TRIM21, a member of the TRIM family of E3 ubiquitin ligases, is increasingly recognized for its role in immune regulation and has been implicated in various malignancies. However, its function in oral squamous cell carcinoma (OSCC) remains undefined. Here, we show that TRIM21 is significantly upregulated in human OSCC tissues and serves as an independent adverse prognostic factor for overall survival. Consistently, systemic Trim21 deficiency significantly suppressed OSCC tumorigenesis in a 4-nitroquinoline 1-oxide-induced oral carcinogenesis model. In contrast, TRIM21 knockdown did not significantly affect OSCC cell proliferation or migration in vitro, suggesting that its tumor-promoting effects may not be primarily mediated by the tumor cell-intrinsic behaviors examined under these conditions. Supporting this notion, bioinformatic analyses revealed strong associations between TRIM21 expression, immune checkpoint-related pathways, and immune cell infiltration. To further assess the contribution of TRIM21 in the tumor microenvironment in vivo, we established an orthotopic tongue allograft model and found that microenvironmental Trim21 deficiency markedly suppressed tumor growth. CyTOF and mIHC analyses further showed that microenvironmental Trim21 deficiency reduced PD-L1 expression on conventional dendritic cells (cDCs) and enhanced the cytotoxic activity of tumor-infiltrating CD8+ T cells. Collectively, TRIM21 promotes OSCC progression predominantly through modulation of the tumor immune microenvironment. This role may involve supporting an immunosuppressive cDC phenotype and restraining CD8+ T-cell-mediated antitumor immunity. TRIM21 may therefore serve as an independent prognostic biomarker and a potential therapeutic target in OSCC, with possible relevance to combination strategies involving immune checkpoint blockade.

Background: Frailty is a fluctuating health state that may worsen or improve over time and is linked to adverse outcomes, including musculoskeletal disorders such as arthritis. However, evidence on whether frailty changes predict arthritis onset remains limited. This study examined the relationship between changes in frailty status and incident arthritis among Chinese adults aged 45 years and older. Methods: We performed a longitudinal cohort analysis using data from the China Health and Retirement Longitudinal Study (CHARLS). Frailty was quantified with a 30-item Frailty Index (FI) and categorized as robust, pre-frail, or frail. Frailty transitions were defined by changes in FI-based categories across survey waves. Incident arthritis was identified as self-reported physician-diagnosed arthritis during follow-up. Associations between frailty transitions and arthritis onset were evaluated using Cox regression, reporting hazard ratios (HRs) and 95% confidence intervals (CIs). Models were adjusted for demographic characteristics, health behaviors, and biochemical indicators, and sensitivity analyses were conducted to verify result stability. Results: Among 4982 participants (mean age 58.97 years; 45.58% female). Relative to robust individuals, baseline pre-frailty (HR 1.67, 95% CI 1.41-1.97) and frailty (HR 2.76, 95% CI 1.97-3.85) were associated with higher arthritis risk. Participants whose frailty status worsened from robust to pre-frail or frail also showed higher arthritis risk (HR 1.68, 95% CI 1.34-2.10). In contrast, transitions from frail to pre-frail or robust were associated with lower risk (HR 0.44, 95% CI 0.21-0.92). Higher cumulative frailty burden and greater frailty progression were also associated with increased arthritis risk. Conclusions: Frailty transitions are strongly associated with incident self-reported physician-diagnosed arthritis. Monitoring frailty trajectories may improve arthritis risk stratification and support prevention strategies.

Rauch–Steindl syndrome is a rare autosomal dominant genetic disorder caused by pathogenic variants in the NSD2 gene, characterized by growth retardation, intellectual disability, and characteristic facial features. Although systemic manifestations have been increasingly recognized, the orofacial phenotype of this syndrome remains insufficiently defined. This report aims to provide a detailed description of the orofacial findings in a patient with Rauch–Steindl syndrome. Here, we report a 17-year-old male with growth retardation, mild intellectual disability, and characteristic facial features. Oral examination revealed a white nodular lesion at the midline of the dorsal tongue, multiple permanent tooth agenesis, and abnormal tooth morphology. Whole-exome sequencing combined with copy number variation analysis identified an approximately 10.13 kb deletion in the 4p16.3 region, encompassing exons 12–14 of the NSD2 gene. According to the American College of Medical Genetics and Genomics guidelines, this deletion was classified as pathogenic, thereby supporting the diagnosis of Rauch–Steindl syndrome. Based on the clinical and mycological findings, the lingual lesion was diagnosed as nodular median rhomboid glossitis with chronic Candida infection. The lesion partially regressed after topical antifungal therapy but persisted at the one-year follow-up. This case expands the phenotypic spectrum of Rauch–Steindl syndrome by delineating its orofacial manifestations, particularly dental agenesis and abnormal tooth development. The occurrence of nodular median rhomboid glossitis may represent a secondary consequence of altered immune homeostasis in a patient with an NSD2 variant, rather than a direct phenotypic manifestation of Rauch–Steindl syndrome. Our findings further support the multisystem involvement associated with NSD2 haploinsufficiency and highlight the importance of comprehensive dental evaluation in patients with this syndrome. Further studies with larger cohorts are warranted to systematically characterize the oral phenotype associated with Rauch–Steindl syndrome.

Oral leukoplakia is oral potentially malignant disorder with an unclear etiology. Emerging evidence indicates a link between metal dyshomeostasis and carcinogenesis. This study is the first to compare serum concentrations of calcium (Ca), magnesium (Mg), selenium (Se), copper (Cu), zinc (Zn), iron (Fe), lead (Pb) and manganese (Mn), as well as the peripheral blood immunological characteristics, between patients with oral leukoplakia and healthy controls, aiming to explore the potential association between metal dyshomeostasis and oral leukoplakia. This cross-sectional-case-control study recruited 89 participants at West China Hospital of Stomatology, including 59 patients with oral leukoplakia and 30 healthy controls. The concentrations of Ca, Mg, Se, Cu, Zn, Fe, Pb and Mn were measured by inductively coupled plasma-mass spectrometry (ICP-MS), and peripheral blood immunological characteristics were quantified using standard clinical chemistry methods. Compared with the control group, the serum Se level in oral leukoplakia patients was significantly decreased and negatively correlated with the degree of dysplasia. However, the Pb level was significantly increased. Patients with oral leukoplakia had abnormal immune function, with significantly decreased percentages of CD3 + T cell and CD8 + T cells, and significantly increased levels of IgA and antinuclear antibodies. Moreover, the Pb was significantly negatively correlated with cellular immunity, while Se was positively correlated with the count of CD8 + T cells. This study indicates a potential association between metal dyshomeostasis and oral leukoplakia, which may be mediated through the immune function, especially abnormal cellular immunity. These findings provide new insights into the etiology and treatment of oral leukoplakia.

The aim of this study was to investigate lymphocyte subsets, especially natural killer (NK) cells, in patients with systemic sclerosis (SSc) and evaluate the diagnostic value of NK cells in secondary pulmonary arterial hypertension (PAH). A total of 115 SSc patients and 100 age- and sex-matched health controls (HCs) were enrolled in this study. Flow cytometry was employed to quantify NK cells, while the association between NK cells and disease activity as well as PAH was investigated to further elucidate its diagnostic potential. The absolute count of NK (CD3-CD56+) cells significantly decreased in SSc patients. There was a negative correlation between the mRSS score and the injury index. The levels of cytokine exhibited significant elevation among SSc patients. Conversely, SSc-PAH patients demonstrated significantly elevated levels of CRP, UA, and BNP. Additionally, there was a significant reduction in the absolute level of NK cells. ROC curve analysis revealed that the optimal cut-off point for NK cells was 185 cells/µL, while for BNP it was 70.50 pg/mL and for UA it was 323.00 µmol/L. Our study revealed a significant inverse correlation between peripheral blood NK cell levels and the incidence of complicated PAH in patients with SSc.

INTRODUCTION:Caveolins (Cav) include Cav-1, Cav-2, and Cav-3, with Cav-1 being the most studied due to its prominent role as a major component of plasma membrane caveolae. Cav-1 is involved in a wide range of cellular functions and plays a key role in regulating signaling pathways related to immune responses and inflammation. Recently, research on Cav-1 in autoimmune diseases (AIDs) has garnered significant interest. METHODS:This paper provides an overview of the research on Cav-1's involvement in AIDs, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic sclerosis, connective tissue disease-associated interstitial lung disease, autoimmune disorders of the nervous system, autoimmune uveitis, autoimmune thyroid disease, and autoimmune myocarditis. RESULTS:Cav-1 plays a critical role in various AIDs, acting as a key protein in inflammatory and immune cells. It regulates multiple signaling processes by controlling the translocation of signaling molecules and modulating various pathways. Cav-1 is increasingly recognized as a biomarker in certain AIDs and may become pivotal in treating these diseases in the future. CONCLUSION:Cav-1 is a crucial player in the pathogenesis of many AIDs and has the potential to serve as both a diagnostic marker and a therapeutic target for these diseases. As research into Cav-1 deepens, it may offer new insights into the diagnosis, treatment, and drug sensitivity of AIDs, emerging as a promising target for future therapeutic strategies.

Autoimmune diseases refer to a group of conditions where the immune system produces an immune response against self-antigens, resulting in tissue damage. These diseases have profound impacts on the health of patients. In recent years, with the rapid development in the field of biomedicine, engineered exosomes have emerged as a noteworthy class of biogenic nanoparticles. By precisely manipulating the cargo and surface markers of exosomes, engineered exosomes have gained enhanced anti-inflammatory, immunomodulatory, and tissue reparative abilities, providing new prospects for the treatment of autoimmune diseases. Engineered exosomes not only facilitate the efficient delivery of bioactive molecules including nucleic acids, proteins, and cytokines, but also possess the capability to modulate immune cell functions, suppress inflammation, and restore immune homeostasis. This review mainly focuses on the applications of engineered exosomes in several typical autoimmune diseases. Additionally, this article comprehensively summarizes the current approaches for modification and engineering of exosomes and outlines their prospects in clinical applications. In conclusion, engineered exosomes, as an innovative therapeutic approach, hold promise for the management of autoimmune diseases. However, while significant progress has been made, further rigorous research is still needed to address the challenges that engineered exosomes may encounter in the therapeutic intervention process, in order to facilitate their successful translation into clinical practice and ultimately benefit a broader population of patients.

BACKGROUND:Psoriasis is a common immune-mediated skin disease that can involve other organs and tissues, including the oral mucosa. Some studies have found an increased proportion of geographic tongue (GT) and fissured tongue (FT) in patients with psoriasis, which appears to be region-specific. OBJECTIVES:The association of psoriasis with GT/FT in Eastern Asian populations remains unknown. Thus, the authors aimed to investigate the association of psoriasis with GT/FT in the Han population in southwestern China. METHODS:This study was conducted on 230 psoriatics and 230 healthy controls at West China Hospital. The authors compared the proportion of subjects with GT/FT in the two groups and compared age, gender, smoking, alcohol consumption, age at onset of psoriasis, duration of psoriasis, nail and joint involvement, Psoriasis Area and Severity Index, Body Surface Area, Dermatology Life Quality Index, and proportion using biologics in psoriatics with or without GT /FT. RESULTS:The authors have found a strong association between psoriasis and FT (p < 0.001), and a non-significant association between psoriasis and GT (p = 0.760). Compared to psoriasis patients without FT, the authors found that psoriasis patients with FT were older (p = 0.021) and had an increased frequency of late-onset psoriasis (p = 0.014); they also had more severe psoriasis (p = 0.047) and poorer quality of life (p = 0.045). STUDY LIMITATIONS:GT has periods of exacerbation and remission, so the authors cannot avoid a deviation of the prevalence of GT in this study from the true prevalence rate. Also, biologics have been found to lead to remission of GT and FT, which may have influenced the GT/FT ratio in the case group in this study. CONCLUSIONS:Psoriasis was associated with FT in the Han population in southwestern China, attention must be paid to the treatment of psoriatics with FT and skin diseases in patients with FT.

Oral leukoplakia (OLK) is one of the most common oral potentially malignant disorders (OPMDs). Preventing malignant transformation is the main purpose of OLK treatment. The treatment approaches of OLK include surgery, chemotherapy, and other therapies, such as photodynamic therapy and CO2 laser. The application of genomic variation-based chemotherapy in OLK deserves further exploration. As chemopreventive drugs, drug resistance and disease recurrence have limited their use in OLK. In this review, we concentrate on the retinoid treatment for OLK, summarizing the current status of retinoids in the treatment of OLK, the mechanism of retinoid action, and the mechanisms of resistance to retinoid therapy, and we highlight the strategies to improve retinoid efficacy in the treatment of OLK, such as the combination of retinoids and epigenetic regulators or metabolism-blocking agents, new synthetic retinoids, and new drug delivery systems of retinoids, providing new methods for the successful clinical application of retinoids in the treatment of OLK.

BACKGROUND:Malignant neoplasms are a well-recognized global public health concern, with significant impacts on human health and quality of life. The interplay between tumors and autoimmune rheumatic diseases is complex, and the resulting tumor-associated rheumatic diseases represent a rare and intricate group of conditions that occur in the context of malignant tumors. In addition, various rheumatic diseases can arise as a consequence of oncology treatment. These diseases present with intricate clinical manifestations and pathological features, often rendering them challenging to diagnose and impacting patients' quality of life. Despite this, they have yet to be fully recognized.METHODS:This article presents a literature review of published original articles and review articles concerning paraneoplastic rheumatic syndromes and rheumatic diseases associated with cancer treatment. We conducted a comprehensive literature search in PubMed, Web of Science and Google Scholar databases, excluding duplicated and irrelevant studies. In cases of duplicated research, we selected articles with higher impact factors for the review.RESULTS:This review focuses on the clinical features, diagnosis, and treatment of paraneoplastic rheumatic diseases, as well as the pathogenesis of these diseases. Additionally, we summarize the autoimmune rheumatic diseases associated with cancer treatment. Ultimately, the goal of this review is to enhance recognition and improve the management of autoimmune rheumatic diseases related to tumors.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is among the most lethal and most prevalent malignant tumors. Glycolysis affects tumor growth, invasion, chemotherapy resistance, and the tumor microenvironment. Therefore, we aimed at identifying a glycolysis-related prognostic model for HNSCC and to analyze its relationship with tumor immune cell infiltrations.MethodsThe mRNA and clinical data were obtained from The Cancer Genome Atlas (TCGA), while glycolysis-related genes were obtained from the Molecular Signature Database (MSigDB). Bioinformatics analysis included Univariate cox and least absolute shrinkage and selection operator (LASSO) analyses to select optimal prognosis-related genes for constructing glycolysis-related gene prognostic index(GRGPI), as well as a nomogram for overall survival (OS) evaluation. GRGPI was validated using the Gene Expression Omnibus (GEO) database. A predictive nomogram was established based on the stepwise multivariate regression model. The immune status of GRGPI-defined subgroups was analyzed, and high and low immune groups were characterized. Prognostic effects of immune checkpoint inhibitor (ICI) treatment and chemotherapy were investigated by Tumor Immune Dysfunction and Exclusion (TIDE) scores and half inhibitory concentration (IC50) value. Reverse transcription-quantitative PCR (RT-qPCR) was utilized to validate the model by analyzing the mRNA expression levels of the prognostic glycolysis-related genes in HNSCC tissues and adjacent non-tumorous tissues.ResultsFive glycolysis-related genes were used to construct GRGPI. The GRGPI and the nomogram model exhibited robust validity in prognostic prediction. Clinical correlation analysis revealed positive correlations between the risk score used to construct the GRGPI model and the clinical stage. Immune checkpoint analysis revealed that the risk model was associated with immune checkpoint-related biomarkers. Immune microenvironment and immune status analysis exhibited a strong correlation between risk score and infiltrating immune cells. Gene set enrichment analysis (GSEA) pathway enrichment analysis showed typical immune pathways. Furthermore, the GRGPIdel showed excellent predictive performance in ICI treatment and drug sensitivity analysis. RT-qPCR showed that compared with adjacent non-tumorous tissues, the expressions of five genes were significantly up-regulated in HNSCC tissues.ConclusionThe model we constructed can not only be used as an important indicator for predicting the prognosis of patients but also had an important guiding role for clinical treatment.

Chemoresistance poses a significant challenge in the treatment of advanced head and neck squamous cell cancer (HNSCC). The role and mechanism of circular RNAs (circRNAs) in HNSCC chemoresistance remain understudied. We conducted circRNA microarray analysis to identify differentially expressed circRNAs in HNSCC. The expression of circRNAs from the tyrosylprotein sulfotransferase 2 (TPST2) gene and miRNAs was evaluated through qPCR, while the circular structure of circTPST2 was verified using Sanger sequencing and RNase R. Through Western blotting, biotin-labeled RNA pulldown, RNA immunoprecipitation, mass spectrometry, and rescue experiments, we discovered miR-770-5p and nucleolin as downstream targets of circTPST2. Functional tests, including CCK8 assays and flow cytometry, assessed the chemoresistance ability of circTPST2, miR-770-5p, and Nucleolin. Additionally, FISH assays determined the subcellular localization of circTPST2, miR-770-5p, and Nucleolin. IHC staining was employed to detect circTPST2 and Nucleolin expression in HNSCC patients. circTPST2 expression was inversely correlated with cisplatin sensitivity in HNSCC cell lines. Remarkably, high circTPST2 expression correlated with lower overall survival rates in chemotherapeutic HNSCC patients. Mechanistically, circTPST2 reduced chemosensitivity through sponge-like adsorption of miR-770-5p and upregulation of the downstream protein Nucleolin in HNSCC cells. The TCGA database revealed improved prognosis for patients with low circTPST2 expression after chemotherapy. Moreover, analysis of HNSCC cohorts demonstrated better prognosis for patients with low Nucleolin protein expression after chemotherapy. We unveil circTPST2 as a circRNA associated with chemoresistance in HNSCC, suggesting its potential as a marker for selecting chemotherapy regimens in HNSCC patients. Further exploration of the downstream targets of circTPST2 advanced our understanding and improved treatment strategies for HNSCC.

Abstract Background: Rheumatoid arthritis (RA) is a chronic autoimmune joint disease characterized by persistent synovitis and systemic inflammation of the joints. Cell therapy, a cellular drug delivery therapy based on the control of immune dysregulation, inflammatory cytokine production, and overall systemic inflammation, is expected to reverse the process of joint destruction when applied to RA. Based on this, the field of cell therapy applied to RA treatment has been gaining attention in recent years and many results have been achieved. Bibliometric analysis can provide insight into the development of a field. This study aims to provide an overview of the knowledge structure and research hotspots of cell therapy in RA through bibliometrics. Method: The Web of Science Core Collection (WoSCC) database was used to search the literature on cellular therapies related to RA between 2003 and 2022. VOSviewers, CiteSpace, and the R package "bibliometrics" were used to perform the bibliometric analysis. Results: This article includes 8822 articles from 107 countries, mainly from China and the United States. Fluctuating growth in the number of articles published on cell therapy applied to RA. The University of Amsterdam, Harvard University, Karolinska Institutet, and Stanford University are the main research institutions. The journal Arthritis research & therapy is the most popular journal in the field, and the journal Annals of rheumatic diseases is the most frequently cited. 41982 authors have published in this field, including more collaborative publications; Tak, paul p, Emery, paul, Doerner, Thomas, Isaacs, john d, Tanaka, and Yoshida have published several papers, while Arnett Fc is the author of most frequently cited paper. The University of Amsterdam has been extensively involved in the publication of papers on this topic. Swedish and Korean scientists have published fewer relevant papers as corresponding authors, but have been extensively involved in the investigation of this topic. Studying the mechanisms of various factors (e.g. immune cells, immune molecules, cytokines, and inflammatory responses) in the occurrence and development of RA and studying the therapeutic strategies of cellular therapies for the future precision treatment of RA are the two main topics in this research area. "T cells", "bone marrow (BM) transplantation", "mesenchymal cells", and "monoclonal antibodies" are the emerging research top keywords of the hot spots. Conclusion: This article is the first bibliometric study that comprehensively summarizes the research trends and their developments in the application of cell therapy to the treatment of RA. The content includes recent research results and hot directions in the field, providing reference information for scholars studying cell therapy and RA.

Abstract Background: Rheumatoid arthritis (RA) is a chronic autoimmune joint disease characterized by persistent synovitis and systemic inflammation of the joints. Cell therapy, a cellular drug delivery therapy based on the control of immune dysregulation, inflammatory cytokine production, and overall systemic inflammation, is expected to reverse the process of joint destruction when applied to RA. Based on this, the field of cell therapy applied to RA treatment has been gaining attention in recent years and many results have been achieved. Bibliometric analysis can provide insight into the development of a field. This study aims to provide an overview of the knowledge structure and research hotspots of cell therapy in RA through bibliometrics. Method: The Web of Science Core Collection (WoSCC) database was used to search the literature on cellular therapies related to RA between 2003 and 2023. VOSviewers, CiteSpace, and the R package "bibliometrics" were used to perform the bibliometric analysis. Results: This article includes 9341 articles from 107 countries, mainly from China and the United States. Fluctuating growth in the number of articles published on cell therapy applied to RA. The University of Amsterdam, Harvard University, Karolinska Institutet, and Stanford University are the main research institutions. The journal Arthritis Research & Therapy is the most popular journal in the field, and the journal Annals of Rheumatic Diseases is the most frequently cited. 44914 authors have published in this field, including more collaborative publications; Tak and Emery have published several papers, while Arnett Fc is the author of most frequently cited paper. The University of Amsterdam has been extensively involved in the publication of papers on this topic. France scientists have published fewer relevant papers as corresponding authors, but have been extensively involved in the investigation of this topic. The thematic analysis identified five research themes. The themes relate to monoclonal antibody therapy, tumour necrosis factor-alpha inhibitor therapy, gene and mesenchymal stem cell therapy, targeted immune cell and cytokine therapy, conventional therapy and novel therapy. Conclusion: This article is the first bibliometric study that comprehensively summarizes the research trends and their developments in the application of cell therapy to the treatment of RA. The content includes recent research results and hot directions in the field, providing reference information for scholars studying cell therapy and RA.

Abstract Background: Head and neck squamous cell cancer (HNSCC) is the most prevalent head and neck malignancy. Chemoresistance is a major challenge in the treatment of advanced HNSCC. Circular RNAs (circRNAs) are essential for the development of cancer and chemoresistance. The role and mechanism of circRNAs in the regulation of HNSCC chemoresistance are much less explored. Methods: CircRNA microarray analysis was used to detect differentially expressed circRNAs in HNSCC. The expression of circTPST2 and miRNAs in HNSCC cells was assessed by qPCR, and the ring structure of circTPST2 was examined using Sanger sequencing, RNase R, and actinomycin D assays. MiR-770-5p and Nucleolin were found to be downstream target molecules of circTPST2 by Western blotting, biotin-labeled RNA pulldown, RNA immunoprecipitation, mass spectrometry, and rescue experiments. Then, the chemoresistance ability of circTPST2, miR-770-5p and Nucleolin was examined through functional tests such as CCK8 assays and flow cytometry assays. FISH assays were performed to determine the location of circTPST2, miR-770-5p, and Nucleolin. IHC staining assays were applied to detect the expression of circTPST2 and Nucleolin in HNSCC patients. Results: The expression level of circTPST2 was negatively related to the cisplatin sensitivity of HNSCC cell lines. Notably, the expression of circTPST2 was negatively correlated with the overall survival rate of chemotherapeutic patients with HNSCC. Mechanistically, circTPST2 could reduce the cisplatin sensitivity of HNSCC cells through sponge-like adsorption of miR-770-5p, and it could also interact with and upregulate the downstream protein Nucleolin to regulate cisplatin sensitivity in HNSCC cells. Finally, according to the analysis of the TCGA database, the prognosis of patients with high miR-770-5p expression is better after chemotherapy. In contrast, according to the analysis of our HNSCC cohorts, the prognosis of patients with low Nucleolin protein expression is better after chemotherapy. Conclusion: Our results identified the chemotherapy resistance-related circRNA circTPST2, indicating that circTPST2 may serve as a promising chemotherapy regimen selection marker in HNSCC.

Objective. The goal of this study was to look into age, genetics,sex, oral mucosa diseases, and systemic diseases as potential risk factors for the geographic tongue (GT) in a Chinese population. Study Design. This retrospective cross-sectional study used the demographic and medical data of 3400 patients between March 2021 and August 2021 from the Department of Oral Medicine at West China Hospital of Stomatology. Binary logistic regression was conducted to analyze the association of GT and age, fissured tongue (FT), burning mouth syndrome (BMS), oral lichen planus (OLP), gastrointestinal disorders, and hematologic disorders and to acquire the adjusted odds ratio (AOR). Results. GT occurred in 3.6% of patients, with 15 out of 123 (12.2%) patients with GT having a family history. Binary logistic regression found age <30 years (AOR: 4.4; [95% CI: 2.8-6.9]), FT (28.8 [17.1-48.4]), BMS (0.3 [0.1-0.6]), OLP (0.2 [0.0-0.5]), and gastrointestinal disorders (4.3 [2.7-6.7]) were significantly associated with GT, and GT was unrelated to recurrent aphthous ulcer (RAU) or systemic diseases such as cardiovascular diseases. Conclusion. In the Chinese population, GT was more prevalent in patients with <30 years of age, FT, and gastrointestinal disorders, and it was less prevalent in BMS and OLP.

Interleukin 34 (IL-34) is a cytokine that shares the receptor with colony-stimulating factor 1 (CSF-1). IL-34 is involved in a broad range of pathologic processes including cancer. We previously demonstrated that IL-34 promoted the proliferation and colony formation of human acute monocytic leukemia (AMoL) cells. However, the mechanism has not been elucidated. Here, by analyzing the gene profiles of Molm13 and THP1 cells overexpressing IL-34 (Molm13-IL-34 and THP1-IL-34), upregulation of the DNA damage-inducible transcript 4 (DDIT4) was detected in both series. Knockdown of DDIT4 effectively inhibited the proliferation, promoted apoptosis and colony formation in Molm13-IL-34 and THP1-IL-34 cells. Our results suggest that DDIT4 mediates the proliferation-promotive effect of IL-34 whereas does not mediate the promotive effect of IL-34 on colony formation in AMoL cells.

Macrophage colony-stimulating factor (M-CSF) regulates both malignant cells and microenvironmental cells. Its splicing isoforms show functional heterogeneity. However, their roles on leukemia have not been well established. Here, the expression of total M-CSF in patients with hematopoietic malignancies was analyzed. The roles of M-CSF isoforms on the progression of acute myeloid leukemia (AML) were studied by establishing MLL-AF9-induced mouse AML models with high level membrane-bound M-CSF (mM-CSF) or soluble M-CSF (sM-CSF). Total M-CSF was highly expressed in myeloid leukemia patients. Furthermore, mM-CSF but not sM-CSF prolonged the survival of leukemia mice. While sM-CSF was more potent to promote proliferation and self-renew, mM-CSF was more potent to promote differentiation. Moreover, isoforms had different effects on leukemia-associated macrophages (LAMs) though they both increase monocytes/macrophages by growth-promoting and recruitment effects. In addition, mM-CSF promoted specific phagocytosis of leukemia cells by LAMs. RNA-seq analysis revealed that mM-CSF enhanced phagocytosis-associated genes and activated oxidative phosphorylation and metabolism pathway. These results highlight heterogeneous effects of M-CSF isoforms on AML progression and the mechanisms of mM-CSF, that is, intrinsically promoting AML cell differentiation and extrinsically enhancing infiltration of macrophages and phagocytosis by macrophages, which may provide potential clues for clinical diagnosis and therapy.

目的:探讨过表达IL 34对急性单核细胞白血病(acute monocytic leukemia,AMoL)细胞恶性生物学行为的影向.方法:构建IL-34过表达载体,制备慢病毒载体pCDH-GFP,感染AMoL细胞系THP1和MOLM-13,通过细胞增殖实验、集落形成实验、PI染色检测细胞周期法和Annexin-V/PI法检测IL-34对AMoL细胞的增殖、集落形成、细胞周期和凋亡的影响,通过流式细胞术分析过表达IL-34对细胞分化表型的影响,通过裸鼠皮下成瘤模型观察肿瘤大小、质量差异和巨噬细胞募集情况.结果:实验组THP1和MOLM-13细胞IL-34 mRNA表达水平分别比对照组提高近4 000倍和近3 000倍(均P＜0.01),表明已成功构建稳定过表达IL-34的AMoL细胞系.体外细胞实验结果显示,过表达IL-34提高THP1和MOLM-13细胞的增殖[72 h:(0.738±0.003) vs(0.646±0.008),(0.290±0.004) vs (0.247±0.004);均P＜0.01]和集落形成能力[(127.00±3.37) vs (86.00±4.08)个,(160.70±4.70) vs(116.70±3.93)个;均P＜0.01],对细胞的凋亡没有显著影响(均P＞0.05);单核-巨噬细胞分化标志物CD11b和CD14表达水平升高,未成熟细胞标志物CD71表达水平减低,表明IL-34促进了AMoL细胞向单核-巨噬细胞方向分化(均P＜0.05).裸鼠体内荷瘤实验可见,过表达IL-34促进瘤组织内巨噬细胞募集(P＜0.01).结论:过表达IL-34提高AMoL细胞的增殖和集落形成能力,促进细胞向单核-巨噬细胞分化,并促进肿瘤内巨噬细胞的募集.

NK cells are indispensable components of tissue microenvironment and play vital in both innate and adaptive immunity. The activation and function of NK cells are affected by tumor microenvironments. NK cells are also important players in leukemic microenvironment. However, their characteristics in leukemic microenvironment, including maturation status, phenotype, subpopulations and functional roles especially immunoregulatory potential, have not been well established. Here, we studied these characteristics of NK cells in MLL-AF9 induced mouse acute myeloid leukemia (AML) model. Increase of more mature NK cells were detected in the AML spleen. Splenic AML microenvironment promoted NK cell activation in early and middle stages of leukemia. Cytotoxicity molecules and cytokines were up-regulated in activated NK cells. Furthermore, NK cells from AML microenvironment regulated T cell function, not only by maintaining the activation of CD4+ and promoting the degranulation of cytotoxic CD8+ T cells but also by influencing the differentiation of CD4+ T cells. Moreover, two NK cell subpopulations marked by DNAM-1 (CD226) had distinct cytokine expression patterns but similar regulatory effects on T cells. Collectively, these findings highlight the significance of immunoregulatory role of NK cells, and suggest novel therapeutic potential for leukemia by manipulating NK cell immunoregulatory activity.