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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (4): 537-544    DOI: 10.3724/zdxbyxb-2021-0252
    
Research progress on neonatal Fc receptor and its application
HU Mangsha1(),WEI Shuli1,ZHOU Wuyuan2,*(),WANG Pingli1,*()
1. Department of Respiratory Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
2. Zhejiang Academy of Science and Technology Information, Hangzhou 310006, China
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Abstract  

Neonatal Fc receptor (FcRn) is a specific receptor for immunoglobulin G (IgG) and albumin, which binds to them in a pH-dependent manner and prevents them from lysosomal degradation to keep a long plasma half-life. In addition, FcRn plays an important role in transmembrane transport of IgG and albumin and in antigen presentation. In autoimmune diseases, anti-FcRn antibody can promote the degradation of pathogenic IgG by competitive binding to FcRn. In infectious diseases, the half-life of drugs can be prolonged by increasing the affinity between therapeutic antibody and FcRn, while the combination of viral antigen and Fc fragment of IgG can cause local immune response of mucosa for disease prevention and treatment. In cancer, albumin as a carrier of anticancer drugs can achieve efficient drug delivery, and FcRn itself may be used as a predictor of the prognosis of cancer patients. This review details the functions of FcRn, highlights its role in autoimmune diseases, infectious diseases and cancer, as well as the mechanism of drug development based on FcRn, to provide a reference for the clinical application and drug development of FcRn.



Key wordsNeonatal Fc receptor      Immunoglobulin G      Albumin      Autoimmune disease      Infectious disease      Cancer      Review     
Received: 03 February 2021      Published: 01 November 2021
CLC:  R392  
Corresponding Authors: ZHOU Wuyuan,WANG Pingli     E-mail: 22018330@zju.edu.cn;pingliwang@zju.edu.cn
Cite this article:

HU Mangsha,WEI Shuli,ZHOU Wuyuan,WANG Pingli. Research progress on neonatal Fc receptor and its application. J Zhejiang Univ (Med Sci), 2021, 50(4): 537-544.

URL:

http://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0252     OR     http://www.zjujournals.com/med/Y2021/V50/I4/537


新生儿Fc受体基础研究和临床应用进展

新生儿Fc受体(FcRn)是免疫球蛋白G(IgG)和白蛋白的特异性受体,通过酸碱度依赖的方式与两者结合,使IgG和白蛋白免于被溶酶体降解而拥有较长的血浆半衰期。FcRn具有实现IgG和白蛋白的跨膜转运及促进抗原提呈的作用。在自身免疫病中,抗FcRn抗体可以通过竞争性结合FcRn,促进致病性IgG的降解;在传染性疾病中,通过增加治疗抗体与FcRn的亲和力,可以延长药物半衰期,而将病毒抗原与IgG的Fc片段结合可以引起黏膜的局部免疫反应,用于疾病防治;在癌症中,FcRn的配体白蛋白作为抗癌药物的载体,可以实现高效给药,而FcRn本身或许可以作为肿瘤患者预后的预测指标。本文综述了FcRn的功能、相关药物研发机制及其在自身免疫病、传染性疾病和癌症中的作用,以期为FcRn的药物研发和临床应用提供参考。


关键词: 新生儿Fc受体,  免疫球蛋白G,  白蛋白,  自身免疫病,  传染病,  癌症,  综述 
Figure 1 Structure of the neonatal Fc receptor
Figure 2 The function of the neonatal Fc receptor
[1]   SIMISTERN E, MOSTOVK E. An Fc receptor structurally related to MHC class Ⅰ antigens[J]Nature, 1989, 337( 6203): 184-187.
doi: 10.1038/337184a0
[2]   OGANESYANV, DAMSCHRODERM M, COOKK E, et al.Structural insights into neonatal Fc receptor-based recycling mechanisms[J]J Biol Chem, 2014, 289( 11): 7812-7824.
doi: 10.1074/jbc.M113.537563
[3]   QIAOS W, KOBAYASHIK, JOHANSENF E, et al.Dependence of antibody-mediated presentation of antigen on FcRn[J]Proc Natl Acad Sci U S A, 2008, 105( 27): 9337-9342.
doi: 10.1073/pnas.0801717105
[4]   ULRICHTSP, GUGLIETTAA, DREIERT, et al.Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans[J]J Clin Invest, 2018, 128( 10): 4372-4386.
doi: 10.1172/JCI97911
[5]   Johnson & Johnson completes acquisition of Momenta Pharmaceuticals, Inc[EB/OL]. (2020-10-01)[2021-02-28]. https://www.jnj.com/johnson-johnson-completes-acquisition-of-momenta-pharmaceuticals-inc
[6]   STORYC M, MIKULSKAJ E, SIMISTERN E. A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus[J]J Exp Med, 1994, 180( 6): 2377-2381.
doi: 10.1084/jem.180.6.2377
[7]   RAGHAVANM, BONAGURAV R, MORRISONS L, et al.Analysis of the pH dependence of the neonatal fc receptor/immunoglobulin G interaction using antibody and receptor variants[J]Biochemistry, 1995, 34( 45): 14649-14657.
doi: 10.1021/bi00045a005
[8]   KIMJ K, TSENM F, GHETIEV, et al.Evidence that the hinge region plays a role in maintaining serum levels of the murine IgG1 molecule[J]Mol Immunol, 1995, 32( 7): 467-475.
doi: 10.1016/0161-5890(95)00019-B
[9]   VAUGHND E, MILBURNC M, PENNYD M, et al.Identification of critical IgG binding epitopes on the neonatal Fc receptor[J]J Mol Biol, 1997, 274( 4): 597-607.
doi: 10.1006/jmbi.1997.1388
[10]   BOOTHB J, RAMAKRISHNANB, NARAYANK, et al.Extending human IgG half-life using structure-guided design Brian[J]mAbs, 2018, 10( 7): 1098-1110.
doi: 10.1107/S0907444993007991
[11]   KIMJ K, FIRANM, RADUC G, et al.Mapping the site on human IgG for binding of the MHC class Ⅰ-related receptor, FcRn[J]Eur J Immunol, 1999, 29( 9): 2819-2825.
doi: 10.1002/(SICI)1521-4141(199909)29:09<2819::AID-IMMU2819>3.0.CO;2-6
[12]   JUNGHANSR P, ANDERSONC L. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor[J]Proc Natl Acad Sci U S A, 1996, 93( 11): 5512-5516.
doi: 10.1073/pnas.93.11.5512
[13]   BRAMBELLF W R, HEMMINGSW A, MORRISI G. A theoretical model of γ-globulin catabolism[J]Nature, 1964, 203( 4952): 1352-1355.
doi: 10.1038/2031352a0
[14]   GANZ, RAMS, VACCAROC, et al.Analyses of the recycling receptor, FcRn, in live cells reveal novel pathways for lysosomal delivery[J]Traffic, 2009, 10( 5): 600-614.
doi: 10.1111/j.1600-0854.2009.00887.x
[15]   BALDWIN IIIW M, VALUJSKIKHA, FAIRCHILDR L. The neonatal Fc receptor: key to homeostasic control of IgG and IgG‐related biopharmaceuticals[J]Am J TransPlant, 2019, 19( 7): 1881-1887.
doi: 10.1111/ajt.15366
[16]   FIRANM, BAWDONR, RADUC, et al.The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of γ-globulin in humans[J]Int Immunol, 2001, 13( 8): 993-1002.
doi: 10.1093/intimm/13.8.993
[17]   LEACH J L, SEDMAK D D, OSBORNE J M, et al. Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport[J]. J Immunol, 1996, 157(8): 3317-3322
[18]   SAKAGAMIM, OMIDIY, CAMPBELLL, et al.Expression and transport functionality of FcRn within rat alveolar epithelium: a study in primary cell culture and in the isolated perfused lung[J]Pharm Res, 2006, 23( 2): 270-279.
doi: 10.1007/s11095-005-9226-0
[19]   HORNBYP J, COOPERP R, KLIWINSKIC, et al.Human and non-human primate intestinal FcRn expression and immunoglobulin G transcytosis[J]Pharm Res, 2014, 31( 4): 908-922.
doi: 10.1007/s11095-013-1212-3
[20]   AKILESHS, HUBERT B, WUH, et al.Podocytes use FcRn to clear IgG from the glomerular basement membrane[J]Proc Natl Acad Sci U S A, 2008, 105( 3): 967-972.
doi: 10.1073/pnas.0711515105
[21]   SCHLACHETZKIF, ZHUC, PARDRIDGEW M. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier[J]J NeuroChem, 2002, 81( 1): 203-206.
doi: 10.1046/j.1471-4159.2002.00840.x
[22]   BURMEISTERW P, GASTINELL N, SIMISTERN E, et al.Crystal structure at 2.2 ? resolution of the MHC-related neonatal Fc receptor[J]Nature, 1994, 372( 6504): 336-343.
doi: 10.1038/372336a0
[23]   KOBAYASHIK, QIAOS W, YOSHIDAM, et al.An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice[J]Gastroenterology, 2009, 137( 5): 1746-1756.e1.
doi: 10.1053/j.gastro.2009.07.059
[24]   BAKERK, QIAOS W, KUOT T, et al.Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cells[J]Proc Natl Acad Sci U S A, 2011, 108( 24): 9927-9932.
doi: 10.1073/pnas.1019037108
[25]   SANDK M K, BERNM, NILSENJ, et al.Unraveling the interaction between FcRn and albumin: opportunities for design of albumin-based therapeutics[J]Front Immunol, 2015, 682.
doi: 10.3389/fimmu.2014.00682
[26]   KENNISTONJ A, TAYLORB M, CONLEYG P, et al.Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody[J]J Biol Chem, 2017, 292( 42): 17449-17460.
doi: 10.1074/jbc.M117.807396
[27]   ROOPENIAND C, AKILESHS. FcRn: the neonatal Fc receptor comes of age[J]Nat Rev Immunol, 2007, 7( 9): 715-725.
doi: 10.1038/nri2155
[28]   IGAWAT, HARAYAK, HATTORIK. Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation[J]Immunol Rev, 2016, 270( 1): 132-151.
doi: 10.1111/imr.12392
[29]   IGAWAT, ISHIIS, TACHIBANAT, et al.Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization[J]Nat Biotechnol, 2010, 28( 11): 1203-1207.
doi: 10.1038/nbt.1691
[30]   IGAWAT, MIMOTOF, HATTORIK. PH-dependent antigen-binding antibodies as a novel therapeutic modality[J]BioChim Biophys Acta, 2014, 1844( 11): 1943-1950.
doi: 10.1016/j.bbapap.2014.08.003
[31]   HIRONIWAN, ISHIIS, KADONOS, et al.Calcium-dependent antigen binding as a novel modality for antibody recycling by endosomal antigen dissociation[J]mAbs, 2016, 8( 1): 65-73.
doi: 10.1080/19420862.2015.1110660
[32]   IGAWAT, MAEDAA, HARAYAK, et al.Engineered monoclonal antibody with novel antigen-sweeping activityin vivo[J/OL]PLoS ONE, 2013, 8( 5): e63236.
doi: 10.1371/journal.pone.0063236
[33]   KENANOVA V, OLAFSEN T, CROW D M, et al. Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments[J]. Cancer Res, 2005, 65(2): 622-631
[34]   BERNM, NILSENJ, FERRARESEM, et al.An engineered human albumin enhances half-life and transmucosal delivery when fused to protein-based biologics[J/OL]Sci Transl Med, 2020, 12( 565): eabb0580.
doi: 10.1126/scitranslmed.abb0580
[35]   AZEVEDOC, NILSENJ, GREVYSA, et al.Engineered albumin-functionalized nanoparticles for improved FcRn binding enhance oral delivery of insulin[J]J Control Release, 2020, 161-173.
doi: 10.1016/j.jconrel.2020.08.005
[36]   ANDERSENJ T, DALHUSB, VIUFFD, et al.Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding[J]J Biol Chem, 2014, 289( 19): 13492-13502.
doi: 10.1074/jbc.M114.549832
[37]   ANDERSENJ T, DALHUSB, CAMERONJ, et al.Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor[J]Nat Commun, 2012, 3( 1): 610.
doi: 10.1038/ncomms1607
[38]   BRODSKYR A. Warm autoimmune hemolytic anemia[J]N Engl J Med, 2019, 381( 7): 647-654.
doi: 10.1016/j.hoc.2015.01.001
[39]   CINESD B, BUSSELJ B, LIEBMANH A, et al.The ITP syndrome: pathogenic and clinical diversity[J]Blood, 2009, 113( 26): 6511-6521.
doi: 10.1182/blood-2009-01-129155
[40]   HOWARDJ F, BRILV, BURNST M, et al.Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis[J/OL]Neurology, 2019, 92( 23): e2661-e2673.
doi: 10.1212/WNL.0000000000007600
[41]   HOWARD JRJ F, BRILV, VUT, et al.Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial[J]Lancet Neurol, 2021, 20( 7): 526-536.
doi: 10.1016/S1474-4422(21)00159-9
[42]   NEWLANDA C, SáNCHEZ-GONZáLEZB, REJT?L, et al.Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia[J]Am J Hematol, 2020, 95( 2): 178-187.
doi: 10.1002/ajh.25680
[43]   LINGL E, HILLSONJ L, TIESSENR G, et al.M281, an anti-FcRn antibody: pharmacodynamics, pharmacokinetics, and safety across the full range of IgG reduction in a first-in-human study[J]Clin Pharmacol Ther, 2019, 105( 4): 1031-1039.
doi: 10.1002/cpt.1276
[44]   ROYS, NANOVSKAYAT, PATRIKEEVAS, et al.M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model[J]Am J Obstet GynEcol, 2019, 220( 5): 498.e1-498.e9.
doi: 10.1016/j.ajog.2019.02.058
[45]   BLUMBERGL J, HUMPHRIESJ E, JONESS D, et al.Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses[J/OL]Sci Adv, 2019, 5( 12): eaax9586.
doi: 10.1126/sciadv.aax9586
[46]   WERTHV P, CULTOND, BLUMBERGL, et al.538 FcRn blockade with SYNT001 for the treatment of pemphigus[J]J Investig Dermatol, 2018, 138( 5): S92.
doi: 10.1016/j.jid.2018.03.546
[47]   KIESSLINGP, LLEDO-GARCIAR, WATANABES, et al.The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: a randomized phase 1 study[J/OL]Sci Transl Med, 2017, 9( 414): eaan1208.
doi: 10.1126/scitranslmed.aan1208
[48]   BRILV, BENATARM, ANDERSENH, et al.Efficacy and safety of rozanolixizumab in moderate to severe generalised myasthenia gravis: a phase 2 randomized control trial[J/OL]Neurology, 2021, 96( 6): e853-e865.
doi: 10.1212/WNL.0000000000011108
[49]   ROBAKT, KA?MIERCZAKM, JARQUEI, et al.Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia[J]Blood Adv, 2020, 4( 17): 4136-4146.
doi: 10.1182/bloodadvances.2020002003
[50]   YAPD Y H, HAIJ, LEEP C H, et al.Safety, tolerability, pharmacokinetics, and pharmacodynamics of HBM9161, a novel FcRn inhibitor, in a phase I study for healthy Chinese volunteers[J]Clin Transl Sci, 2021.,
[51]   Alexion and Affibody announce partnership to co-develop anti-FcRn Affibody? molecule[EB/OL]. (2019-03-20)[2021-02-28]. https://www.affibody.se/alexion-and-affibody-announce-partnership-to-co-develop-anti-fcrn-affibody-molecule/
[52]   CINESD B, ZAITSEVS, RAUOVAL, et al.FcRn augments induction of tissue factor activity by IgG-containing immune complexes[J]Blood, 2020, 135( 23): 2085-2093.
doi: 10.1182/blood.2019001133
[53]   LIUX, PALANIYANDIS, ZHUI, et al.Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor[J]Nat Commun, 2019, 10( 1): 3020.
doi: 10.1038/s41467-019-10865-y
[54]   MCGHEEJ R. A mucosal gateway for vaccines[J]Nat Biotechnol, 2011, 29( 2): 136-138.
doi: 10.1038/nbt.1766
[55]   YOSHIDAM, CLAYPOOLS M, WAGNERJ S, et al.Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells[J]Immunity, 2004, 20( 6): 769-783.
doi: 10.1016/j.immuni.2004.05.007
[56]   LUL, PALANIYANDIS, ZENGR, et al.A neonatal Fc receptor-targeted mucosal vaccine strategy effectively induces HIV-1 antigen-specific immunity to genital infection[J]J Virol, 2011, 85( 20): 10542-10553.
doi: 10.1128/jvi.05441-11
[57]   ZHANGY, ZHOUZ, ZHUS L, et al.A novel RSV F-Fc fusion protein vaccine reduces lung injury induced by respiratory syncytial virus infection[J]Antiviral Res, 2019, 11-22.
doi: 10.1016/j.antiviral.2019.02.017
[58]   KOS Y, PEGUA, RUDICELLR S, et al.Enhanced neonatal Fc receptor function improves protection against primate SHIV infection[J]Nature, 2014, 514( 7524): 642-645.
doi: 10.1038/nature13612
[59]   GAUDINSKIM R, COATESE E, HOUSERK V, et al.Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: a phase 1 open-label clinical trial in healthy adults[J/OL]PLoS Med, 2018, 15( 1): e1002493.
doi: 10.1371/journal.pmed.1002493
[60]   DALL’ACQUAW F, KIENERP A, WUH. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn)[J]J Biol Chem, 2006, 281( 33): 23514-23524.
doi: 10.1074/jbc.M604292200
[61]   KANGC, XIAL, CHENY, et al.A novel therapeutic anti-HBV antibody with increased binding to human FcRn improves in vivo PK in mice and monkeys[J]Protein Cell, 2018, 9( 1): 130-134.
doi: 10.1007/s13238-017-0438-y
[62]   Xencor and Vir Biotechnology enter license agreement for use of Xtend? XmAb? antibody technology in investigational antibodies to treat COVID-19[EB/OL].(2020-03-25)[2021-02-28]. https://investors.xencor.com/news-releases/news-release-details/xencor-and-vir-biotechnology-enter-license-agreement-use-xtendtm
[63]   ZHAOX, ZHANGG, LIUS, et al.Human neonatal Fc receptor is the cellular uncoating receptor for enterovirus B[J]Cell, 2019, 177( 6): 1553-1565.e16.
doi: 10.1016/j.cell.2019.04.035
[64]   DALLONEAUE, BAROUKHN, MAVRIDISK, et al.Downregulation of the neonatal Fc receptor expression in non-small cell lung cancer tissue is associated with a poor prognosis[J]Oncotarget, 2016, 7( 34): 54415-54429.
doi: 10.18632/oncotarget.10074
[65]   BAKERK, RATHT, FLAKM B, et al.Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer[J]Immunity, 2013, 39( 6): 1095-1107.
doi: 10.1016/j.immuni.2013.11.003
[66]   SHIL, ZHANGW, ZOUF, et al.KLHL21, a novel gene that contributes to the progression of hepatocellular carcinoma[J]BMC Cancer, 2016, 16( 1): 815.
doi: 10.1186/s12885-016-2851-7
[67]   SWIERCZR, MOM, KHAREP, et al.Loss of expression of the recycling receptor, FcRn, promotes tumor cell growth by increasing albumin consumption[J]Oncotarget, 2017, 8( 2): 3528-3541.
doi: 10.18632/oncotarget.13869
[68]   LARSENM T, MANDRUPO A, SCHELDEK K, et al.FcRn overexpression in human cancer drives albumin recycling and cell growth; a mechanistic basis for exploitation in targeted albumin-drug designs[J]J Control Release, 2020, 53-63.
doi: 10.1016/j.jconrel.2020.03.004
[69]   CASTANEDAD C, DHOMMéEC, BARANEKT, et al.Lack of FcRn impairs natural killer cell development and functions in the tumor microenvironment[J]Front Immunol, 2018, 2259.
doi: 10.3389/fimmu.2018.02259
[70]   LIUH, SUNM, LIUZ, et al.KRAS-enhanced macropinocytosis and reduced FcRn-mediated recycling sensitize pancreatic cancer to albumin-conjugated drugs[J]J Control Release, 2019, 40-53.
doi: 10.1016/j.jconrel.2019.01.014
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