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Dynamic salivary cytokine profile of recurrent aphthous stomatitis patients in thalidomide maintenance treatment
沙利度胺维持治疗中复发性阿弗他口炎患者的动态唾液细胞因子谱

Wei Wei 1 ⋅ 1 ⋅ ^(1)*{ }^{1} \cdot Yiwen Deng 2 ⋅ 2 ⋅ ^(2)*{ }^{2} \cdot Yufeng Wang 2 ⋅ 2 ⋅ ^(2)*{ }^{2} \cdot Hui Yao 2 ⋅ 2 ⋅ ^(2)*^{2} \cdot Guanhuan Du 2 ⋅ 2 ⋅ ^(2)*{ }^{2} \cdot Guoyao Tang 2 2 ^(2)^{2}
魏 魏 1 ⋅ 1 ⋅ ^(1)*{ }^{1} \cdot 一文 邓 2 ⋅ 2 ⋅ ^(2)*{ }^{2} \cdot 玉峰 王 2 ⋅ 2 ⋅ ^(2)*{ }^{2} \cdot 慧 姚 2 ⋅ 2 ⋅ ^(2)*^{2} \cdot 冠环 杜 2 ⋅ 2 ⋅ ^(2)*{ }^{2} \cdot 国尧 2 2 ^(2)^{2} 唐

Received: 31 October 2023 / Accepted: 24 January 2024
收稿日期： 2023-10-31 / 录用日期： 2024-01-24
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024
© 作者，经德国 Springer-Verlag GmbH 独家许可，是 Springer Nature 2024 的一部分

Abstract  抽象

Objective To dynamically compare the longitudinal (time axis) and transverse (between groups) differences of the salivary cytokines during thalidomide maintenance treatment of recurrent aphthous stomatitis. Methods A randomized, controlled, clinical trial was performed. After the initial prednisone treatment, thalidomide ( 50 mg / d 50 mg / d 50mg//d50 \mathrm{mg} / \mathrm{d} vs. 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} ) was used as a maintenance drug for 4 or 8 weeks. The salivary IL-4, 5, 6, 10, TNF- α α alpha\alpha, and IFN- γ γ gamma\gamma were dynamically detected with a cytometric bead array. Results Overall, the level of six elevated salivary cytokines after prednisone treatment was significantly downregulated, remained low during thalidomide maintenance, and rebounded at recurrence. The effect of 50 mg / d 50 mg / d 50mg//d50 \mathrm{mg} / \mathrm{d} thalidomide on the salivary cytokines was not superior to 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} medication. The relapse-free period following drug withdrawal was the longest in the subgroup using 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} thalidomide for 8 weeks. The order of magnitude of IL-6 was the most obvious, and at week 8, only the level of IL-6 in the group ( 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} thalidomide for 8 weeks) continued to decline compared with the other groups. Conclusion Thalidomide maintenance treatment can effectively sustain low levels of salivary IL-4, 5, 6, 10, TNF- α α alpha\alpha, and IFN- γ γ gamma\gamma of recurrent aphthous stomatitis patients. IL-6 displayed a good correlation with the disease and is expected to become an index for diagnosis and follow-up. Clinical relevance Low-dose long-term thalidomide maintenance treatment was supported for recurrent aphthous stomatitis. Trial registration Trial registration number of ChiCTR-IPR-16009759 at http://www.chictr.org/index.aspx.
目的 动态比较沙利度胺维持治疗复发性阿弗他口炎期间唾液细胞因子的纵向（时间轴）和横向（组间）差异。方法 进行了一项随机、对照、临床试验。在初始泼尼松治疗后，沙利度胺 （ 50 mg / d 50 mg / d 50mg//d50 \mathrm{mg} / \mathrm{d} vs. 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} ） 用作维持药物 4 或 8 周。用细胞仪微珠阵列动态检测唾液 IL-4 、 5 、 6 、 10 、 TNF - α α alpha\alpha 和 IFN- γ γ gamma\gamma 。结果 总体而言，泼尼松治疗后 6 种唾液细胞因子升高水平显著下调，在沙利度胺维持期间保持较低水平，并在复发时反弹。 50 mg / d 50 mg / d 50mg//d50 \mathrm{mg} / \mathrm{d} 沙利度胺对唾液细胞因子的影响并不优于 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} 药物。在使用 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} 沙利度胺的亚组中，停药后无复发期最长，长达 8 周。IL-6 的数量级最明显，在第 8 周时，与其他组相比，只有组 （ 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} 沙利度胺 8 周） 的 IL-6 水平持续下降。结论 沙利度胺维持治疗可有效维持复发性阿弗他口炎患者唾液 IL-4 、 5 、 6 、 10 、 TNF- α α alpha\alpha 和 IFN- γ γ gamma\gamma 水平较低。IL-6 与疾病具有良好的相关性，有望成为诊断和随访的指标。临床相关性： 支持低剂量长期沙利度胺维持治疗治疗复发性阿弗他口炎。试验注册 http://www.chictr.org/index.aspx 年的 ChiCTR-IPR-16009759 的试用注册号。

Keywords Recurrent aphthous stomatitis ⋅ ⋅ *\cdot Randomized controlled clinical trial ⋅ ⋅ *\cdot Thalidomide ⋅ ⋅ *\cdot Prednisone ⋅ ⋅ *\cdot Cytokines
关键词 复发性阿弗他口炎 ⋅ ⋅ *\cdot 随机对照临床试验 ⋅ ⋅ *\cdot 沙利度胺 ⋅ ⋅ *\cdot 泼尼松 ⋅ ⋅ *\cdot 细胞因子

Introduction  介绍

Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disease with an unknown etiology and pathogenesis, affecting up to 25 % 25 % 25%25 \% of the general population [1]. An immune imbalance is considered an important factor in the cause of RAS. The enhanced immune response to specific areas of the oral mucosa in vivo leads to ulceration. Although this reaction is known to be caused by a cascade reaction of improperly activated cytokines, the initiating factors remain unknown.
复发性阿弗他口炎 （RAS） 是最常见的口腔黏膜疾病，病因和发病机制尚不清楚，累及多达 25 % 25 % 25%25 \% 普通人群 [1]。免疫失衡被认为是导致 RAS 的重要因素。体内对口腔粘膜特定区域的增强免疫反应导致溃疡。尽管已知该反应是由未正确激活的细胞因子的级联反应引起的，但引发因素仍然未知。
The efficacy of prednisone and thalidomide in the treatment for RAS has been established and widely used [2] to effectively decrease the frequency and number of ulcers and relieve pain [3].
泼尼松和沙利度胺治疗 RAS 的疗效已经确定并被广泛使用 [2] 可有效降低溃疡的频率和数量并缓解疼痛 [3]。
By promoting keratinocyte proliferation and migration, thalidomide treatment may accelerate ulcer healing [4, 5]. Thalidomide also possesses immunomodulatory and anti-inflammatory effects, which may be involved. In our
沙利度胺治疗通过促进角质形成细胞增殖和迁移，可以加速溃疡愈合 [4， 5]。沙利度胺还具有免疫调节和抗炎作用，这可能涉及。在我们的
previous published trial [6] to optimize various maintenance doses and courses of thalidomide for patients with RAS, the clinical data has suggested that the effect of high-dose thalidomide on cytokines was not superior to low-dose thalidomide. Moreover, no significant difference was observed in the selected salivary cytokines between the different groups before and after treatment, which confirmed the above conclusion. This study primarily focused on data mining of the dynamical comparison of the longitudinal (time axis) and transverse (between different groups) salivary cytokine profiles in the process of drug treatment and maintenance.
先前发表的试验 [6] 为了优化 RAS 患者沙利度胺的各种维持剂量和疗程，临床数据表明，高剂量沙利度胺对细胞因子的影响并不优于低剂量沙利度胺。此外，治疗前后不同组之间选定的唾液细胞因子未观察到显著差异，证实了上述结论。本研究主要侧重于药物治疗和维持过程中纵向 （时间轴） 和横向 （不同组间） 唾液细胞因子谱动态比较的数据挖掘。

Materials and methods  材料和方法

Study participants  研究参与者

This randomized controlled clinical trial was prospectively conducted from November 2016 to November 2018 in the Department of Oral Medicine, Shanghai Ninth People’s Hospital, Shanghai, China. According to the clinical history and manifestation of the ulcers, the diagnosis of minor RAS was made as described previously [ 7 , 8 ] [ 7 , 8 ] [7,8][7,8]. The participants were enrolled based on the inclusion and exclusion criteria, as follows: Inclusion criteria: (1) aged 18-75 years; (2) a history of RAS for over 12 months; (3) a recurrence interval of about 14 days (the patient occurred one or two episodes of aphthae in 1 month before enrollment); (4) fresh minor ulcers available within 2 days of eruption and without treatment with topical and systemic medication; (5) women who have gone through menopause and reject pregnancy; (6) men who agree with using birth control measures with their sex partners; and (7) patients had repeated recurrences not of insufficient responding on previous treatments. Exclusion criteria: (1) herpetiform ulcer or major aphthous ulcer; (2) patients who suffered from peripheral neuropathy; (3) ulcer associated with a systemic disease, such as Behcet’s disease or Crohn’s disease; (4) a history of allergies to prednisone or thalidomide or a known history of serious drug hypersensitivity; (5) pregnant or lactating women and women who plan to become pregnant; and (6) chronic disease requiring treatment with immunomodulators, hormones, cytotoxic drugs, or nonsteroidal anti-inflammatory drugs that affect the oral mucosa. The specific details are described in our previously published research [6].
该随机对照临床试验于 2016 年 11 月至 2018 年 11 月在中国上海市第九人民医院口腔内科前瞻性进行。根据溃疡的临床病史和表现，如前所述诊断为轻度 RAS [ 7 , 8 ] [ 7 , 8 ] [7,8][7,8] 。参与者根据纳入和排除标准入组，如下： 纳入标准： （1） 年龄在 18-75 岁之间;（2） 超过 12 个月的 RAS 病史;（3） 复发间隔约 14 天（患者入组前 1 个月内出现 1 次或 2 次口疮发作）;（4） 出疹后 2 天内有新鲜的轻微溃疡，且未接受局部和全身药物治疗;（5） 已绝经并排斥妊娠的妇女;（6） 同意与性伴侣采取节育措施的男性;（7） 患者反复复发，而不是对先前治疗的反应不足。排除标准： （1） 疱疹样溃疡或重度阿弗他溃疡;（2） 患有周围神经病变的患者;（3） 与全身性疾病相关的溃疡，例如白塞病或克罗恩病;（4） 对泼尼松或沙利度胺过敏史或已知的严重药物超敏反应史;（5） 孕妇或哺乳期妇女以及计划怀孕的妇女;（6） 需要使用影响口腔粘膜的免疫调节剂、激素、细胞毒性药物或非甾体抗炎药治疗的慢性疾病。具体细节在我们之前发表的研究 [6] 中进行了描述。

Treatment  治疗

A total of 125 patients were enrolled and randomly assigned to five groups. All the participates received primary treatment (prednisone, Pengyi Pharmaceutical Co., Ltd., H32021728) orally every morning at a starting dose of 15 mg / d 15 mg / d 15mg//d15 \mathrm{mg} / \mathrm{d} for 7 days. All of the participates were then
共纳入 125 例患者并随机分为 5 组。所有参与者每天早上口服初级治疗 （泼尼松，鹏逸药业股份有限公司，H32021728），起始剂量为 15 mg / d 15 mg / d 15mg//d15 \mathrm{mg} / \mathrm{d} 7 天。所有参与者当时都是
randomly divided into a control group (prednisone 10 mg / d 10 mg / d 10mg//d10 \mathrm{mg} / \mathrm{d} for the next 3 days, and then 5 mg / d 5 mg / d 5mg//d5 \mathrm{mg} / \mathrm{d} for the next 3 days, P group) and an experimental group (thalidomide, Changzhou Pharmaceutical Co., Ltd., H32026129), which included four subgroups: 50 mg / d 50 mg / d 50mg//d50 \mathrm{mg} / \mathrm{d} for 4 (H1 group) and 8 weeks (H2 subgroup), and 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} for 4 (L1 group) and 8 weeks (L2 group) (Fig. 1). Fifteen healthy volunteers were recruited as normal controls ( N group).
随机分为对照组（泼尼松 10 mg / d 10 mg / d 10mg//d10 \mathrm{mg} / \mathrm{d} 3 天，然后 5 mg / d 5 mg / d 5mg//d5 \mathrm{mg} / \mathrm{d} 3 天，P 组）和实验组（沙利度胺，常州药业股份有限公司，H32026129），包括 4 个亚组（ 50 mg / d 50 mg / d 50mg//d50 \mathrm{mg} / \mathrm{d} H1 组）和 8 周（H2 亚组），以及 25 mg / d 25 mg / d 25mg//d25 \mathrm{mg} / \mathrm{d} 4 个亚组（L1 组）和 8 周（L2 组）（图 1）。招募 15 名健康志愿者作为正常对照 （ N 组）。

Cytokine profile in a whole unstimulated saliva examination by CBA
CBA 在整个无刺激唾液检查中的细胞因子谱

The levels of IL-4, IL-5, IL-6, IL-10, TNF- α α alpha\alpha, and IFN- γ γ gamma\gamma expression in the whole unstimulated saliva (WUS) samples were detected dynamically at four different time points (Day1, Day7, W4, and W8) using a multiplex bead-based cytometric bead array (CBA). The laboratory methods for WUS collection and CBA experiment were performed as described in our previous study [9] and the manufacturer’s instructions. Briefly, samples of at least 1 mL of WUS were taken from the participants and aliquoted to Eppendorf tubes without any prior processing about 8:00 a.m. The saliva samples were immediately frozen at − 80 ∘ C − 80 ∘ C -80^(@)C-80^{\circ} \mathrm{C} until all the samples had been collected for later analysis. The total protein in saliva was quantified by using a BCA protein assay kit (Thermo Fisher, Waltham, MA). A panel of cytokine concentrations, including IL-4, IL-5, IL-6, IL-10, IFN- γ γ gamma\gamma, and TNF- α α alpha\alpha, was determined by using the BD CBA Human Enhanced Sensitivity Flex Sets (capable of detecting cytokine concentrations as low as 0.274 pg / mL 0.274 pg / mL 0.274pg//mL0.274 \mathrm{pg} / \mathrm{mL} ). All data were analyzed by using FCAP Array V3 software (BD Biosciences company) [10].
使用基于多重微珠的细胞计数微珠阵列 （CBA） 在四个不同的时间点 （第 1 天、第 7 天、第 4 周和第 8 周） 动态检测整个未刺激唾液 （WUS） 样本中 IL-4 、 IL-5 、 IL-6 、 IL-10 、 TNF 和 α α alpha\alpha IFN- γ γ gamma\gamma 表达的水平。WUS 采集和 CBA 实验的实验室方法按照我们之前的研究 [9] 和制造商的说明进行。简而言之，从参与者身上采集至少 1 mL WUS 的样本，并在上午 8：00 左右未经任何事先处理就分装到 Eppendorf 管中。唾液样本立即冷冻， − 80 ∘ C − 80 ∘ C -80^(@)C-80^{\circ} \mathrm{C} 直到收集完所有样本以供以后分析。使用 BCA 蛋白测定试剂盒 （Thermo Fisher， Waltham， MA） 定量唾液中的总蛋白。通过使用BD CBA人增强灵敏度Flex Sets（能够检测低至的细胞因子浓度）测定一组细胞因子浓度，包括IL-4、IL-5、IL-6、IL-10、IFN- γ γ gamma\gamma 和TNF- α α alpha\alpha 0.274 pg / mL 0.274 pg / mL 0.274pg//mL0.274 \mathrm{pg} / \mathrm{mL} 。所有数据均使用 FCAP Array V3 软件（BD Biosciences 公司）[10] 进行分析。

Statistical analysis  统计分析

Differences in the quantitative and qualitative variables between the two groups were calculated using a Student’s t t tt-test and chi-square or Fisher’s exact test, respectively. If the quantitative variables did not follow a normal distribution, the differences between the two groups were calculated with a Mann-Whitney U U UU test. Comparisons between before and after treatment of the same patient were calculated with a Wilcoxon signed-rank test or paired-samples t t tt-test, where appropriate.
两组之间定量和定性变量的差异分别使用 Student t t tt 检验和卡方检验或 Fisher 精确检验计算。如果定量变量不服从正态分布，则使用 Mann-Whitney U U UU 检验计算两组之间的差异。在适当的情况下，使用 Wilcoxon 符号秩检验或配对样本 t t tt 检验计算同一患者治疗前后之间的比较。
SPSS version 23.0 (SPSS Inc., Chicago, IL) software was used to analyze all of the data. All statistical graphs were created using Graph Prism 9 (GraphPad, San Diego, CA). For continuous variables, the median (interquartile range, IQR, Q1-Q3) or arithmetical mean ± ± +-\pm standard deviation was used, depending on the distribution, as assessed by a Kolmogorov-Smirnov test. The obtained results were compared using a nonparametric Wilcoxon test. The nonparametric variables among the study groups were assessed with
使用 SPSS 23.0 版（SPSS Inc.，芝加哥，伊利诺伊州）软件分析所有数据。所有统计图表均使用 Graph Prism 9（GraphPad，加利福尼亚州圣地亚哥）创建。对于连续变量，根据分布，使用中位数（四分位间距，IQR，Q1-Q3）或算术平均 ± ± +-\pm 标准差，通过 Kolmogorov-Smirnov 检验评估。使用非参数 Wilcoxon 检验比较获得的结果。研究组之间的非参数变量通过
Fig. 1 Flow diagrams of the trial. Visit 1 (D1): Before treatment; Visit 2 (D7): After 7 days of prednisone treatment, the ulcers of patients in various subgroups were almost healed; Visit 3 (W4): After 4 weeks of thalidomide treatment, end of GroupH1 and L1; Visit 4 (W8): After 8 weeks of thalidomide treatment, end of GroupH2 and L2
图 1 试验流程图。第 1 次就诊 （D1）：治疗前;第 2 次就诊 （D7）：泼尼松治疗 7 天后，各亚组患者的溃疡几乎愈合;第 3 次就诊 （W4）：沙利度胺治疗 4 周后，H1 和 L1 组结束;第 4 次就诊（第 8 周）：沙利度胺治疗 8 周后，H2 和 L2 组结束

pairwise comparisons using the Dunn-Bonferroni approach for any dependent variables for which the Kruskal-Wallis test was significant. All two-tailed P P PP values < 0.05 < 0.05 < 0.05<0.05 were considered statistically significant.
使用 Dunn-Bonferroni 方法对 Kruskal-Wallis 检验显著的任何因变量进行成对比较。所有双尾 P P PP 值 < 0.05 < 0.05 < 0.05<0.05 都被认为具有统计学意义。
The number of patients (percentage of the appropriate group) was reported for the categorical variables. The contingency tables were analyzed by using a Pearson’s χ 2 χ 2 chi^(2)\chi^{2} test or Fisher’s exact test, where appropriate.
报告分类变量的患者数量（适当组的百分比）。在适当的情况下，使用 Pearson χ 2 χ 2 chi^(2)\chi^{2} 检验或 Fisher 精确检验对列联表进行分析。

Results  结果

Baseline demographic characteristics and cytokine profiles of different groups
不同群体的基线人口学特征和细胞因子谱

As shown in Table 1, there was no significant difference of age, gender, or body mass index (BMI) in all groups before treatments. The results of pairwise comparison of the median expression of various cytokines in saliva samples between the five patient groups showed that only IL-4 had a significant difference between H 1 and H 2 groups ( P = 0.01 ) ( P = 0.01 ) (P=0.01)(P=0.01).
如表 1 所示，治疗前各组的年龄、性别或体重指数 （BMI） 无显著差异。对 5 组患者唾液样本中各种细胞因子的中位表达进行成对比较的结果显示，H 1 组和 H 2 组 ( P = 0.01 ) ( P = 0.01 ) (P=0.01)(P=0.01) 之间只有 IL-4 存在显著差异。

Overall ulcer-free period and protection period after drug withdrawal
整体无溃疡期和停药后保护期

During medication, the relapse rates of H1, H2, L1, L2, and P P PP were 29.2 % , 27.3 % , 18.2 % , 9.5 % 29.2 % , 27.3 % , 18.2 % , 9.5 % 29.2%,27.3%,18.2%,9.5%29.2 \%, 27.3 \%, 18.2 \%, 9.5 \%, and 4.3 % 4.3 % 4.3%4.3 \%, respectively. There was no significance observed between the groups. The overall ulcer-free period in the 8 -week treatment group was significantly longer than that in the prednisone group and
用药期间，H1 、 H2 、 L1 、 L2 和 P P PP were 29.2 % , 27.3 % , 18.2 % , 9.5 % 29.2 % , 27.3 % , 18.2 % , 9.5 % 29.2%,27.3%,18.2%,9.5%29.2 \%, 27.3 \%, 18.2 \%, 9.5 \% 的复发率分别为 、 和 4.3 % 4.3 % 4.3%4.3 \% 。两组之间未观察到显著性。8 周治疗组总体无溃疡期显著长于泼尼松组，
4-week treatment group; however, no significant difference was observed between the H1 and L1 groups. In contrast to prednisone or the H 1 , H 2 H 1 , H 2 H1,H2\mathrm{H} 1, \mathrm{H} 2, and L 1 group, a relapse-free period after drug withdrawal of the L2 group was significantly longer than that of the other groups (Table 2 and 3).
4周治疗组;然而，H1 组和 L1 组之间未观察到显著差异。与泼尼松或 H 1 , H 2 H 1 , H 2 H1,H2\mathrm{H} 1, \mathrm{H} 2 和 L 1 组相比，L2 组停药后的无复发期明显长于其他组（表 2 和 3）。

Trend chart of cytokines of different groups at each time point
各时间点不同群体细胞因子的趋势图

The trend chart (Fig. 2) showed that the trends for the six salivary cytokines were similar after treatment. Moreover, the levels decreased after prednisone treatment, remained low during thalidomide maintenance, and increased again after withdrawal. Although the logarithmic coordinate system was only used for the Y Y YY axis, the levels of IL-6 remained high and fluctuated the most obviously. Unlike other groups, only the level of IL-6 in the L2 group continued to decline.
趋势图（图 2）显示 6 种唾液细胞因子在处理后的趋势相似。此外，泼尼松治疗后水平降低，沙利度胺维持期间保持较低水平，停药后水平再次升高。虽然对数坐标系仅用于轴， Y Y YY 但 IL-6 的水平仍然很高，波动最明显。与其他组不同，只有 L2 组的 IL-6 水平持续下降。
To illustrate the cytokine profile at the time of recurrence, R was shown on the trend curve. Because recurrence may occur during and after medication, the time axis was processed in two segments to account for this issue.
为了说明复发时的细胞因子谱，R 显示在趋势曲线上。由于用药期间和服药后可能发生复发，因此将时间轴分为两个部分来处理以说明此问题。

D1, D7, and recurrence  D1、D7 和复发

The clinical information and date of recurrence could be obtained from relapsed cases through recall; however, it was often difficult to accurately obtain saliva samples at the time of recurrence. To reduce the error caused by too few samples in each group, the relapsed data must be merged for analysis.
通过召回可以从复发病例中获得临床信息和复发日期;然而，在复发时通常很难准确获取唾液样本。为了减少每组中样本太少引起的误差，必须合并复发数据进行分析。
  1. Wei Wei and Yiwen Deng contributed equally to this work and are co-first authors.
    Wei Wei 和 Yiwen 邓对这项工作做出了同等贡献，并且是共同第一作者。
    Guanhuan Du  杜冠欢
    dgh-09@163.com
    Guoyao Tang  唐国尧
    tanggy@shsmu.edu.cn
    1 Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University School of Medicine Ear Institute, Shanghai Key Laboratory of Translational Medicine On Ear and Nose Diseases, Shanghai 200092, China
    1 上海交通大学医学院附属新华医院耳鼻咽喉头颈外科，上海交通大学医学院耳科耳研究所，上海市耳鼻疾病转化医学重点实验室，上海200092
    2 Department of Oral Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
    2 上海交通大学医学院附属第九人民医院口腔医学科，上海交通大学口腔医学院，国家口腔医学中心，国家口腔医学临床医学研究中心，上海市口腔医学重点实验室，上海200011