesis of intestinal BS. RNA sequencing and real-time quantitative PCR (qPCR) showed that the positive regulation of tumor necrosis factor-α (TNF-α) production in peripheral blood mononuclear cells (PBMCs) of intestinal BS patients may be related to the upregulation of polo like kinase 1 (PLK1) in PBMCs (P = 0.012). The plasma TNF-α protein level in intestinal BS was significantly higher than in healthy controls (HCs; P = 0.009). PBMCs of intestinal BS patients and HCs were co-cultured with human normal IECs (NCM460) to explore the interaction between immunological cells and IECs. Using IFI16 knockdown, PBMC-NCM460 co-culture, TNF-α neutralizing monoclonal antibody (mAb), stimulator of interferon genes (STING) agonist 2'3'-cGAMP, and the PLK1 inhibitor SBE 13 HCL, we found that PLK1 promotes the secretion of TNF-α from PBMCs of intestinal BS patients, which causes overexpression of IFI16 and induces apoptosis of IECs via the STING-TBK1 pathway. The expressions of IFI16, TNF-α, cleaved caspase 3, phosphorylated STING (pSTING) and phosphorylated tank binding kinase 1 (pTBK1) in the intestinal ulcer tissue of BS patients were significantly higher than that of HCs (all P < 0.05). PLK1 in PBMCs of intestinal BS patients increased TNF-α secretion, inducing IEC apoptosis via activation of the IFI16-STING-TBK1 pathway. PLK1 and the IFI16-STING-TBK1 pathway may be new therapeutic targets for intestinal BS.

TRIM28 facilitates type I interferon activation by targeting TBK1.

Type I interferons play a fundamental role in innate host defense against viral infections by eliciting the induction of an antiviral gene program that serves to inhibit viral replication. Activation of type I interferon is regulated by the IRF3 transcription factor, which undergoes phosphorylation-dependent activation by the upstream kinase, TBK1, during viral infection. However, the mechanisms by which TBK1 achieves activation to support signaling to IRF3 remain incompletely understood. Here we identified the E3 ubiquitin ligase, tripartite motif containing 28 (TRIM28), as a positive regulator of type I interferon activation by facilitating TBK1 signaling. Genetic deletion of TRIM28 via CRISPR-Cas9 editing resulted in impaired type I interferon activation upon both RNA and DNA virus challenge, corresponding with increased susceptibility to virus infections in TRIM28 knockout cells. Mechanistically, TRIM28 interacted with TBK1 and mediated the assembly of K63-linked ubiquitin chains onto TBK1, a post-translational modification shown to augment TBK1 signal transmission events. TRIM28 knockout cells further displayed defective TBK1 phosphorylation and complex assembly with IRF3, resulting in impaired IRF3 phosphorylation. Altogether, our data demonstrate TBK1 to be a novel substrate for TRIM28 and identify TRIM28 as an essential regulatory factor in controlling innate antiviral immune responses.

CURRENT NEURAL NETWORKS DEMONSTRATE POTENTIAL IN AUTOMATED CERVICAL VERTEBRAL MATURATION STAGE CLASSIFICATION BASED ON LATERAL CEPHALOGRAMS.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Neural networks for classification of cervical vertebrae maturation: a systematic review. Mathew R, Palatinus S, Padala S, Alshehri A, Awadh W, Bhandi S, Thomas J, Patil S. Angle Orthod. 2022 Nov 1;92(6):796-804. SOURCE OF FUNDING: No financial support was reported. TYPE OF STUDY/DESIGN: Systematic review.

White spot lesion-related perception of aesthetics and treatment satisfaction among orthodontic patients, orthodontists and other dental specialists.

OBJECTIVE: To investigate the impact of various degrees of white spot lesions (WSLs) of maxillary anterior teeth on the aesthetic perception and treatment satisfaction among orthodontic patients, orthodontists and other dental specialists and to evaluate the differences among the three groups. METHODS: A total of 45 orthodontic patients (OP), 45 orthodontists (OR) and 45 other dental specialists (OS) were recruited. Subjective evaluations of perceived aesthetics and treatment satisfaction were performed towards eight digitally generated photographs of maxillary anterior teeth with incremental degrees of WSLs using a numerical visual analogue scale (VAS) from 0 to 100. Data were collected and analysed with descriptive statistics, repeated one-way analysis of variance and multivariable generalized estimating equations. RESULTS: A total of 135 valid questionnaires were collected. Regarding aesthetic scores for WSLs, OP gave more positive scores than OR and OS (p < .05) towards excessive white spot formation without colouration and were more tolerant than OR (p < .05) towards excessive white spot formation with slight colouration. The level of treatment satisfaction for slight to severe WSLs without cavitation was higher in OP than OR. Patients with higher education levels had more negative scores for aesthetic perception and treatment satisfaction (p < .05). Patients who brushed teeth more frequently scored lower in treatment satisfaction (p < .05). CONCLUSIONS: Orthodontists were the most critical when evaluating aesthetics and treatment satisfaction for slight to severe WSLs without cavitation. For orthodontic patients, better oral hygiene habits and higher education levels were associated with more critical attitudes towards WSLs.

THE USE OF DENTAL PATIENT-REPORTED OUTCOMES AMONG COMPARATIVE OBSERVATIONAL STUDIES IN ORTHODONTICS: A METHODOLOGICAL STUDY.

OBJECTIVE: To identify and summarize the presence and characteristics of dental patient-reported outcomes (dPROs) and dental patient-reported outcome measures (dPROMs) within comparative observational studies published in 5 leading orthodontic journals. METHODS: Electronic searching was performed to identify intervention (therapeutic or preventive) related comparative observational studies published in selected journals between 2015 and 2021. Two authors extracted the characteristics of each included study independently and in duplicate and summarized the dPROs and dPROMs used in these studies. All dPROs were classified into 2 general types (oral health-related quality of life [OHRQoL] and others), while dPROMs were divided into 3 categories (single-item questionnaires, generic multiple-item questionnaires, and specific multiple-item questionnaires). In addition, dPROMs were examined, if they evaluated the 4 dimensions of OHRQoL (oral function, orofacial pain, orofacial appearance, and psychosocial impact). RESULTS: A total of 683 observational studies were eligible and included of which 117 (17.1%) used dPROs and dPROMs. Seven different dPROs (OHRQoL, patients' satisfaction with treatment, preferences, concerns, compliance, duration, and unwanted events) and 33 different dPROMs (including 8 single-item questionnaires, 11 generic multiple-item questionnaires, and 14 specific multiple-item questionnaires) were identified in these studies. OHRQoL was the most commonly used dPRO (92/117, 78.6%), while Oral Health Impact Profile 14 (OHIP-14) was the most frequently used dPROM (20/92, 21.7%). In terms of study design, cross-sectional studies had the highest proportion of dPRO usage (62/148, 41.9%), followed by cohort studies (63/505, 12.5%) and case-control studies (1/30, 3.3%). CONCLUSIONS: Only one-sixth of comparative observational studies published in leading orthodontic journals could reflect patients' perspectives. Observational studies in orthodontics need to provide more patient-important information through the use of dPROs and dPROMs.

DENTAL PATIENT-REPORTED OUTCOMES UPDATE 2023.

The emergence and rapid development of disruptive innovations are quickly turning our profession into personalized dentistry, built upon evidence-based, data-oriented, and patient-centered research. In order to help improve the quality and quantity of patient-centered evidence in dentistry, further promote the wide and standard use of dental patient-reported outcomes (dPROs) and dental patient-reported outcome measures (dPROMs), the Journal of Evidence-Based Dental Practice has put together this special issue, the third of a series entitled Dental Patient-Reported Outcomes Update. A total of 7 solicited articles are collected in this issue. To put them into a broader perspective, this review provides a concise summary of key, selected PRO and dPRO articles published during 2023. A brief introduction to those articles included in this Special Issue follows. Four main domains are covered in this Special Issue: (1) dPROs and digital dentistry, (2) standardization of dPRO-related methodology, (3) current usage of dPROs and dPROMs in published research, and (iv) the significance and relevance of dPRO usage.

Clinical heterogeneity and five phenotypes identified in pediatric Behçet's syndrome: a cohort study from Shanghai Behçet's syndrome database.

OBJECTIVES: Behçet's syndrome (BS) is a rare disease of unknown etiology, with limited reports especially in pediatric BS. The clinical characteristics and phenotypes of pediatric BS as a highly heterogeneous variable vessel vasculitis were investigated in this study. METHODS: A cross-sectional study was conducted to compare clinical variables and descriptive characteristics of BS by age of onset and gender. Cluster analysis was then performed to identify the phenotypes of pediatric BS. RESULTS: A total of 2082 BS patients were included in this study, 1834 adults and 248 children. Compared with adult-onset BS, pediatric BS had a higher incidence of folliculitis [relative risks (RR) and 95% confidence interval (CI) 1.3 (1.0-1.5)], uveitis of the left eye [RR and 95% CI 2.3 (1.0-5.0)], intestinal ulcer complications [RR and 95% CI 2.1 (1.1-4.2)], pericarditis [RR and 95% CI 2.5 (1.0-6.2)], and psychiatric disorders [RR and 95% CI 2.8(1.0-7.9)], while the incidence of thrombocytopenia was lower [RR 0.2 (0.1-1.0)]. Among pediatric BS, females had more genital ulcers, while males were more likely to have skin lesions, panuveitis, vascular involvement, venous lesions, cardiac involvement, and aortic aneurysms. Cluster analysis classified pediatric BS into five clusters (C1-C5): C1 (n = 61, 24.6%) showed gastrointestinal (GI) involvement; C2 (n = 44, 17.7%) was the central nervous system (CNS) type where 23 cases overlapped joint involvement; in C3 (n = 35, 14.1%), all patients presented with arthritis or arthralgia; all patients in C4 (n = 29, 11.7%) manifested ocular involvement, with a few patients overlapping with GI involvement or joint damage; C5 (n = 79, 31.9%) was the mucocutaneous type, presenting both oral ulcers, genital ulcers, and skin lesions. CONCLUSIONS: The clinical features of pediatric and adult BS differ significantly. Male and female pediatric BS also have a distinct demography. Five phenotypes including GI, CNS, joint, ocular, and mucocutaneous types were identified for pediatric BS.

Fat mass and obesity-associated protein (FTO) affects midpalatal suture bone remodeling during rapid maxillary expansion.

BACKGROUND: The fat mass and obesity-associated protein (FTO) is an RNA demethylase that contributes to several physiological processes. Nonetheless, the impact of FTO on bone remodeling in the midpalatal suture while undergoing rapid maxillary expansion (RME) remains unclear. METHODS: First, to explore the expression of FTO in the midpalatal suture during RME, six rats were randomly divided into two groups: Expansion group and Sham group (springs without being activated). Then, suture mesenchymal stem cells (SuSCs) were isolated as in vitro model. The expression of FTO was knocked down by small interfering RNA to study the effect of FTO on the osteogenic differentiation of SuSCs. Finally, to evaluate the function of FTO in the process of bone remodeling in the midpalatal suture, ten rats were randomly divided into two groups: FB23-2 group (10 µM, a small molecule inhibitor of FTO) and DMSO group (control). RESULTS: Increased arch width and higher expression of OCN and FTO in the midpalatal area were observed in expansion group (P < .05). In the in vitro model, the mRNA expression levels of Runx2, Bmp2, Col1a1, Spp1, and Tnfrsf11b were decreased (P < .05) upon knocking down FTO. Additionally, the protein levels of RUNX2 and OPN were also decreased (P < 0.05). Adding FB23-2, a small-molecule inhibitor targeting FTO, to the medium of SuSCs caused a decrease in the mRNA expression levels of Runx2, Bmp2, Col1a1, Spp1, and Tnfrsf11b (P < 0.05). There was a statistically significant difference in evaluating the expression of OCN and OPN on the palatal suture between the FB23-2 and DMSO groups (P < .05). LIMITATION: The molecular mechanisms by which FTO regulates SuSCs osteogenesis remain to be elucidated. The FTO conditional knock out mouse model can be established to further elucidate the role of FTO during RME. CONCLUSION: FTO contributes to the osteogenic differentiation of SuSCs and plays a promoting role in midpalatal suture bone remodeling during the RME.

GLOSSARY FOR DENTAL PATIENT-CENTERED OUTCOMES.

Dental patient-centered outcomes can improve the relevance of clinical study results to dental patients and generate evidence to optimize health outcomes for dental patients. Dental patient-reported outcomes (dPROs) are of great importance to patient-centered dental care. They can be used to evaluate the health outcomes of an individual patient about the impact of oral diseases and treatment, and to assess the quality of oral health care delivery for a health care entity. dPROs are measured with dental patient-reported outcome measures (dPROMs). dPROMs should be validated and tested before wider dissemination and application to ensure that they can accurately capture the intended dPROs. Evidence suggests inadequate dPRO usage among dental trials, as well as potential flaws in some existing dPROMs. This Glossary presents a collection of main terms in dental patient-centered outcomes to help clinicians and researchers read and understand patient-centered clinical studies in dentistry.

Effects of Thalidomide on Erythropoiesis and Iron Homeostasis in Transfusion-Dependent ß-Thalassemia.

Thalidomide is a therapeutic option for patients with ß-thalassemia by increasing fetal hemoglobin and thereby reducing the requirement for blood transfusions. However, information on changes in erythropoiesis and iron homeostasis during thalidomide treatment is lacking. This study investigated the effects of thalidomide treatment on hematologic, erythropoietic, and ironstatus parameters in 22 patients with transfusion-dependent ß-thalassemia (TDT). Thalidomide significantly improved anemia endpoints, including increases in hemoglobin (p<0.001), red blood cells (p<0.001), and hematocrit (p<0.001), as well as reducing erythropoietin levels (p=0.033) and ameliorating erythropoiesis. Thalidomide treatment significantly reduced serum iron levels (p=0.018) and transferrin saturation (p=0.039) and increased serum transferrin levels (p=0.030). Thalidomide had no observed effect on serum ferritin or hepcidin, but changes in hepcidin (r=0.439, p=0.041) and serum iron (r=-0.536, p=0.010) were significantly correlated with hemoglobin increment. This comprehensive study indicates that thalidomide treatment can ameliorate erythropoiesis and iron homeostasis in patients with TDT, thus supporting the effectiveness of this drug.

In vitro evaluation of an easy-to-remove orthodontic adhesive with photochromic property.

OBJECTIVES: To develop a photochromic bracket adhesive (PCA) with modification using photochromic material and evaluate the biocompatibility, bond strength, photochromic property, and adhesive removal efficiency. MATERIALS AND METHODS: The resin-modified glass ionomer powder was mixed with the photochromic material and then blended with the liquid agent to form PCA. Biocompatibility was evaluated by CCK-8 kit, and shear bond strength (SBS) was measured. Stereoscopic microscopy and quantitative color analysis were used to assess the photochromic property. Bracket bonding and debonding procedures were performed on a head simulator with the assistance of an ultraviolet radiator. The effectiveness of adhesive removal during bonding and debonding procedures was assessed using a stereomicroscope. Removal time was recorded, and the enamel damage index after debonding was analyzed. RESULTS: CCK-8 assay and SBS test indicated that 5wt.% mixing ratios of the photochromic material did not compromise the biocompatibility and SBS of the adhesive (PCA5). PCA5 showed photochromic properties and could help the operator remove adhesive more thoroughly without increasing enamel damage. CONCLUSIONS: Photochromic adhesive (PCA5) can be good for orthodontic adhesive removal and therefore has good clinical translation potential.

Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway.

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1WT) as a potential diagnostic and prognostic biomarker for non-small cell lung cancer (NSCLC), but how IDH1WT modulates NSCLC progression remains elusive. Here, we report that IDH1WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1WT interacts with and stabilizes PHGDH and fragile X-related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1WT-PHGDH and IDH1WT-FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine-depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1WT in serine metabolism, highlighting IDH1WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

Association between adenotonsillar hypertrophy and dentofacial characteristics of children seeking for orthodontic treatment: A cross-sectional study.

OBJECTIVE: To compare the dentofacial characteristics of children with and without adenoid and/or tonsillar hypertrophy. METHODS: A consecutive sample of orthodontic patients aged 6-12 that took pre-treatment lateral cephalograms were included in this study. Those with history of previous orthodontic treatment, adenoidectomy or tonsillectomy, or craniofacial anomalies were excluded. The diagnosis of adenoid and tonsillar hypertrophy was based on Fujioka's and Baroni's methods, according to which the subjects were divided into four groups: the adenoid hypertrophy only (AHO) group; tonsillar hypertrophy only (THO) group; combined adenoid and tonsillar hypertrophy (AH+TH) group; and no adenoid or tonsillar hypertrophy (NH) group. Cephalograms were used for skeletal and dental measurement. Data were analyzed using one-way ANOVA, LSD post-hoc tests and Chi-square test. RESULTS: A total of 598 patients were included. Compared with the NH group, the THO group had significantly larger SNB angle (P < 0.001), as well as significantly smaller ANB angle (P<0.001) and Wits value (P = 0.001). The U1-L1 angle of AHO group was significantly smaller than that in the NH group (P = 0.035). The proportion of adenoid hypertrophy in Class II patients was significantly higher than that in Class III patients (P = 0.001). The proportion of tonsillar hypertrophy in Class III patients was significantly higher than that in Class I patients (P < 0.001) and Class II patients (P < 0.001). CONCLUSION: Over 80 % of children seeking orthodontic treatment had either adenoid or tonsillar hypertrophy. Children with adenoid hypertrophy tend to have skeletal Class II malocclusion, while those with tonsillar hypertrophy tend to have skeletal Class III malocclusion.

Clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in Chinese population with mismatch repair deficient urothelial carcinoma: a real-world study.

Urothelial carcinoma (UC) with deficient mismatch repair (dMMR) is a specific subtype of UC characterized by the loss of mismatch repair (MMR) proteins and its association with Lynch syndrome (LS). However, comprehensive real-world data on the incidence, clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in the Chinese patients with dMMR UC remains unknown. We analyzed 374 patients with bladder urothelial carcinoma (BUC) and 232 patients with upper tract urothelial carcinoma (UTUC) using tissue microarrays, immunohistochemistry, and targeted next-generation sequencing. Results showed the incidence of dMMR UC was higher in the upper urinary tract than in the bladder. Genomic analysis identified frequent mutations in KMT2D and KMT2C genes and LS was confirmed in 53.8% of dMMR UC cases. dMMR UC cases displayed microsatellite instability-high (MSI-H) (PCR method) in 91.7% and tumor mutational burden-high (TMB-H) in 40% of cases. The density of intratumoral CD8+ T cells correlated with better overall survival in dMMR UC patients. Positive PD-L1 expression was found in 20% cases, but some patients positively responded to immunotherapy despite negative PD-L1 expression. Our findings provide valuable insights into the characteristics of dMMR UC in the Chinese population and highlights the relevance of genetic testing and immunotherapy biomarkers for treatment decisions.