Oral lichen planus (OLP) is a prevalent chronic inflammatory condition that affects the oral mucosa. Histologically, it is characterized by the liquefaction and degeneration of basal epithelial cells, indicating a disruption of the basal layer architecture, which may represent an early event in the disease’s pathogenesis. However, the molecular mechanisms underlying this epithelial damage remain poorly understood. In our study, histological staining and transmission electron microscopy revealed aberrant cell death in the basal epithelial layer of OLP tissues. Immunodetection demonstrated the presence of phosphorylated mixed lineage kinase domain-like protein (pMLKL), a key marker of necroptosis, specifically localized to basal keratinocytes. Notably, interferon type I (IFN-I), particularly IFNα, was significantly upregulated in OLP mucosa compared to healthy controls. The expression of Z-DNA binding protein 1 (ZBP1), an IFN-stimulated gene and an upstream regulator of necroptosis, was elevated in pMLKL-positive epithelial cells. In vitro stimulation with IFNα2a induced the expression of ZBP1 and pMLKL in HaCaT keratinocytes, while ZBP1 knockdown abrogated MLKL phosphorylation. Collectively, these results suggest that, in the context of increased IFN-I signaling, ZBP1 is aberrantly upregulated in the OLP epithelium, promoting necroptosis in basal keratinocytes. This necroptotic activity may contribute to the damage and disruption of the basal layer, providing novel insights into the pathogenesis of OLP and highlighting potential molecular targets for therapeutic intervention.

BACKGROUND:Refractory oral lichen planus (OLP) poses a treatment challenge due to its chronic nature, symptoms, and potential for malignant transformation. Total glucosides of paeony (TGP), a botanical immunomodulator that targets NF-κB and Th17 pathways, have demonstrated promise in managing OLP. However, robust clinical evidence from real-world settings remains lacking. PURPOSE:This study aimed to assess the effectiveness and safety of TGP as an add-on therapy for patients with symptomatic refractory OLP in a real-world clinical trial setting. STUDY DESIGN:This multicenter, pragmatic, randomized, active-controlled trial (Chinese Clinical Trial Registry: ChiCTR-IPR-16,010,156) enrolled 448 adults with symptomatic refractory OLP from five Chinese centers between January 2017 and December 2020. The pragmatic design assessed TGP under real-world conditions. METHODS:Participants were randomly assigned in a 1:1 ratio to receive basic therapy (tapering prednisone from 15 mg to 5 mg over 4 weeks plus standardized oral hygiene; n = 222) or basic therapy plus TGP (0.6 g three times daily for 12 months; n = 226). The primary endpoint was the time from randomization to complete response (CR), defined as reducing the VAS pain score and Thongprasom sign score to 0 or 1 (or to 0 if the baseline score was 1). RESULTS:The TGP group demonstrated significantly faster achievement of CR and higher CR rates compared to controls (53.9% vs. 34.4%; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.52-2.82; p < 0.0001) and better overall response rates at 12 months (70.6% vs. 44.4%; odds ratio [OR] 2.99; 95% CI 2.01-4.44; p < 0.0001). Patients receiving TGP also experienced greater improvements in sleep quality (PSQI responder rate: HR 1.49, p = 0.038). The safety analysis primarily showed mild adverse events, with a higher incidence of diarrhea in the TGP group (5.5% vs. 0.9%), but no severe events or treatment discontinuations. CONCLUSION:As an add-on therapy, TGP significantly improved clinical outcomes in refractory OLP in a real-world setting, demonstrating immunomodulatory effects and a favorable safety profile. These pragmatic trial results support TGP as a promising and effective long-term add-on therapy for the long-term management of this potentially malignant disorder.

To investigate whether noninvasive reflectance confocal microscopy (RCM)–derived vascular parameters can serve as objective predictors of therapeutic response to pulsed dye laser (PDL) treatment in patients with port wine stain (PWS), given the wide variability in clinical outcomes. We retrospectively reviewed the records of 240 patients with facial PWS who underwent RCM imaging before a scheduled PDL session, yielding their image datasets stratified by treatment history. The superficial vessel depth (SVD), maximum vessel diameter (MVD), and vessel density (VD) were quantified. Among 25 treatment-naïve patients with follow-up evaluations, treatment efficacy after a single PDL session was graded on a standardized quartile scale. Associations between RCM parameters and clinical outcomes were evaluated using nonparametric tests and Fisher’s exact test, as appropriate. A longitudinal analysis was performed in 14 patients with available pre- and post-treatment RCM data. Vascular parameters differed significantly among groups stratified by prior PDL sessions. With increasing treatment sessions, SVD increased whereas MVD decreased significantly (both p < 0.05), while VD showed no significant difference. Among treatment-naïve patients, baseline MVD > 40 μm was associated with a significantly higher response rate than MVD ≤ 40 μm (p < 0.001). In the longitudinal subset, effective responders showed a significant post-treatment reduction in MVD, whereas ineffective responders did not. Baseline MVD assessed by RCM may serve as a potential imaging biomarker for predicting PDL response in patients with PWS. Larger vessels were associated with more favorable clinical improvement, while smaller vessels tended to show poorer response. These preliminary findings require validation in larger prospective cohorts before clinical implementation.

Introduction The advancement of AI-assisted oral disease diagnosis critically relies on the availability of annotated, high-quality datasets and resilient deep learning architectures. Nevertheless, progress in this domain has been impeded by the scarcity of publicly accessible data and inadequate benchmarking of existing models. To address these limitations, we introduced a meticulously curated dataset encompassing three prevalent oral mucosal diseases and undertook a thorough assessment of five deep learning models, focusing on their performance in concurrent lesion segmentation and classification. Methods This study involved the compilation of a dataset comprising 808 high-resolution clinical images, encompassing three distinct oral mucosal pathologies: oral lichen planus, oral leukoplakia, and oral benign ulcers. Data collections were facilitated through clinical practices, and the images were subsequently annotated by three oral medicine specialists, who provided both diagnostic labels and pixel-level segmentation masks. To ascertain the dataset's utility and efficacy, five sophisticated deep learning architectures were benchmarked for their capacity to perform simultaneous segmentation and classification tasks. Results Our benchmark evaluation indicated robust model performance on the proposed dataset. For the task of lesion segmentation, the optimal model achieved a mean Dice coefficient of 0.768 ± 0.031. Concurrently, an accuracy of 0.940 ± 0.013 was attained for disease classification. These findings collectively affirmed the dataset's substantial suitability for the development and rigorous assessment of AI models within authentic diagnostic contexts. Conclusion The proposed dataset presented a standardised benchmark to facilitate the advancement of AI development in dental applications. Combined with rigorous deep learning validation, we provided a reproducible framework for precise lesion localisation and accurate disease identification. Clinical Relevance The proposed integrated dataset-model pipeline facilitates the development of dependable AI tools capable of aiding clinicians in prompt diagnosis, mitigating diagnostic inconsistencies, and augmenting decision-making processes within standard oral health care practices.

Aim or purpose: To investigate the etiology of vitamin B12 deficiency-related glossitis (B12-def glossitis) in a regional hospital in China and evaluate its diagnostic value for autoimmune gastritis (AIG). Materials and methods: This study included patients who presented with tongue pain, burning sensations, or recurrent oral ulcers between May 2022 and February 2024. Patients with glossitis and confirmed B12 deficiency were classified as B12-def glossitis, while those with other oral mucosal conditions were categorized as non-B12-def glossitis. All subjects underwent hematological tests, gastroscopy, and histopathological examinations except for patients who underwent total gastrectomy. Based on AIG diagnostic criteria, patients were divided into an AIG group (case group) and a non-AIG group (control group). The diagnostic efficacy of B12-def glossitis for AIG was assessed by calculating sensitivity, specificity, the Youden index, and the Kappa statistic. This research protocol was approved by the Medical Ethics Committee of the First Affiliated Hospital of Soochow University (2021-285). Results: A total of 127 patients were included, of whom 81 were diagnosed with B12-def glossitis. Among them, 10 had a history of total gastrectomy, while 71 did not. Of these 71 patients, 63 (88.7%) were diagnosed with AIG. The sensitivity, specificity, and Youden index of B12-def glossitis for diagnosing AIG were 0.969, 0.846, and 0.815, respectively, with a Kappa value of 0.825. Conclusions: AIG is the primary cause of B12-def glossitis in this cohort of Chinese patients. B12-def glossitis demonstrates high effectiveness and reliability in diagnosing AIG.

Background Oral lichen planus (OLP) is commonly accepted as an interface mucositis. The immunogen from keratinocytes is considered as the agonist priming the topical immunity. Our previous study has identified increased dendritic cell (DC) infiltration and TLR9 expression in OLP lesions. Heat shock protein 90 (HSP90) has been widely considered as an autoantigen and TLR9 agonist that could activate DCs. However, the significance and impact of HSP90 as an immunogen in OLP remain unclear. Objective To investigate the effects of the HSP90 complex from OLP lesion tissues on DCs activation and the polarization of naïve T cells. Methods The expression pattern of HSP90 in OLP lesions and healthy control mucosa was evaluated by single-cell RNA sequence, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and immunoblotting. The HSP90 complex was further extracted by immunoprecipitation from the OLP lesions and healthy control mucosa as the agonist of DCs. The peripheral DCs were collected and stimulated with the extractives. When challenged, DCs’ expression of interferon-alpha and MHC molecules was detected by flow cytometry. Hence, after cocultured with pre-stimulated DCs, polarization of naïve T cells was investigated by cytokines profile analysis. Results HSP90 expression was significantly greater in the lamina propria of OLP lesion and closely related with lymphocyte infiltration. The HSP90 complex in OLP lesion tissues activated DCs via TLR9 and increased their interferon-α secretion and MHC II expression. Prestimulated DCs increased the proportion of Th17 cells. Conclusions The HSP90 complex isolated from OLP lesion tissue activated a TLR9/interferon-α pathway of DC and further promoted the polarization of naïve T cells towards Th17 immunity.

Objectives:To search for a new classification scheme for oral lichen planus (OLP) and oral lichenoid lesions (OLL) based on innate lymphoid cells (ILCs) and to evaluate the clinical significance of this classification for diagnosis and treatment. Subjects and methods:This study was based on a clinical cohort and applied flow cytometry to prospectively analyze the ILC subgroups and proportions in OLP and OLL lesions using SPSS software (version 26.0) to attempt cluster analysis to classify diseases at the cellular level based on the phenotype and quantity of ILCs cells, analyze the correlation between the new classification of diseases and clinical risk factors based on the patient's clinical background information and classification results, and evaluate the differences in therapeutic effects among patients in different groups in corresponding clinical cohorts. Results:In the OLP and OLL groups, the ILC compartment consisted mainly of ILC1 (75.02% ± 27.55% and 72.99% ± 25.23%, respectively), ILC2 (1.49% ± 4.12% and 1.72% ± 3.18%, respectively), and ILC3 (16.52% ± 19.47% and 18.77% ± 18.12%, respectively). Using k-means clustering and two-step clustering, patients could be clustered into three groups that did not respond equally to the same treatment. Using k-means clustering, there was a statistically significant difference in REU scores between the ILC1 advantage group and the OLL subgroup before and after treatment (P = 0.02), which was not observed in two-step clustering. This indicates that k-means clustering may have greater value in the clinical application of OLL. In the ILC1 absolute advantage group, using HCQ + TGP for one month could effectively treat the patients regardless of the use of k-means clustering or two-step clustering (P ≤0.001), whereas the other groups did not. Conclusions:This study provides a preliminary OLP and OLL classification method based on ILC subgroups that can guide the cytological classification of diseases to a certain extent. Further clinical application values should be verified in subsequent cohort studies.

BackgroundOral lichen planus (OLP) is a chronic, immune-mediated disorder affecting 2%-4% of the population. Corticosteroids are commonly used for treatment, but responses vary, likely due to differences in lymphocyte profiles. This study evaluated the impact of CD20+ B cells and CD38+ plasma cells on corticosteroid efficacy in OLP patients.Patients and MethodsThis retrospective study included 101 patients with symptomatic, diffuse, and severe OLP. Immunohistochemical staining identified CD3+ T cells, CD20+ B cells, and CD38+ plasma cells in tissue lesions. All patients received prednisone, and outcomes were assessed using Reticulation/Erosion/Ulceration (REU) and Visual Analog Scale (VAS) scores. Statistical analyses compared treatment responses based on lymphocyte profiles.ResultsAll patients showed CD3-positive T cell infiltration. Patients in the CD20- group showed significantly greater reductions in REU and VAS scores than the CD20+ group, indicating that B cell infiltration may reduce corticosteroid efficacy. Conversely, CD38+ patients exhibited greater score reductions than CD38- patients, suggesting that plasma cells may enhance responsiveness to treatment. The CD38+/CD20- group exhibited the most favorable response; the CD38-/CD20+ group had the least.ConclusionsInfiltration by B cells and plasma cells influences corticosteroid response in OLP. B cells are associated with reduced efficacy, while plasma cells correlate with improved treatment outcomes.

Oral lichen planus (OLP) is a prevalent chronic inflammatory condition that affects the oral mucosa. Histologically, it is characterized by the liquefaction and degeneration of basal epithelial cells, indicating a disruption of the basal layer architecture, which may represent an early event in the disease’s pathogenesis. However, the molecular mechanisms underlying this epithelial damage remain poorly understood. In our study, histological staining and transmission electron microscopy revealed aberrant cell death in the basal epithelial layer of OLP tissues. Immunodetection demonstrated the presence of phosphorylated mixed lineage kinase domain-like protein (pMLKL), a key marker of necroptosis, specifically localized to basal keratinocytes. Notably, interferon type I (IFN-I), particularly IFNα, was significantly upregulated in OLP mucosa compared to healthy controls. The expression of Z-DNA binding protein 1 (ZBP1), an IFN-stimulated gene and an upstream regulator of necroptosis, was elevated in pMLKL-positive epithelial cells. In vitro stimulation with IFNα2a induced the expression of ZBP1 and pMLKL in HaCaT keratinocytes, while ZBP1 knockdown abrogated MLKL phosphorylation. Collectively, these results suggest that, in the context of increased IFN-I signaling, ZBP1 is aberrantly upregulated in the OLP epithelium, promoting necroptosis in basal keratinocytes. This necroptotic activity may contribute to the damage and disruption of the basal layer, providing novel insights into the pathogenesis of OLP and highlighting potential molecular targets for therapeutic intervention.

Aim or purpose: Angiotensin II receptor blocker (ARB) was reported to be associated with oral lichenoid lesion (OLL), however, its clinical and histopathological manifestations need to be further described. To analyze the clinical and histopathological manifestations of suspicious OLL patients using ARB drugs and discover their potential characters. Materials and methods: A retrospective case series of patients using ARB drugs diagnosed with OLL between 2021–2022 (n=16) was conducted. Demographic data, systemic medical history, ARB type, concomitant medications, and histopathological images of mucosa were collected. Descriptive statistics were used for data summarization. Results: The median patient age was 54.6±10.6 years (50% male) with all patients using ARB drugs for hypertension, and 43.75% only used ARB drugs before oral manifestation while 31.25% used at least two cardiovascular drugs including ARB. Clinical manifestation showed 81.25% lesions were symmetrical and reticular lesion of the buccal mucosa was most frequent. Histopathology diagnose indicated 10 OLL, 2 oral lichen planus (OLP), 2 oral leukoplakia (OLK) and 2 uncertain diagnoses, and especially, we observed plasma cell infiltration in 11 specimens, perivascular inflammation and diffuse distribution of lymphocytic infiltration throughout the lamina propria in OLL specimens, which differ from the typical histopathological features of OLP. Conclusions: Although this study is limited by sample size and retrospective design bias, it indicates that ARB-associated OLL may have similar clinical manifestations but different histopathological manifestations with OLP. We recommend histopathologic examination to establish the diagnosis of ARB-related OLL and guide treatment.

BackgroundOral lichen planus (OLP) and oral lichenoid lesions (OLL) are chronic immune-mediated mucosal disorders with heterogeneous clinical presentations. While T cell-mediated mechanisms have been extensively studied, the role of humoral immunity, particularly B cell activation and plasma cell differentiation, remains insufficiently understood.MethodsRNA sequencing datasets from healthy oral mucosa and OLP lesions were integrated and analyzed to identify differentially expressed genes. Consensus clustering based on a validated tertiary lymphoid structure (TLS) signature genes (TSGs) was used to define immune subtypes. Associations with clinical severity and recurrence were validated in an independent RNA-seq cohort. Immunohistochemistry analysis of CD20+ B cells and CD38+ plasma cells was conducted in a separate clinical cohort of OLP/OLL patients.ResultsBased on TSGs, two immune subtypes were identified: Subtype A was enriched for CCL3, IL2RA, and IL1R2. Subtype B exhibited elevated expression of humoral activation markers IRF4 and TNFRSF17 and enrichment of B cell-related pathways. Transcriptomic features of Subtype B were significantly associated with erosive and recurrent OLP cases. Immunohistochemistry confirmed that CD20+ B cells were enriched in TLS-like structures (P < 0.001), whereas CD38+ plasma cells were closely linked to erosive phenotypes (P = 0.038).ConclusionsTLS-associated B cell maturation and plasma cell infiltration define a humoral activation axis linked to unfavorable clinical outcomes in OLP/OLL. The presence of activated B cells and plasma cells correlates with erosive and recurrent disease phenotypes, highlighting their potential as prognostic biomarkers and therapeutic targets for improving disease management.

OBJECTIVES:The priming mechanism of adaptive immunity in oral mucositis remains unclarified. This study aimed to elucidate the mechanisms of oral lichen planus (OLP), with a specific focus on the role of inducible tertiary lymphoid structures (iTLSs) and stromal-immune microenvironments within OLP. MATERIALS AND METHODS:We employed single-cell RNA sequencing and multiplex immunofluorescence staining to characterize the spatial characteristics and transcriptional signature of iTLSs in OLP. To investigate whether the presence of iTLSs influences the disease severity of OLP, we retrospectively collected clinical data from OLP patients. RESULTS:Based on single-cell resolution analysis, we identified distinct cellular compositions and fibroblast-immune cells interactions within the iTLSs of OLP. We highlighted the critical role of CCL19+ fibroblasts in T-cell chemotaxis, promoting the development of iTLSs. Lymphotoxin was demonstrated to activate fibroblasts expressing CCL19. We revealed a significant correlation between the presence of iTLSs and increased severity of OLP, marked by more atrophic-erosive forms and higher disease scores in patients with iTLSs. CONCLUSIONS:The present research proposed the fibroblast-immune cell interactions within iTLSs as essential factors in OLP's inflammatory milieu, indicating iTLSs as the priming structure of T-cell immunity in the local oral mucosa.

This meta-analysis systematically evaluated the effectiveness and safety of immune checkpoint inhibitors (ICIs) in treating advanced cervical cancer, emphasizing their potential as transformative therapeutic options in this complex clinical landscape. EMBASE, Web of Science, PubMed, and the Cochrane Library were thoroughly searched for articles on the outcomes of ICIs in advanced cervical cancer patients. A pooled analysis was performed to evaluate the objective response rate (ORR: reported as an odds ratio (OR), progression-free survival (PFS; hazard ratio (HR), overall survival (OS; HR), and safety outcomes risk ratio (RR). Subgroup and sensitivity analyses were also conducted to identify potential sources of bias and heterogeneity. Our meta-analysis included 5 studies involving 3,112 patients. Compared with standard therapies, treatment with immune checkpoint inhibitors (ICIs) significantly improved the objective response rate (ORR; OR = 1.68, 95

Stromal-immune cells interaction and their contribution in the pathogenesis of oral mucositis, remained not fully understood. This made it hard to clarify the underlying mechanism linking systemic immunity and regional immune microenvironment. The present study aims to elucidate the underpinnings of oral lichen planus (OLP) by focusing on the role of inducible tertiary lymphoid structures (iTLSs) and their impact on disease progression. Employing single-cell RNA sequencing and multiple immunofluorescences, we identified distinct cellular compositions and stromal-immune cells interactions within the iTLSs of OLP. We particularly highlighted the role of CCL19+ fibroblasts and HEV cells. These stromal cells might play a crucial role in facilitating lymphocytes trafficking from peripheral blood to the local inflammation sites within oral mucosa, thereby promoting the formation of iTLSs in OLP. Our findings also revealed a significant correlation between the presence of iTLSs and increased severity of OLP, marked by more atrophic-erosive forms and higher REU scores in patients with iTLSs. The present research offered new insights into the pathogenic mechanisms of OLP, proposing the stromal-immune cell interactions within iTLSs as essential factors in the disease's inflammatory milieu. These findings contributed to uncovering the specific regional pathological features in OLP. Hence, the characterization of iTLSs provided a fundamental foundation for further studies in oral mucosal immunity.

For high-reliability systems in military, aerospace, and railway fields, the challenges of reliability analysis lie in dealing with unclear failure mechanisms, complex fault relationships, lack of fault data, and uncertainty of fault states. To overcome these problems, this paper proposes a reliability analysis method based on T-S fault tree analysis (T-S FTA) and Hyper-ellipsoidal Bayesian network (HE-BN). The method describes the connection between the various system fault events by T-S fuzzy gates and translates them into a Bayesian network (BN) model. Combining the advantages of T-S fault tree modeling with the advantages of Bayesian network computation, a reliability modeling method is proposed that can fully reflect the fault characteristics of complex systems. Experts describe the degree of failure of the event in the form of interval numbers. The knowledge and experience of experts are fused with the D-S evidence theory to obtain the initial failure probability interval of the BN root node. Then, the Hyper-ellipsoidal model (HM) constrains the initial failure probability interval and constructs a HE-BN for the system. A reliability analysis method is proposed to solve the problem of insufficient failure data and uncertainty in the degree of failure. The failure probability of the system is further calculated and the key components that affect the system’s reliability are identified. The proposed method accounts for the uncertainty and incompleteness of the failure data in complex multi-state systems and establishes an easily computable reliability model that fully reflects the characteristics of complex faults and accurately identifies system weaknesses. The feasibility and accuracy of the method are further verified by conducting case studies.

Background/purpose Oral lichen planus (OLP) is a chronic inflammatory disorder characterized by basement membrane disruption, which plays a crucial role in its pathogenesis. Matrix metalloproteinases (MMPs), a group of proteolytic enzymes, contribute to the degradation of the basement membrane. The specific MMPs secreted by keratinocytes in OLP lesions and relevant regulatory mechanisms are not fully understood. This study aimed to investigate the involvement of MMPs in OLP pathogenesis, focusing on their expression in keratinocytes and regulatory mechanisms. Materials and methods MMP mRNA expression in OLP epithelium was analyzed using RNA sequencing data obtained from the Gene Expression Omnibus (GEO) database. Mucosa samples from 30 OLP patients and 30 healthy controls were collected to observe the expression and regulation of MMPs in keratinocytes. The involvement of the mitogen-activated protein kinase (MAPK) pathway in MMP regulation was studied using HaCaT cells. Results RNA sequencing analysis revealed upregulation of MMP1 and MMP9 in OLP epithelium. MMP9 expression was predominantly observed in basal keratinocytes of OLP lesions. Elevated levels of phosphorylated c-Jun N-terminal kinase (JNK), a component of the MAPK pathway, were detected in OLP samples and co-localized with MMP9 in keratinocytes. Activation of the JNK pathway in HaCaT cells induced MMP9 expression, implicating JNK signaling in MMP9 regulation. Conclusion Keratinocytes contribute to OLP pathogenesis by secreting MMP9 through JNK pathway activation. This understanding may provide insights into targeted therapeutic interventions for this chronic recurrent disease.

ObjectivesTo investigate the effects of the heat shock protein 90 (HSP90) complex from oral lichen planus (OLP) lesion tissues on dendritic cell (DC) activation and the polarization of na & iuml;ve T cells.MethodsExpression of HSP90 in OLP lesions and healthy control (HC) mucosa was evaluated by single-cell RNA sequence, IHC, qRT-PCR, and immunoblotting. HSP90 complex was extracted by immunoprecipitation from oral mucosa as the agonist of DCs. Expression of IFN-alpha and MHC was detected by flow cytometry. After cocultured with pre-stimulated DCs, polarization of na & iuml;ve T cells was investigated by cytokine analysis.ResultsHSP90 was significantly higher in the lamina propria of OLP lesion and closely related to lymphocyte infiltration. HSP90 complex of OLP lesion activated DCs via TLR9 and increased their IFN-alpha secretion and MHC II expression. Pre-stimulated DCs increased the proportion of Th17 cells.ConclusionsHSP90 complex isolated from OLP lesion activated TLR9/IFN-alpha of DCs and further promoted the polarization of na & iuml;ve T cells toward Th17 immunity.