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KDM6B-Mediated HADHA Demethylation/Lactylation Regulates Cementogenesis. KDM6B 介导的 HADHA 去甲基化/乳化调控骨水泥生成
Pub Date : 2024-11-21 DOI: 10.1177/00220345241286460
Z Yang, H Wang, J Xiao, Q Yang, J Sun, H Liu, L Ma, X Huang, C Wang, X Wang, Z Cao

Cementum, a bone-like tissue, is an essential component of periodontium, and periodontitis can lead to degenerative changes in the cementum, eventually resulting in tooth loss. The therapeutic strategy for advanced periodontitis is to achieve periodontal regeneration, of which cementum regeneration is a key criterion. Cementoblasts are responsible for cementogenesis, and their mineralization counts in cementum regeneration. However, research is still limited. Thus, novel treatment targets are required. The expression levels of lysine (K)-specific demethylase 6B (KDM6B), fatty acid oxidation (FAO), and cementogenic markers were detected by quantitative polymerase chain reaction, Western blot, immunofluorescence, and immunohistochemical assays. FAO levels were analyzed by assay kit. In vivo, injection of GSK-J4 into mice detected the influence of KDM6B on cementum formation. Chromatin immunoprecipitation sequencing, transcriptomic RNA sequencing, subsequent chromatin immunoprecipitation-quantitative polymerase chain reaction and overexpression of HADHA (hydroxyacyl-coA dehydrogenase trifunctional multienzyme complex subunit alpha) elucidated the KDM6B-Hadha axis. Global lactylation was detected by Western blot. Lactylation proteomics clarified the modified sites of HADHA. Mutating these sites and applying coimmunoprecipitation confirmed their significance. Knockdown of Kdm6b was utilized to assess its regulation on the lactylation of HADHA, FAO, and mineralization levels. FAO and KDM6B expression was elevated during cementoblast mineralization. KDM6B targeted Hadha and activated its transcription, thereby increasing FAO levels and promoting mineralization. Lactylation occurred in the process of mineralization, and KDM6B could regulate the lactylation of HADHA to promote FAO and mineralization. Overexpression of Hadha and the addition of lactate sodium could rescue the inhibition of mineralization by knockdown of Kdm6b. In summary, during cementoblast mineralization, KDM6B regulates HADHA by mediating histone demethylation and lactylation, thereby upregulating FAO and thus promoting mineralization.

牙骨质是一种骨样组织,是牙周的重要组成部分,牙周炎会导致牙骨质发生退行性变化,最终导致牙齿脱落。晚期牙周炎的治疗策略是实现牙周再生,而牙骨质再生是其中的关键标准。骨水泥母细胞负责骨水泥的生成,其矿化在骨水泥再生中起着重要作用。然而,这方面的研究仍然有限。因此,需要新的治疗目标。本研究通过定量聚合酶链式反应、Western 印迹、免疫荧光和免疫组化检测了赖氨酸(K)特异性去甲基化酶 6B (KDM6B)、脂肪酸氧化(FAO)和骨水泥生成标志物的表达水平。FAO水平通过检测试剂盒进行分析。在体内,向小鼠注射 GSK-J4 可检测 KDM6B 对骨水泥形成的影响。染色质免疫共沉淀测序、转录组RNA测序、随后的染色质免疫共沉淀-定量聚合酶链反应和过表达HADHA(羟基乙酰辅酶脱氢酶三功能多酶复合物亚基α)阐明了KDM6B-HADHA轴。通过 Western 印迹检测了全乳化作用。乳化蛋白质组学明确了 HADHA 的修饰位点。突变这些位点并应用免疫共沉淀证实了它们的重要性。通过敲除 Kdm6b 来评估其对 HADHA 乳化、FAO 和矿化水平的调控。在水泥母细胞矿化过程中,FAO和KDM6B的表达升高。KDM6B 靶向 Hadha 并激活其转录,从而提高 FAO 水平并促进矿化。矿化过程中会发生乳化作用,KDM6B可以调节HADHA的乳化作用,从而促进FAO和矿化。过量表达Hadha和添加乳酸钠可以挽救Kdm6b敲除对矿化的抑制。综上所述,在水泥母细胞矿化过程中,KDM6B通过介导组蛋白去甲基化和乳酸化来调节HADHA,从而上调FAO,进而促进矿化。
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引用次数: 0
System Dynamics Modeling of Caries Severity States in Long-Term Care. 长期护理中龋病严重程度的系统动力学模型。
Pub Date : 2024-11-21 DOI: 10.1177/00220345241290139
B Turton, J Griffith, J A Jones, S R Baker, A Singh, K Rawal, J Calabrese, M Henshaw

Dental caries among long-term care (LTC) residents is a persistent and complex problem driven by social and structural factors. Systems thinking may be useful in considering novel approaches to reducing disease. This study aimed to develop a system dynamics model to simulate the progression of dentate older adults in LTC through caries severity states and estimate the effects of 3 intervention scenarios on the progression of caries: preventive topical fluoride (TF), arrest of caries with silver diamine fluoride (SDF), and a combination of TF and SDF. Dentate older adults in LTC were categorized into 4 caries severity states by their number of untreated carious lesions. The model assumed that changes in severity states were consistent with incidence rates reported in the literature and available billing data for dental care and that individuals move in and out of the system by entering and exiting the facility or experiencing edentulism. For all scenarios, the proportion of dentate older adults in LTC with 1 or more untreated lesions stays stable, the distribution of disease shifts from a high severity state, and the system approaches equilibrium after 4 y. The TF intervention predicts minimal impacts on decreasing the proportion of dentate older adults with 1 or more untreated lesions (2.5% decrease), while the SDF intervention and the combination interventions were most disruptive. There was a 29.6% and 33.6% decrease, respectively. Given the specific population dynamics in LTC, these findings suggest that long-term (greater than 4 y) interventions should be designed to address both the management of existing lesions and their incidence. This system dynamics model allows researchers to render institution-specific data points from LTCs to estimate the effects of proposed interventions at the respective site.

受社会和结构因素的影响,长期护理(LTC)居民的龋齿是一个长期存在的复杂问题。系统思维可能有助于考虑减少疾病的新方法。本研究旨在开发一个系统动力学模型,以模拟长期护理机构中患有牙齿的老年人龋齿严重程度的发展过程,并估算三种干预方案对龋齿发展的影响:预防性局部氟化物(TF)、用二胺氟化银抑制龋齿(SDF)以及 TF 和 SDF 的组合。根据未治疗龋损的数量,将患有牙齿龋齿的长者分为 4 种龋病严重程度。该模型假定严重程度状态的变化与文献报道的发病率和现有的牙科护理账单数据一致,并且个人通过进入和离开医疗机构或出现牙齿脱落而进出系统。在所有方案中,患有 1 个或 1 个以上未经治疗的牙科病变的长者在 LTC 中的比例保持稳定,疾病分布从高严重度状态转变,系统在 4 年后接近平衡。分别减少了 29.6% 和 33.6%。考虑到长期护理中特定的人口动态,这些研究结果表明,长期(超过 4 年)干预措施的设计应同时解决现有病变的管理和发病率问题。这种系统动力学模型使研究人员能够利用来自长者照护中心的特定机构数据点来估计拟议干预措施在相应地点的效果。
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引用次数: 0
Terahertz Imaging Detects Oral Cariogenic Microbial Domains Characteristics. 太赫兹成像检测口腔致龋微生物域特征。
Pub Date : 2024-11-21 DOI: 10.1177/00220345241287733
A Zhang, L Lei, L Cheng, H Yin, C Zhang, J Luo, F Wu, M Hu, R Cheng, T Hu

Dental caries, associated with plaque biofilm, is highly prevalent and significantly burdens public health. Streptococcus mutans is the main cariogenic bacteria that adheres to the tooth surface and forms an abundant extracellular polysaccharide matrix (EPS) as a cariogenic biofilm scaffold. S. mutans RNase III-encoding gene (rnc) and a putative chromosome segregation protein-encoding gene (smc) are potentially associated with EPS production. In addition, complex interactions between S. mutans and other oral microorganisms synergistically or antagonistically affect the cariogenicity. Commensal streptococci suppress the growth of cariogenic pathogens, whereas Candida albicans mediates the formation of cariogenic biofilm through aggregation and dual-species biofilm formation with S. mutans. However, label-free detection of cariogenic microbial interactions with the EPS matrix is still challenging during laboratory investigations. Herein, we hypothesized that the S. mutans rnc-smc operon affects EPS production and aimed to observe streptococci, S. mutans, and S. mutans-C. albicans using terahertz scanning near-field optical microscopy (THz s-SNOM). The light in the 0.1- to 0.3-THz frequency range interacted with the sample through a nano-probe tip by a point-by-point scanning process. Additional noise reduction of the original image was achieved by a dual kernel Gaussian filter. The monospecies of streptococci, S. mutans smc/rnc mutants, and the dual-species of S. mutans-C. albicans were scanned by THz s-SNOM. This technique provided terahertz near-field scanning images of S. mutans smc/rnc mutants, streptococci, and dual-species of S. mutans-C. albicans. Additional analysis of the original images potentially revealed the structures of the strains, such as cell diameters and cell wall thickness. In conclusion, the results suggested that the S. mutans rnc-smc operon regulates EPS production. Furthermore, this novel label-free detection of a THz near-field scanning technique had the potential to observe the morphologies of bacterial cells and EPS matrix.

龋齿与牙菌斑生物膜有关,发病率很高,给公共卫生造成了巨大负担。变异链球菌是主要的致龋细菌,它粘附在牙齿表面并形成丰富的胞外多糖基质(EPS)作为致龋生物膜支架。S. mutans 的 RNase III 编码基因(rnc)和推测的染色体分离蛋白编码基因(smc)可能与 EPS 的产生有关。此外,变异链球菌与其他口腔微生物之间复杂的相互作用会协同或拮抗地影响致龋性。共生链球菌抑制致龋病原体的生长,而白色念珠菌则通过与变异棒状杆菌聚集和形成双种生物膜来介导致龋生物膜的形成。然而,在实验室研究中,无标记检测致龋微生物与 EPS 基质之间的相互作用仍具有挑战性。在此,我们假设变异棒状杆菌的 rnc-smc 操作子会影响 EPS 的产生,并利用太赫兹扫描近场光学显微镜(THz s-SNOM)观察链球菌、变异棒状杆菌和变异棒状杆菌-白喉杆菌。通过逐点扫描过程,0.1-0.3 太赫兹频率范围内的光通过纳米探针尖端与样品相互作用。双核高斯滤波器对原始图像进行了额外的降噪处理。太赫兹 s-SNOM 扫描了单种链球菌、变异链球菌 smc/rnc 突变体和变异链球菌-白喉杆菌双种。该技术提供了变异棒状杆菌 smc/rnc 突变体、链球菌和变异棒状杆菌-白种人双种的太赫兹近场扫描图像。对原始图像的其他分析可能会揭示菌株的结构,如细胞直径和细胞壁厚度。总之,研究结果表明,变异杆菌 rnc-smc 操作子调控 EPS 的产生。此外,这种新型无标记检测太赫兹近场扫描技术还具有观察细菌细胞和 EPS 基质形态的潜力。
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引用次数: 0
Explainable Deep Learning Approaches for Risk Screening of Periodontitis. 用于牙周炎风险筛查的可解释深度学习方法。
Pub Date : 2024-11-19 DOI: 10.1177/00220345241286488
B Suh, H Yu, J-K Cha, J Choi, J-W Kim

Several pieces of evidence have been reported regarding the association between periodontitis and systemic diseases. Despite the emphasized significance of prevention and early diagnosis of periodontitis, there is still a lack of a clinical tool for early screening of this condition. Therefore, this study aims to use explainable artificial intelligence (XAI) technology to facilitate early screening of periodontitis. This is achieved by analyzing various clinical features and providing individualized risk assessment using XAI. We used 1,012 variables for a total of 30,465 participants data from National Health and Nutrition Examination Survey (NHANES). After preprocessing, 9,632 and 5,601 participants were left for all age groups and the over 50 y age group, respectively. They were used to train deep learning and machine learning models optimized for opportunistic screening and diagnosis analysis of periodontitis based on Centers for Disease Control and Prevention/ American Academy of Pediatrics case definition. Local interpretable model-agnostic explanations (LIME) were applied to evaluate potential associated factors, including demographic, lifestyle, medical, and biochemical factors. The deep learning models showed area under the curve values of 0.858 ± 0.011 for the opportunistic screening and 0.865 ± 0.008 for the diagnostic dataset, outperforming baselines. By using LIME, we elicited important features and assessed the combined impact and interpretation of each feature on individual risk. Associated factors such as age, sex, diabetes status, tissue transglutaminase, and smoking status have emerged as crucial features that are about twice as important than other features, while arthritis, sleep disorders, high blood pressure, cholesterol levels, and overweight have also been identified as contributing factors to periodontitis. The feature contribution rankings generated with XAI offered insights that align well with clinically recognized associated factors for periodontitis. These results highlight the utility of XAI in deep learning-based associated factor analysis for detecting clinically associated factors and the assistance of XAI in developing early detection and prevention strategies for periodontitis in medical checkups.

关于牙周炎与全身性疾病之间的关联,已有多项证据报道。尽管牙周炎的预防和早期诊断意义重大,但目前仍缺乏早期筛查牙周炎的临床工具。因此,本研究旨在利用可解释人工智能(XAI)技术促进牙周炎的早期筛查。这是通过分析各种临床特征并利用 XAI 提供个性化风险评估来实现的。我们使用了来自美国国家健康与营养调查(NHANES)的 30465 名参与者数据中的 1012 个变量。经过预处理后,所有年龄组和 50 岁以上年龄组的参与者数据分别为 9,632 人和 5,601 人。根据美国疾病控制和预防中心/美国儿科学会的病例定义,这些数据被用于训练优化的深度学习和机器学习模型,以进行牙周炎的机会性筛查和诊断分析。本地可解释模型-诊断解释(LIME)用于评估潜在的相关因素,包括人口统计、生活方式、医疗和生化因素。深度学习模型显示,机会性筛查的曲线下面积值为 0.858 ± 0.011,诊断数据集的曲线下面积值为 0.865 ± 0.008,均优于基线值。通过使用 LIME,我们得出了一些重要特征,并评估了每个特征对个体风险的综合影响和解释。年龄、性别、糖尿病状况、组织转谷氨酰胺酶和吸烟状况等相关因素成为关键特征,其重要性是其他特征的两倍,而关节炎、睡眠障碍、高血压、胆固醇水平和超重也被认为是牙周炎的诱因。用 XAI 生成的特征贡献排名提供的见解与临床公认的牙周炎相关因素非常吻合。这些结果凸显了 XAI 在基于深度学习的关联因素分析中检测临床关联因素的实用性,以及 XAI 在体检中协助制定牙周炎早期检测和预防策略的作用。
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引用次数: 0
Geo-Net: Geometry-Guided Pretraining for Tooth Point Cloud Segmentation. Geo-Net:用于牙齿点云分割的几何引导预训练。
Pub Date : 2024-11-16 DOI: 10.1177/00220345241292566
Y Liu, X Liu, C Yang, Y Yang, H Chen, Y Yuan

Accurately delineating individual teeth in 3-dimensional tooth point clouds is an important orthodontic application. Learning-based segmentation methods rely on labeled datasets, which are typically limited in scale due to the labor-intensive process of annotating each tooth. In this article, we propose a self-supervised pretraining framework, named Geo-Net, to boost segmentation performance by leveraging large-scale unlabeled data. The framework is based on the scalable masked autoencoders, and 2 geometry-guided designs, curvature-aware patching algorithm (CPA) and scale-aware reconstruction (SCR), are proposed to enhance the masked pretraining for tooth point cloud segmentation. In particular, CPA is designed to assemble informative patches as the reconstruction unit, guided by the estimated pointwise curvatures. Aimed at equipping the pretrained encoder with scale-aware modeling capacity, we also propose SCR to perform multiple reconstructions across shallow and deep layers. In vitro experiments reveal that after pretraining with large-scale unlabeled data, the proposed Geo-Net can outperform the supervised counterparts in mean Intersection of Union (mIoU) with the same amount of annotated labeled data. The code and data are available at https://github.com/yifliu3/Geo-Net.

在三维牙齿点云中精确划分单个牙齿是一项重要的正畸应用。基于学习的分割方法依赖于标注数据集,由于标注每颗牙齿的过程耗费大量人力,因此数据集的规模通常有限。在本文中,我们提出了一个名为 Geo-Net 的自监督预训练框架,通过利用大规模非标记数据来提高分割性能。该框架基于可扩展的掩码自动编码器,并提出了两种几何导向设计,即曲率感知修补算法(CPA)和尺度感知重构(SCR),以增强用于牙齿点云分割的掩码预训练。其中,CPA 的设计目的是以估计的点曲率为指导,将信息补丁组合成重建单元。为了使预训练编码器具备规模感知建模能力,我们还提出了 SCR,以执行跨浅层和深层的多重重建。体外实验表明,在使用大规模无标注数据进行预训练后,在使用相同数量的标注数据的情况下,所提出的 Geo-Net 在平均联合交叉(mIoU)方面优于有监督的同行。代码和数据可在 https://github.com/yifliu3/Geo-Net 上获取。
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引用次数: 0
Epithelial RANKL Limits Experimental Periodontitis via Langerhans Cells. 上皮 RANKL 通过朗格汉斯细胞限制实验性牙周炎的发生
Pub Date : 2024-11-01 Epub Date: 2024-10-06 DOI: 10.1177/00220345241274370
Y Netanely, O Barel, R Naamneh, Y Jaber, S Yacoub, Y Saba, K Zubeidat, O Saar, L Eli-Berchoer, S Yona, A Brand, T Capucha, A Wilensky, K Loser, B E Clausen, A-H Hovav

Due to its capacity to drive osteoclast differentiation, the receptor activator of nuclear factor kappa-β ligand (RANKL) is believed to exert a pathological influence in periodontitis. However, RANKL was initially identified as an activator of dendritic cells (DCs), expressed by T cells, and exhibits diverse effects on the immune system. Hence, it is probable that RANKL, acting as a bridge between the bone and immune systems, plays a more intricate role in periodontitis. Using ligature-induced periodontitis (LIP), rapid alveolar bone loss was detected that was later halted even though the ligature was still present. This late phase of LIP was also linked with immunosuppressive conditions in the gingiva. Further investigation revealed that the ligature prompted an immediate migration of RANK-expressing Langerhans cells (LCs) and EpCAM+ DCs, the antigen-presenting cells (APCs) of the gingival epithelium, to the lymph nodes, followed by an expansion of T regulatory (Treg) cells in the gingiva. Subsequently, the ligatured gingiva was repopulated by monocyte-derived RANK-expressing EpCAM+ DCs, while gingival epithelial cells upregulated RANKL expression. Blocking RANKL signaling with monoclonal antibodies significantly reduced the frequencies of Treg cells in the gingiva and prevented gingival immunosuppression. In addition, RANKL signaling facilitated the differentiation of LCs from bone marrow precursors. To further investigate the role of RANKL, we used K14-RANKL mice, in which RANKL is overexpressed by gingival epithelial cells. The elevated RANKL expression shifted the steady-state frequencies of LCs and EpCAM+ DCs within the epithelium, favoring LCs over EpCAM+ DCs. Following ligature placement, heightened levels of Treg cells were observed in the gingiva of K14-RANKL mice, and alveolar bone loss was significantly reduced. These findings suggest that RANKL-RANK interactions between gingival epithelial cells and APCs are crucial for suppressing gingival inflammation, highlighting a protective immunological role for RANKL in periodontitis that was overlooked due to its osteoclastogenic activity.

核因子 kappa-β 配体受体激活剂(RANKL)具有驱动破骨细胞分化的能力,因此被认为对牙周炎具有病理影响。然而,RANKL 最初被认为是树突状细胞(DC)的激活剂,由 T 细胞表达,对免疫系统有多种影响。因此,作为骨与免疫系统之间的桥梁,RANKL很可能在牙周炎中扮演着更为复杂的角色。利用结扎诱导的牙周炎(LIP),可以检测到牙槽骨的快速流失,即使结扎仍然存在,这种流失随后也会停止。LIP 的后期阶段还与牙龈的免疫抑制条件有关。进一步的研究发现,结扎会促使牙龈上皮的抗原呈递细胞(APCs)--表达 RANK 的朗格汉斯细胞(LCs)和 EpCAM+ DCs 立即迁移到淋巴结,随后牙龈中的 T 调节(Treg)细胞也会扩张。随后,单核细胞衍生的表达 RANK 的 EpCAM+ DCs 重新填充了结扎的牙龈,而牙龈上皮细胞则上调了 RANKL 的表达。用单克隆抗体阻断RANKL信号传导可显著降低牙龈中Treg细胞的频率,防止牙龈免疫抑制。此外,RANKL 信号还能促进骨髓前体 LCs 的分化。为了进一步研究 RANKL 的作用,我们使用了 K14-RANKL 小鼠,在这种小鼠中,牙龈上皮细胞过量表达 RANKL。RANKL 表达的升高改变了上皮细胞内 LCs 和 EpCAM+ DCs 的稳态频率,LCs 比 EpCAM+ DCs 更受青睐。结扎后,在 K14-RANKL 小鼠的牙龈中观察到了更高水平的 Treg 细胞,牙槽骨流失也显著减少。这些研究结果表明,牙龈上皮细胞和APCs之间的RANKL-RANK相互作用对抑制牙龈炎症至关重要,凸显了RANKL在牙周炎中的保护性免疫作用,而这一作用因其破骨细胞活性而被忽视。
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引用次数: 0
Periodontitis and Diabetes Differentially Affect Inflammation in Obesity. 牙周炎和糖尿病对肥胖症炎症的影响各不相同
Pub Date : 2024-11-01 Epub Date: 2024-10-09 DOI: 10.1177/00220345241280743
S SantaCruz-Calvo, S Saraswat, H Hasturk, D R Dawson, X D Zhang, B S Nikolajczyk

Periodontitis (PD) potentiates systemic inflammatory diseases and fuels a feed-forward loop of pathogenic inflammation in obesity and type 2 diabetes (T2D). Published work in this area often conflates obesity with obesity-associated T2D; thus, it remains unclear whether PD similarly affects the inflammatory profiles of these 2 distinct systemic diseases. We collected peripheral blood mononuclear cells (PBMCs) from cross-sectionally recruited subjects to estimate the ability of PD to affect cytokine production in human obesity and/or T2D. We analyzed 2 major sources of systemic inflammation: T cells and myeloid cells. Bioplex quantitated cytokines secreted by PBMCs stimulated with T cell- or myeloid-targeting activators, and we combinatorially analyzed outcomes using partial least squares discriminant analysis. Our data show that PD significantly shifts peripheral T cell- and myeloid-generated inflammation in obesity. PD also changed myeloid- but not T cell-generated inflammation in T2D. T2D changed inflammation in samples from subjects with PD, and PD changed inflammation in samples from subjects with T2D, consistent with the bidirectional relationship of inflammation between these 2 conditions. PBMCs from T2D subjects with stage IV PD produced lower amounts of T cell and myeloid cytokines compared with PBMCs from T2D subjects with stage II to III PD. We conclude that PD and T2D affect systemic inflammation through overlapping but nonidentical mechanisms in obesity, indicating that characterizing both oral and metabolic status (beyond obesity) is critical for identifying mechanisms linking PD to systemic diseases such as obesity and T2D. The finding that stage IV PD cells generate fewer cytokines in T2D provides an explanation for the paradoxical findings that the immune system can appear activated or suppressed in PD, given that many studies do not report PD stage. Finally, our data indicate that a focus on multiple cellular sources of cytokines will be imperative to clinically address the systemic effects of PD in people with obesity.

牙周炎(PD)会加剧全身炎症性疾病,并助长肥胖和 2 型糖尿病(T2D)致病性炎症的前馈循环。该领域已发表的研究往往将肥胖与肥胖相关的 T2D 混为一谈;因此,目前仍不清楚牙周炎是否会同样影响这两种不同系统疾病的炎症特征。我们收集了横断面招募对象的外周血单核细胞(PBMCs),以评估 PD 影响人类肥胖和/或 T2D 中细胞因子产生的能力。我们分析了全身炎症的两个主要来源:T细胞和骨髓细胞。Bioplex 定量分析了受 T 细胞或髓样细胞靶向激活剂刺激的 PBMC 所分泌的细胞因子,我们使用偏最小二乘法判别分析对结果进行了组合分析。我们的数据显示,肥胖症患者的外周 T 细胞和髓细胞引发的炎症发生了明显变化。PD也改变了T2D患者髓细胞产生的炎症,但没有改变T细胞产生的炎症。T2D改变了PD受试者样本中的炎症,而PD改变了T2D受试者样本中的炎症,这与这两种情况之间炎症的双向关系一致。与 T2D II 至 III 期患者的 PBMC 相比,T2D IV 期患者的 PBMC 产生的 T 细胞和髓细胞因子较少。我们的结论是,PD 和 T2D 通过重叠但不相同的机制影响肥胖症的全身炎症,这表明要确定 PD 与肥胖症和 T2D 等全身疾病的关联机制,口腔和代谢状态(肥胖症除外)的特征至关重要。在 T2D 中,IV 期 PD 细胞产生的细胞因子较少,这一发现为免疫系统在 PD 中可能出现激活或抑制的矛盾发现提供了解释,因为许多研究并未报告 PD 的分期。最后,我们的数据表明,要在临床上解决肥胖症患者腹膜透析的系统性影响,就必须关注细胞因子的多种细胞来源。
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引用次数: 0
Nuclear TOP1MT Confers Cisplatin Resistance via Pseudogene in HNSCC. 核 TOP1MT 在 HNSCC 中通过伪基因产生顺铂抗性
Pub Date : 2024-11-01 Epub Date: 2024-10-09 DOI: 10.1177/00220345241272017
T Tong, P S Zhai, X Qin, Z Zhang, C W Li, H Y Guo, H L Ma

Cisplatin resistance is one of the major causes of treatment failure in head and neck squamous cell carcinoma (HNSCC). There is an urgent need to uncover the underlying mechanism for developing effective treatment strategies. A quantitative proteomics assay was used to identify differential proteins in cisplatin-resistant cells. Mitochondrial topoisomerase I (TOP1MT) localization was determined using laser confocal microscopy and nucleocytoplasmic separation assay. Chromatin immunoprecipitation sequencing, dual-luciferase reporter assay, and RNA immunoprecipitation were used to identify the interaction between pseudogenes, miRNAs, and real genes. In vivo experiments verified the interaction between TOP1MT and pseudogenes on cisplatin resistance. TOP1MT was identified as a driving factor of cisplatin resistance in vitro, in vivo, and in HNSCC patients. Moreover, TOP1MT exceptionally translocated to the nucleus in cisplatin-resistant HNSCC cells in a signal peptide-dependent manner. Nuclear TOP1MT (nTOP1MT) transcriptionally regulated the mitochondrial functional pseudogene MTATP6P1, which bound to miR-137 and miR-491-5p as a competing endogenous RNA (ceRNA) and promoted the expression of MTATP6. An increase in MTATP6 enhanced mitochondrial oxidative phosphorylation (OXPHOS), which conferred cisplatin resistance in HNSCC. Our findings revealed that nTOP1MT transcriptionally activated MTAPT6P1 and increased MTATP6 expression via ceRNA, which facilitated OXPHOS and cisplatin resistance. These results provide novel insight for overcoming cisplatin resistance in HNSCC.

顺铂耐药性是头颈部鳞状细胞癌(HNSCC)治疗失败的主要原因之一。目前迫切需要揭示其潜在机制,以制定有效的治疗策略。本研究采用定量蛋白质组学分析方法来鉴定顺铂耐药细胞中的差异蛋白质。线粒体拓扑异构酶I(TOP1MT)的定位是通过激光共聚焦显微镜和核胞质分离试验确定的。染色质免疫共沉淀测序、双荧光素酶报告分析和 RNA 免疫共沉淀被用来鉴定伪基因、miRNA 和真基因之间的相互作用。体内实验验证了 TOP1MT 与伪基因之间在顺铂抗性上的相互作用。在体外、体内和 HNSCC 患者中,TOP1MT 被确定为顺铂耐药性的驱动因素。此外,在顺铂耐药的 HNSCC 细胞中,TOP1MT 例外地以信号肽依赖的方式转位到细胞核中。核TOP1MT(nTOP1MT)转录调控线粒体功能假基因MTATP6P1,MTATP6P1作为竞争性内源性RNA(ceRNA)与miR-137和miR-491-5p结合,促进MTATP6的表达。MTATP6的增加增强了线粒体氧化磷酸化(OXPHOS),从而赋予了HNSCC顺铂抗性。我们的研究结果表明,nTOP1MT可通过ceRNA转录激活MTAPT6P1并增加MTATP6的表达,从而促进OXPHOS和顺铂抗性。这些结果为克服 HNSCC 的顺铂耐药性提供了新的见解。
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引用次数: 0
Surrogate Endpoints: CONSORT and SPIRIT Extensions. 替代终点:CONSORT 和 SPIRIT 扩展。
Pub Date : 2024-11-01 Epub Date: 2024-10-06 DOI: 10.1177/00220345241275479
F Schwendicke, N S Jakubovics
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引用次数: 0
A Review of Immunotherapy for Head and Neck Cancer. 头颈癌免疫疗法综述。
Pub Date : 2024-11-01 Epub Date: 2024-10-06 DOI: 10.1177/00220345241271992
J W Goetz, G Rabinowits, N Kalman, A Villa

The introduction of immune checkpoint inhibitors (ICIs) to oncological care has transformed the management of various malignancies, including head and neck squamous cell carcinoma (HNSCC), offering improved outcomes. The first-line treatment of recurrent and malignant HNSCC for many years was combined platinum, 5-fluorouracil, and cetuximab. Recently, the ICI pembrolizumab was approved as a first-line treatment, with or without chemotherapy, based on tumor and immune cell percentage of programmed-death ligand 1 (PD-L1). Multiple head and neck (HN) cancer trials have subsequently explored immunotherapies in combination with surgery, chemotherapy, and/or radiation. Immunotherapy regimens may be personalized by tumor biomarker, including PD-L1 content, tumor mutational burden, and microsatellite instability. However, further clinical trials are needed to refine biomarker-driven protocols and standardize pathological methods to guide combined regimen timing, sequencing, and deescalation. Gaps remain for protocols using immunotherapy to reverse oral premalignant lesions, particularly high-risk leukoplakias. A phase II nonrandomized controlled trial, using the ICI nivolumab, showed a 2-y cancer-free survival of 73%, although larger trials are needed. Guidelines are also needed to standardize the role of dental evaluation and care before, during, and after immunotherapy, specifically in regard to oral immune-related adverse events and their impact on cancer recurrence. Standardized diagnostic and oral care coordination strategies to close these gaps are needed to ensure continued success of HN cancer immunotherapy.

在肿瘤治疗中引入免疫检查点抑制剂(ICIs)改变了包括头颈部鳞状细胞癌(HNSCC)在内的各种恶性肿瘤的治疗方法,从而改善了治疗效果。多年来,复发性和恶性 HNSCC 的一线治疗方法是联合使用铂、5-氟尿嘧啶和西妥昔单抗。最近,根据肿瘤和免疫细胞中程序性死亡配体 1(PD-L1)的百分比,ICI pembrolizumab 被批准作为一线治疗药物,无论是否进行化疗。随后,多项头颈部(HN)癌症试验探索了免疫疗法与手术、化疗和/或放疗的联合应用。免疫疗法方案可根据肿瘤生物标志物(包括 PD-L1 含量、肿瘤突变负荷和微卫星不稳定性)进行个性化设计。然而,还需要进一步的临床试验来完善生物标志物驱动的方案,并规范病理学方法,以指导联合方案的时机、排序和降级。利用免疫疗法逆转口腔癌前病变(尤其是高风险白斑)的方案仍存在空白。一项采用 ICI nivolumab 的 II 期非随机对照试验显示,2 年无癌生存率为 73%,但仍需进行更大规模的试验。还需要制定指南来规范免疫疗法前、中、后牙科评估和护理的作用,特别是口腔免疫相关不良事件及其对癌症复发的影响。需要标准化的诊断和口腔护理协调策略来缩小这些差距,以确保 HN 癌症免疫疗法的持续成功。
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引用次数: 0
期刊
Journal of dental research
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