Supramolecular artificial Nano-AUTACs enable tumor-specific metabolism protein degradation for synergistic immunotherapy.

Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.

Metal coordination nanotheranostics mediated by nucleoside metabolic inhibitors potentiate STING pathway activation for cancer metalloimmunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an effective way to initiate an immune response against tumors, and the research on agonists targeting STING has become a new hotspot in the development of antitumor drugs. However, as a novel STING agonist, the limited bioavailability and activation routes of manganese ions (Mn2+) significantly hinder its antitumor effects. To address these challenges, we have designed a metal-coordinated nucleoside metabolic inhibitor (gemcitabine, Gem)-induced metal nanotheranostic (MGP) with PEGylation. This formulation synergistically enhanced the immune response against cancer cells by sensitizing the cGAS-STING pathway and promoting immunogenic cell death (ICD). Modified with PEG derivatives, MGP was efficiently delivered to the tumor site and was internalized by cancer cells. Upon internalization, the release of Mn2+ triggered the activation of the cGAS-STING pathway, while the release of Gem induced DNA damage. On the one hand, the damaged DNA caused by Gem leaked into the cytoplasm, synergistically amplified Mn2+-induced activation of the cGAS-STING pathway, and induced the production of the tumor cytotoxic factor IFN-ß. On the other hand, Mn2+-mediated chemodynamic therapy (CDT) exhibited an ICD effect, which further synergized with the activation of the cGAS-STING pathway to promote dendritic cells (DCs) maturation and antigen-specific T cells infiltration. Both in vitro and in vivo studies have demonstrated that MGP nanotheranostics could elicit a robust antitumor effect, especially when combined with anti-PD-1. This study provided a new paradigm for intensifying immune activation by constructing metal coordination nanotheranostics.

Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD-L1 in Cancer Therapy.

Cancer immunotherapy using anti-programmed death-ligand 1 (PD-L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD-L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD-L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD-L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD-L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD-L1 can fundamentally transform the current status of PD-L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD-L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD-L1 (including mPD-L1, cPD-L1, nPD-L1, and exoPD-L1). Then an in-depth analysis of the regulatory mechanisms and potential therapeutic targets of PD-L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD-L1 therapeutics strategies.

Childhood lichenoid granulomatous stomatitis: a case report and literature review / 口腔疾病防治

Objective@#To investigate the classification, clinical manifestations, diagnosis, differential diagnosis and treatment of oral lichenoid lesions and provide a reference for clinical practice.@*Methods@#Hospital ethical approval and patient informed consent were obtained. We report a case of oral lichenoid lesion in children and review the diagnosis and treatment of oral lichenoid damage in the literature.@*Results@#The patient experienced repeated rupture of the dorsal surface of the tongue with pain for more than 3 years. There was a large area of tongue back surface erosion with an irregular shape, surrounded by pearly-white lines. The left erosive area was accompanied by tissue hyperplasia, which was approximately 1.5 cm × 2.0 cm, with tough texture and broad masses. The pathological diagnosis of the patient was oral lichenoid lesion. After biopsy of the dorsal surface of the tongue, the pathological diagnosis of the patient was granulomatous inflammation. The final diagnosis of lichenoid granulomatous stomatitis was made on the basis of the patient's intraoral damage features, systemic history, medication history and histopathological findings. A review of the literature suggests that oral lichenoid lesions have an unknown etiology and need to be clinically differentiated from oral lichen planus, oral lichenoid drug reactions, oral lichenoid contact damage and chronic ulcerative stomatitis. The clinical treatment of oral lichen planus is based on the topical and/or systemic use of glucocorticoids.@*Conclusion@#There are still no uniform criteria for the classification and diagnosis of oral lichenoid lesions. They rely mainly on history taking, clinical manifestations and histopathological findings, and the treatment is mainly based on the topical and/or systemic use of glucocorticoids.

Oral health-related quality of life and associated factors among a sample from East China with severe early childhood caries: a cross-sectional study.

BACKGROUND: To investigate the oral health-related quality of life (OHRQoL) and associated factors among a sample from East China with severe early childhood caries (S-ECC). METHODS: A total of 316 children with S-ECC and their parents were recruited to participate in a cross-sectional study. Children were examined for caries status using criteria proposed by World Health Organization (WHO). The accompanying parent was required to provide demographic information and complete two validated questionnaires in Chinese: the early childhood oral health impact scale (ECOHIS) and the 5-item oral health impact profile (OHIP). RESULTS: The study had a 98.1% response rate. Finally, the data of 300 children and their parents were analyzed. Mothers cared for their children far more than fathers in the included family (78.7% mother, 21.3% father). The mean age of children was 4.1 ± 0.7 years, ranging from 3 to 5. The mean dmft score was 13.8 ± 3.8. Few (13.7%) children never had a toothache. ECOHIS scores ranged from 0 to 38, with a mean score of 16.2 ± 7.2. The mean OHIP score was 2.9 ± 2.7. The parental age, family income, residence, history of pain, the dmft scores and parents' OHIP showed associations with ECOHIS scores or domain scores (P < 0.05). The multiple regression analysis showed that the history of pain, accompanying parents' OHIP, and the dmft scores were mainly associated with ECOHIS and child impact (P < 0.05); parental age was associated with family impact (P = 0.024). CONCLUSIONS: The parent's OHRQoL was associated with the children's OHRQoL, indicating that policymakers and clinical practitioners should improve both children's and their parents' oral health. Furthermore, the caries severity and the history of dental pain impacted children's OHRQoL.

Intelligent lesion blood-brain barrier targeting nano-missiles for Alzheimer's disease treatment by anti-neuroinflammation and neuroprotection.

The treatment of Alzheimer's disease (AD) is one of the most difficult challenges in neurodegenerative diseases due to the insufficient blood‒brain barrier (BBB) permeability and unsatisfactory intra-brain distribution of drugs. Therefore, we established an ibuprofen and FK506 encapsulated drug co-delivery system (Ibu&FK@RNPs), which can target the receptor of advanced glycation endproducts (RAGE) and response to the high level of reactive oxygen species (ROS) in AD. RAGE is highly and specifically expressed on the lesion neurovascular unit of AD, this property helps to improve targeting specificity of the system and reduce unselective distribution in normal brain. Meanwhile, these two drugs can be specifically released in astrocytes of AD lesion in response to high levels of ROS. As a result, the cognition of AD mice was significantly improved and the quantity of Aß plaques was decreased. Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons. Besides, the neuroinflammation dominated by NF-κB pathway was significantly inhibited with decreased NF-κB and IL-1ß in the brain. Overall, Ibu&FK@RNPs can efficiently and successively target diseased BBB and astrocytes in AD lesion. Thus it significantly enhances intracephalic accumulation of drugs and efficiently treats AD by anti-neuroinflammation and neuroprotection.

Clinical outcomes of dental treatment under general anesthesia and its effects on the caries activity and body growth of children: a 2-year retrospective study.

OBJECTIVES: To analyze clinical outcomes of dental treatment under general anesthesia (DGA) and its effects on children's caries activity status and body growth within 2 years after the treatment. MATERIALS AND METHODS: The case data and 2-year follow-up records of children who underwent DGA from February 2017 to February 2018 were collected and analyzed. The general characteristics of the sample, the success rates of treatment procedures, the caries recurrence rate, the caries activity test scores, and the BMI of all the children were described. The caries activity levels between children with and without caries recurrence at 24 months after DGA were compared before and after DGA to explore the relationship between caries activity level and caries recurrence. The correlation between BMI level and caries recurrence was explored using Cox regression analysis. RESULTS: A total of 94 children consisting of 46 boys and 48 girls were included in this study. The average dmft score before DGA was 13.90. Within 2 years after the treatment, composite fillings and strip crowns of the anterior teeth achieved similar success rates, around 90%; SSCs showed a similar success rate to composite fillings of posterior teeth (P = 1.000); the clinical success rate of pulpectomy was 90.43%. All the children showed no caries relapse at 1 month after DGA. The number of children with caries relapse at 6-, 12-, and 24-month post-treatment was 24 (25.53%), 35 (37.23%), and 53 (56.38%), respectively. The caries activity scores at each follow-up were significantly lower than those before the treatment (P < 0.0001). Children with caries relapse within 2 years after DGA showed no significantly different caries activity scores than children without caries relapse before and after the treatment. The proportion of children with normal BMI at 12 months after DGA was significantly higher than that before DGA (P = 0.007), and the difference was still very significant at 24 months after DGA (P < 0.0001). Statistical results showed a correlation between BMI level before DGA and caries recurrence (P < 0.001). CONCLUSIONS: Dental treatment under general anesthesia achieves acceptable clinical outcomes in this study. Children's caries activity scores decrease significantly. Low or high BMI levels before DGA drift towards normal after the treatment. CLINICAL RELEVANCE: Acceptable outcomes are achieved within 2 years after dental treatment under general anesthesia. However, children with abnormal BMI before the treatment tend to have caries relapse.

Dental maturation in a Chinese sample using Demirjian method.

BACKGROUND: Dental calcification information is relevant for clinical, archaeological, and forensic applications. However, dental maturity measurements in current cohorts of Chinese children are insufficient. AIM: This study aimed to establish the mandibular dental maturity table and determine the accuracy of dental age estimation using the Demirjian method in a Chinese sample. SUBJECTS AND METHODS: Permanent mandibular teeth, excluding the third molar, in 2091 panoramic radiographs of 1008 males and 1083 females aged 3-15 were graded, and dental age was estimated according to Demirjian's criteria. Age-of-attainment was calculated with probit regression for each stage by sex, and sex differences were analysed using the Mann-Whitney U test. Dental age was compared with chronological age using paired t-tests. RESULTS: Although females showed earlier age-of-attainment than males, significant sex differences were only found in stages D-G (p < 0.05). The Demirjian method overestimated the dental age in both males (0.68 ± 1.05 years) and females (0.59 ± 0.97 years). CONCLUSIONS: The relationship between mineralisation stage and chronological age in this study can be applied as a reference for mandibular dental maturity of Chinese children and adolescents. The Demirjian method overestimated the chronological ages of this sample.

[Radiographic study of the age for crown and root length completion stages of permanent teeth in male and female children].

PURPOSE: To determine the age medians for crown and root length completion stages of permanent teeth (except for the third molars) and to study gender differences in crown and root length completion stages by radiographic examinations. METHODS: The development of permanent teeth (except for the third molars) was evaluated from 3304 panoramic radiographs of children aged between 3 and 18 years by Haavikko's method. Statistical analysis was performed using SPSS 25.0 software package. Age medians for crown and root length completion stages of permanent teeth were calculated. Gender differences were analyzed by Mann-Whitney U test. RESULTS: There were no significant gender differences in crown completion stages of central incisor and first molar, of which P values were 0.143 (for maxillary central incisor), 0.122 (for maxillary first molar), 0.191 (for mandibular central incisor) and 0.558 (for mandibular first molar), while girls were found to be ahead of boys for crown completion stages of other teeth. In maxilla, girls were found to be ahead of boys for root length completion stages except for lateral incisor, second premolar and second molar, of which P values were 0.057, 0.130 and 0.294; in mandible, except for second premolar and second molar, girls were observed to be ahead of boys for root length completion stages, of which P values were 0.428 and 0.057. CONCLUSIONS: It is concluded that girls are advanced than boys for crown and root length completion stages in most teeth. There is a similarity in gender differences for crown and root length completion stages between maxilla and mandible.