切换至 "中华医学电子期刊资源库"
高级检索
中华肝脏外科手术学电子杂志

中华肝脏外科手术学电子杂志 ›› 2025, Vol. 14 ›› Issue (06) : 962 -972. doi: 10.3877/cma.j.issn.2095-3232.2025.06.022

基础研究

基于血清和组织外泌体多组学分析筛选胰腺癌诊断和预后标志物
吴刚1, 严燃星2, 严鑫3, 阎婧3, 何跃明3, 朱倩3,†()   
  1. 1　430064　武汉科技大学附属天佑医院肝胆胰外科
    2　435500　湖北省黄梅县人民医院肝胆胰腹外疝外科
    3　430071　武汉大学中南医院肝胆胰外科
  • 收稿日期:2025-06-20 出版日期:2025-12-10
  • 通信作者: 朱倩
  • 基金资助:
    中华慈善总会英才科研基金项目(ZKL-KY-2024-006)

Screening of diagnostic and prognostic markers of pancreatic cancer based on multi-omics analysis of serum and tissue exosomes

Gang Wu1, Ranxing Yan2, Xin Yan3, Jing Yan3, Yueming He3, Qian Zhu3,†()   

  1. 1 Department of Hepatobiliary and Pancreatic Surgery, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan 430064, China
    2 Department of Hepatobiliary, Pancreatic and Abdominal Hernia Surgery, Huangmei People's Hospital, Huanggang 435500, China
    3 Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
  • Received:2025-06-20 Published:2025-12-10
  • Corresponding author: Qian Zhu
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

吴刚, 严燃星, 严鑫, 阎婧, 何跃明, 朱倩. 基于血清和组织外泌体多组学分析筛选胰腺癌诊断和预后标志物[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(06): 962-972.

Gang Wu, Ranxing Yan, Xin Yan, Jing Yan, Yueming He, Qian Zhu. Screening of diagnostic and prognostic markers of pancreatic cancer based on multi-omics analysis of serum and tissue exosomes[J/OL]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(06): 962-972.

目的

基于血清和组织外泌体多组学分析筛选胰腺导管腺癌（PDAC）早期诊断和预后标志物。

方法

研究标本来源于武汉大学中南医院招募的2020年手术治疗8例PDAC患者和3名健康供者。首先，从健康供者和PDAC患者组织和血清中分离外泌体，电子显微镜和分子标记对其粒度和蛋白质含量进行鉴定。随后，通过microRNA（miRNA）转录组学方法鉴定PDAC特异性的外泌体miRNA。验证样本来自22例PDAC患者和20名健康供者，进一步验证所鉴定的miRNA，并在最终分析中通过ROC曲线下面积（AUC）和Brier评分来评估这些miRNA诊断PDAC的能力。生存分析采用Kaplan-Meier法和Log-rank检验。

结果

结果鉴定并验证了5个低表达水平的miRNA（hsa-miR-142-3p、hsa-miR-199b-3p、hsa-miR-221-3p、hsa-miR-222-3p和hsa-miR-584-5p）和1个高表达水平的miRNA（hsa-miR-148a-3p），其中2个表达水平最高miRNA为miR142-3p 和 miR148a-3p。与癌旁组织和健康供者血清相比，这2个miRNA在PDAC患者组织源性细胞外囊泡(Ti-EVs)和血清源性细胞外囊泡(Se-EVs)中得到进一步验证。Kaplan-Meier生存曲线显示，miR142-3p和miR148a-3p表达降低与PDAC患者的总体生存期（OS）和无复发生存期（RFS）的不良预后明显相关(χ2=36.314，5.218和7.047，4.924；P<0.05)。预测误差曲线显示，miR142-3p、miR148a-3p和CA19-9的组合导致的预测误差最小。ROC分析显示，基于miR142-3p和miR148a-3p联合CA19-9模型组合预测的AUC为0.747，大于单独CA19-9模型的0.716。

结论

胰腺癌外泌体miRNA-142-3p和miRNA-148a-3p在PDAC中发挥抑癌基因作用，miRNA-142-3p或miRNA-148a-3p低表达PDAC患者预后不良，是PDAC潜在的诊断和预后新标志物。

关键词: 胰腺导管腺癌, 微核糖核酸, 外泌体, 诊断, 预后
Objective

To screen early diagnostic and prognostic markers of pancreatic ductal adenocarcinoma (PDAC) based on multi-omics analysis of serum and tissue exosomes.

Methods

The samples were collected from 8 PDAC patients undergoing surgery and 3 healthy donors admitted to Zhongnan Hospital of Wuhan University in 2020. Exosomes were isolated from tissues and serum of healthy donors and PDAC patients. The particle size and protein content were identified by electron microscope and molecular markers. Subsequently, PDAC-specific exosomal microRNA (miRNA) was identified by miRNA transcriptomics. The verified samples were obtained from 22 PDAC patients and 20 healthy donors to further verify the identified miRNAs. In the final analysis, the diagnostic ability of these miRNAs for PDAC was evaluated by the area under the ROC curve (AUC) and Brier score. Kaplan-Meier method and Log-rank test were used for survival analysis.

Results

5 miRNAs with low expression levels (hsa-miR-142-3p, hsa-miR-199b-3p, hsa-miR-221-3p, hsa-miR-222-3p and hsa-miR-584-5p) and 1 with high expression level were identified and verified. Two miRNAs with the highest expression levels were miR142-3p and miR148a-3p. Compared with adjacent tissues and healthy donor sera, these two miRNAs were further verified in tissue-derived extracellular vesicles (Ti-EVs) and serum-derived extracellular vesicles (Se-EVs) of PDAC patients. Kaplan-Meier curve showed that the down-regulated expression levels of miR142-3p and miR148a-3p were significantly correlated with poor prognosis of overall survival (OS) and recurrence-free survival (RFS) of PDAC patients (χ2=36.314, 5.218 and 7.047, 4.924; all P<0.05). The prediction error curve indicated that the combination of miR142-3p, miR148a-3p and CA19-9 yielded the smallest prediction error. ROC analysis revealed that the AUC based on the combination of miR142-3p and miR148a-3p combined with CA19-9 model was 0.747, larger than that of the model using CA19-9 alone.

Conclusions

The exosomes of pancreatic cancer, miRNA-142-3p and miRNA-148a-3p, play an anti-oncogene role in PDAC. PDAC patients with low expression of miRNA-142-3p or miRNA-148a-3p achieve poor prognosis, which are novel potential diagnostic and prognostic markers for PDAC.

Key words: Pancreatic ductal adenocarcinoma (PDAC), microRNA (miRNA), Exosome, Diagnosis, Prognosis
表1 PDAC患者临床特征
样本 年龄(岁) 性别 胆囊炎 黄疸 消瘦 减轻黄疸 CA19-9(kU/L) 肿瘤大小(cm) TNM 分期 包膜浸润 脂肪浸润 血管浸润 输血 术后出血
T1-N1 75 男 无 无 无 无 >1 000 4×3×3 T2N0M0 有 有 无 有 无
T2-N2 60 男 无 无 无 无 1 000 3×2×2 T2N0M1 有 有 有 有 无
T3-N3 60 男 无 无 无 无 40.05 4×4×3 T2N2M0 有 有 有 无 有
T4-N4 58 男 无 无 无 无 1 081 4×4×4 T2N0M0 有 无 有 无 无
T5-N5 69 男 有 有 有 PTCD >1 000 3×2×1 T2N2M0 无 有 有 有 无
T6-N6 63 女 无 无 无 无 >1 000 3×2×1 T2N1M0 无 无 有 无 无
T7-N7 68 男 无 有 有 PTCD 920.10 3×2×1 T2N0M0 无 无 有 无 有
T8-N8 49 女 有 有 无 PTCD 30.53 2×2×1 T1cN0M0 无 无 无 无 无
图1 PDAC患者Ti-EVs和Se-EVs的特征表现 注：a为Ti-EVs和Se-EVs纳米颗粒大小；b为Ti-EVs和Se-EVs透射电镜示均呈圆形和杯状凹形；c为Se-EVs和Ti-EVs的Western blot检测；Ti-EVs为组织源性细胞外囊泡，Se-EVs为血清源性细胞外囊泡，PDAC为胰腺导管腺癌
图2 PDAC患者Ti-EVs和Se-EVs每个样品中不同生物型RNA百分率 注：rRNA为核糖体RNA，snRNA为核小RNA，snoRNA为核仁小RNA，tRNA为转运RNA，Repbase为重复序列数据库，Ti-EVs为组织源性细胞外囊泡，Se-EVs为血清源性细胞外囊泡，PDAC为胰腺导管腺癌；N为癌旁组织，T为癌组织
表2 PDAC患者不同分组外泌体miRNA差异表达最高20个miRNA
序号 G1 G2 G3 G4
1 hsa-let-7c-5p hsa-let-7c-5p hsa-miR-16-5p hsa-miR-16-5p
2 hsa-let-7b-5p hsa-let-7b-5p hsa-let-7a-5p hsa-let-7c-5p
3 hsa-let-7a-5p hsa-let-7a-5p hsa-let-7f-5p hsa-let-7a-5p
4 hsa-let-7f-5p hsa-let-7f-5p hsa-let-7c-5p hsa-let-7f-5p
5 hsa-let-7e-5p hsa-miR-125b-5p hsa-miR-126-3p hsa-miR-126-3p
6 hsa-miR-148a-3p hsa-miR-125a-5p hsa-let-7e-5p hsa-let-7e-5p
7 hsa-miR-375-3p hsa-miR-16-5p hsa-miR-142-3p hsa-miR-122-5p
8 hsa-miR-125b-5p hsa-let-7e-5p hsa-let-7b-5p hsa-let-7b-5p
9 hsa-miR-125a-5p hsa-miR-21-5p hsa-miR-223-3p hsa-miR-486-5p
10 hsa-miR-16-5p hsa-miR-199b-3p hsa-let-7i-5p hsa-let-7i-5p
11 hsa-miR-21-5p hsa-let-7i-5p hsa-miR-26a-5p hsa-miR-92a-3p
12 hsa-miR-30a-5p hsa-miR-148a-3p hsa-miR-26b-5p hsa-miR-142-3p
13 hsa-miR-30d-5p hsa-miR-30a-5p hsa-miR-30a-5p hsa-miR-223-3p
14 hsa-miR-199b-3p hsa-miR-143-3p hsa-miR-486-5p hsa-miR-26b-5p
15 hsa-miR-200c-3p hsa-miR-26a-5p hsa-miR-21-5p hsa-miR-30a-5p
16 hsa-let-7i-p hsa-miR-30d-5p hsa-miR-92a-3p hsa-miR-26a-5p
17 hsa-miR-26a-5p hsa-miR-200c-3p hsa-miR-103a-3p hsa-miR-21-5p
18 unconservative_21_1433793 hsa-miR-7-5p hsa-miR-107 hsa-miR-103a-3p
19 hsa-miR-7-5p hsa-miR-26b-5p hsa-miR-30d-5p hsa-miR-107
20 hsa-miR-26b-5p hsa-miR-375-3p hsa-miR-146a-5p hsa-miR-93-5p
表3 不同数据库中注释的PDAC患者差异miRNA靶基因数量（个）
对比组 COG GO KEGG KOG NR Pfam SWISS-PROT eggNOG
G1比G2 4 979 14 831 15 293 10 800 15 785 14 839 15 734 15 448
G2比G4 5 918 17 525 18 118 12 618 18 751 17 554 18 661 18 317
G3比G4 3 727 11 181 11 555 8 130 11 922 11 159 11 872 11 684
图3 PDAC患者外泌体Se-EVs差异表达蛋白结合网络图 注：PDAC为胰腺导管腺癌，Se-EVs为血清源性细胞外囊泡
图4 PDAC患者外泌体转录组学和蛋白组学联合分析 注：a为1个上调miRNAs鉴定出5个上调和6个下调的蛋白；b 为5个下调miRNA鉴定出8个上调和9个下调的蛋白；红色为上调蛋白，绿色为下调蛋白；PDAC为胰腺导管腺癌
图5 健康人群和PDAC患者miR142-3p 和 miR148a-3p表达 注：miRNA 142-3p和miRNA 148a-3p在PDAC肿瘤组织和血清中的表达一致，且明显低于匹配对照组；PDAC为胰腺导管腺癌
图6 PDAC患者Kaplan-Meier生存曲线 注：PDAC为胰腺导管腺癌
图7 基于miR142-3p 和 miR148a-3p表达的模型对PDAC患者生存预后价值 注：a为miR142-3p、miR148a-3p和CA19-9组合的预测误差曲线；b为基于联合miR142-3p和 miR148a-3p的预测及基于CA19-9预测的ROC分析；PDAC为胰腺导管腺癌
[1]
Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(7): 493-502. DOI: 10.1038/s41575-021-00457-x.
[2]
Collisson EA, Bailey P, Chang DK, et al. Molecular subtypes of pancreatic cancer[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(4): 207-220. DOI: 10.1038/s41575-019-0109-y.
[3]
Godfrey JD, Morton JP, Wilczynska A, et al. miR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus[J]. Cell Death Dis, 2018, 9: 644. DOI: 10.1038/s41419-018-0628-4.
[4]
Mizrahi JD, Surana R, Valle JW, et al. Pancreatic cancer[J]. Lancet, 2020, 395(10242): 2008-2020. DOI: 10.1016/s0140-6736(20)30974-0.
[5]
Park W, Chawla A, O’Reilly EM. Pancreatic cancer[J]. JAMA, 2021, 326(9): 851. DOI: 10.1001/jama.2021.13027.
[6]
Joyce DP, Kerin MJ, Dwyer RM. Exosome-encapsulated microRNAs as circulating biomarkers for breast cancer[J]. Int J Cancer, 2016, 139(7): 1443-1448. DOI: 10.1002/ijc.30179.
[7]
Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer[J]. Nature, 2015, 523(7559): 177-182. DOI: 10.1038/nature14581.
[8]
Zou X, Wei J, Huang Z, et al. Identification of a six-miRNA panel in serum benefiting pancreatic cancer diagnosis[J]. Cancer Med, 2019, 8(6): 2810-2822. DOI: 10.1002/cam4.2145.
[9]
Li SR, Man QW, Gao X, et al. Tissue-derived extracellular vesicles in cancers and non-cancer diseases: present and future[J]. J Extracell Vesicles, 2021, 10(14): e12175. DOI: 10.1002/jev2.12175.
[10]
EL Andaloussi S, Mäger I, Breakefield XO, et al. Extracellular vesicles: biology and emerging therapeutic opportunities[J]. Nat Rev Drug Discov, 2013, 12(5): 347-357. DOI: 10.1038/nrd3978.
[11]
Chen L, Zhang YH, Wang S, et al. Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways[J]. PLoS One, 2017, 12(9): e0184129. DOI: 10.1371/journal.pone.0184129.
[12]
Kanehisa M, Sato Y, Kawashima M, et al. KEGG as a reference resource for gene and protein annotation[J]. Nucleic Acids Res, 2016, 44(D1): D457-D462. DOI: 10.1093/nar/gkv1070.
[13]
Mistry J, Chuguransky S, Williams L, et al. Pfam: the protein families database in 2021[J]. Nucleic Acids Res, 2021, 49(D1): D412-D419. DOI: 10.1093/nar/gkaa913.
[14]
Vella LJ, Scicluna BJ, Cheng L, et al. A rigorous method to enrich for exosomes from brain tissue[J]. J Extracell Vesicles, 2017, 6(1): 1348885. DOI: 10.1080/20013078.2017.1348885.
[15]
Batagov AO, Kurochkin IV. Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3'-untranslated regions[J]. Biol Direct, 2013, 8: 12. DOI: 10.1186/1745-6150-8-12.
[16]
Bolukbasi MF, Mizrak A, Ozdener GB, et al. miR-1289 and “zipcode”-like sequence enrich mRNAs in microvesicles[J]. Mol Ther Nucleic Acids, 2012, 1: e10. DOI: 10.1038/mtna.2011.2.
[17]
Nabhan JF, Hu R, Oh RS, et al. Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein[J]. Proc Natl Acad Sci USA, 2012, 109(11): 4146-4151. DOI: 10.1073/pnas.1200448109.
[18]
Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs[J]. Nat Commun, 2013, 4: 2980. DOI: 10.1038/ncomms3980.
[19]
Matsumura T, Sugimachi K, Iinuma H, et al. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer[J]. Br J Cancer, 2015, 113(2): 275-281. DOI: 10.1038/bjc.2015.201.
[20]
Van Giau V, An SSA. Emergence of exosomal miRNAs as a diagnostic biomarker for Alzheimer's disease[J]. J Neurol Sci, 2016, 360: 141-152. DOI: 10.1016/j.jns.2015.12.005.
[21]
He G, Peng X, Wei S, et al. Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications[J]. Mol Cancer, 2022, 21(1): 19. DOI: 10.1186/s12943-021-01440-5.
[22]
Parolini I, Federici C, Raggi C, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells[J]. J Biol Chem, 2009, 284(49): 34211-34222. DOI: 10.1074/jbc.M109.041152.
[23]
唐晋元, 杨陈凤麟, 梁冬乐, 等. 外泌体在肝内胆管癌中的作用[J]. 临床肝胆病杂志, 2024, 40(1): 181-186. DOI: 10.12449/JCH240130.
[24]
Peng L, Sang H, Wei S, et al. circCUL2 regulates gastric cancer malignant transformation and cisplatin resistance by modulating autophagy activation via miR-142-3p/ROCK2[J]. Mol Cancer, 2020, 19(1): 156. DOI: 10.1186/s12943-020-01270-x.
[25]
Shang A, Gu C, Wang W, et al. Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p-TGF-β1 axis[J]. Mol Cancer, 2020, 19(1): 117. DOI: 10.1186/s12943-020-01235-0.
[26]
Tan YF, Chen ZY, Wang L, et al. miR-142-3p functions as an oncogene in prostate cancer by targeting FOXO1[J]. J Cancer, 2020, 11(6): 1614-1624. DOI: 10.7150/jca.41888.
[27]
Liang L, Fu J, Wang S, et al. miR-142-3p enhances chemosensitivity of breast cancer cells and inhibits autophagy by targeting HMGB1[J]. Acta Pharm Sin B, 2020, 10(6): 1036-1046. DOI: 10.1016/j.apsb.2019.11.009.
[28]
Mansoori B, Duijf PHG, Mohammadi A, et al. miR-142-3p targets HMGA2 and suppresses breast cancer malignancy[J]. Life Sci, 2021, 276: 119431. DOI: 10.1016/j.lfs.2021.119431.
[29]
MacKenzie TN, Mujumdar N, Banerjee S, et al. Triptolide induces the expression of miR-142-3p: a negative regulator of heat shock protein 70 and pancreatic cancer cell proliferation[J]. Mol Cancer Ther, 2013, 12(7): 1266-1275. DOI: 10.1158/1535-7163.MCT-12-1231.
[30]
Zhang X, Chen F, Huang P, et al. Exosome-depleted miR-148a-3p derived from hepatic stellate cells promotes tumor progression via ITGA5/PI3K/Akt axis in hepatocellular carcinoma[J]. Int J Biol Sci, 2022, 18(6): 2249-2260. DOI: 10.7150/ijbs.66184.
[31]
Liang L, Xu WY, Shen A, et al. Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9[J]. Acta Pharmacol Sin, 2022, 43(11): 2946-2955. DOI: 10.1038/s41401-022-00893-8.
[32]
Martino E, Balestrieri A, Aragona F, et al. miR-148a-3p promotes colorectal cancer cell ferroptosis by targeting SLC7A11[J]. Cancers, 2023, 15(17): 4342. DOI: 10.3390/cancers15174342.
[1] 罗兵, 董凤群, 牛艺臻, 王锟, 程志华, 刘宏强. 胎儿超声心动图在单纯性肺动脉瓣狭窄及预后评估中的价值[J/OL]. 中华医学超声杂志（电子版）, 2025, 22(08): 740-747.
[2] 薛兆强, 袁寅. 双镜联合保功能胃癌根治术治疗早期近端胃癌的临床研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(06): 628-632.
[3] 贺雅莉, 黄丽, 杨培娟. 功能保留手术在低位直肠癌治疗中的研究进展[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(06): 701-704.
[4] 杨志, 夏雪峰, 管文贤. DeepSurv深度学习模型辅助胃癌术后精准化疗策略研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(05): 501-505.
[5] 徐其银, 韩尚志. 术前结合术后营养支持对直肠癌患者康复的影响[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(05): 543-546.
[6] 张聪, 李成. 胰头区恶性肿瘤外科手术预后现状及相关因素的研究进展[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(05): 574-578.
[7] 田超, 黄若曦, 蒋茂林, 谢崇伟, 刁鹏飞, 钟苏权, 陈东, 王航涛, 陈桂柳, 陈虞娟, 李国良. 不同亚型前列腺癌新辅助化疗后盆腔淋巴结转移的风险因素及时间分布[J/OL]. 中华腔镜泌尿外科杂志(电子版), 2025, 19(06): 727-735.
[8] 许梓锋, 黄展森, 狄金明. 胡桃夹综合征诊治进展[J/OL]. 中华腔镜泌尿外科杂志(电子版), 2025, 19(06): 784-791.
[9] 胡博文, 胡亚兰, 梁辉. 前列腺癌早期筛查的常见方法及最新研究进展[J/OL]. 中华腔镜泌尿外科杂志(电子版), 2025, 19(06): 800-808.
[10] 杨刚, 黄徐建, 朱建交, 熊永福, 李敬东. 两种不同类型肝门周围胆管癌临床病理特征及生存预后[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(06): 931-938.
[11] 孟泓宇, 戴锦辉, 胡嘉金, 李光辉. 炎性细胞因子与胰腺导管腺癌的因果关系：一项孟德尔随机化研究[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(06): 948-955.
[12] 韩博, 崔宏帅, 鞠倩, 张琳. 不同吻合方式在结肠癌腹腔镜右半结肠切除术中的应用效果及预后分析[J/OL]. 中华消化病与影像杂志(电子版), 2025, 15(05): 431-435.
[13] 周厚宁, 崔巧玲, 付瑞标. 营养风险指数、营养控制状态评分和尿素肌酐比值对胃癌患者营养和预后的评价[J/OL]. 中华消化病与影像杂志(电子版), 2025, 15(05): 444-448.
[14] 高兴梅, 周洁容, 杨溢, 张孟祥, 张仲谋, 李斌. 重症肺炎患者血磷水平轨迹与短期预后之间的关系[J/OL]. 中华临床医师杂志(电子版), 2025, 19(07): 479-485.
[15] 宁雯琪, 张永利. 脓毒症心肌病的研究进展：基础、临床与展望[J/OL]. 中华临床医师杂志(电子版), 2025, 19(06): 461-466.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号

AI
小
编
AI小编
你好！我是《中华医学电子期刊资源库》AI小编，有什么可以帮您的吗？