The Journal of Practical Medicine ›› 2024, Vol. 40 ›› Issue (23): 3419-3426.doi: 10.3969/j.issn.1006-5725.2024.23.022
• Reviews • Previous Articles
Xiao XIAO1,Fangyi LONG2,Gang. WANG1
Received:
2024-09-02
Online:
2024-12-10
Published:
2024-12-16
Contact:
Gang. WANG
CLC Number:
Xiao XIAO,Fangyi LONG,Gang. WANG. Dual role and new strategies of pyroptosis in cancer therapy[J]. The Journal of Practical Medicine, 2024, 40(23): 3419-3426.
1 |
SHI J, GAO W, SHAO F. Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death[J]. Trends Biochem Sci, 2017, 42(4):245-254. doi:10.1016/j.tibs.2016.10.004
doi: 10.1016/j.tibs.2016.10.004 |
2 |
VASUDEVAN S O, BEHL B, RATHINAM V A. Pyroptosis-induced inflammation and tissue damage[J]. Semin Immunol, 2023, 69:101781. doi:10.1016/j.smim.2023.101781
doi: 10.1016/j.smim.2023.101781 |
3 |
WEI Y, YANG L, PANDEYA A, et al. Pyroptosis-Induced Inflammation and Tissue Damage[J]. J Mol Biol, 2022, 434(4):167301. doi:10.1016/j.jmb.2021.167301
doi: 10.1016/j.jmb.2021.167301 |
4 |
FANG Y, TANG Y, HUANG B. Pyroptosis: A road to next-generation cancer immunotherapy[J]. Semin Immunol, 2023, 68:101782. doi:10.1016/j.smim.2023.101782
doi: 10.1016/j.smim.2023.101782 |
5 |
FARIA S S, COSTANTINI S, DE LIMA V, et al. NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer[J]. J Biomed Sci, 2021, 28(1):26. doi:10.1186/s12929-021-00724-8
doi: 10.1186/s12929-021-00724-8 |
6 |
COOKSON B T, BRENNAN M A. Pro-inflammatory programmed cell death[J]. Trends Microbiol, 2001, 9(3):113-114. doi:10.1016/s0966-842x(00)01936-3
doi: 10.1016/s0966-842x(00)01936-3 |
7 |
GALLUZZI L, LOPEZ-SOTO A, KUMAR S, et al. Caspases Connect Cell-Death Signaling to Organismal Homeostasis[J]. Immunity, 2016,44(2):221-231. doi:10.1016/j.immuni.2016.01.020
doi: 10.1016/j.immuni.2016.01.020 |
8 |
XU H, YUAN Z, QIN K, et al. The molecular mechanism and evolutionary divergence of caspase 3/7-regulated gasdermin E activation[J]. Elife, 2024, 12:RP89974. doi:10.7554/elife.89974
doi: 10.7554/elife.89974 |
9 |
DE VASCONCELOS N M, VAN OPDENBOSCH N, VAN GORP H, et al. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture[J]. Cell Death Differ, 2019, 26(1):146-161. doi:10.1038/s41418-018-0106-7
doi: 10.1038/s41418-018-0106-7 |
10 |
HERR D R, YAM T, TAN W, et al. Ultrastructural Characteristics of DHA-Induced Pyroptosis[J]. Neuromolecular Med, 2020, 22(2):293-303. doi:10.1007/s12017-019-08586-y
doi: 10.1007/s12017-019-08586-y |
11 |
ZHANG J H, XU M. DNA fragmentation in apoptosis[J]. Cell Res, 2000, 10(3):205-211. doi:10.1038/sj.cr.7290049
doi: 10.1038/sj.cr.7290049 |
12 |
DEVANT P, KAGAN J C. Molecular mechanisms of gasdermin D pore-forming activity[J]. Nat Immunol, 2023, 24(7):1064-1075. doi:10.1038/s41590-023-01526-w
doi: 10.1038/s41590-023-01526-w |
13 |
MOLLA M D, AKALU Y, GETO Z, et al. Role of Caspase-1 in the Pathogenesis of Inflammatory-Associated Chronic Noncommunicable Diseases[J]. J Inflamm Res, 2020, 13:749-764. doi:10.2147/jir.s277457
doi: 10.2147/jir.s277457 |
14 |
RAO Z, ZHU Y, YANG P, et al. Pyroptosis in inflammatory diseases and cancer[J]. Theranostics, 2022, 12(9):4310-4329. doi:10.7150/thno.71086
doi: 10.7150/thno.71086 |
15 |
LIU Y R, WANG J Q, LI J. Role of NLRP3 in the pathogenesis and treatment of gout arthritis[J]. Front Immunol, 2023, 14:1137822. doi:10.3389/fimmu.2023.1137822
doi: 10.3389/fimmu.2023.1137822 |
16 |
LI C, CHEN M, HE X, et al. A mini-review on ion fluxes that regulate NLRP3 inflammasome activation[J]. Acta Biochim Biophys Sin (Shanghai), 2021, 53(2):131-139. doi:10.1093/abbs/gmaa155
doi: 10.1093/abbs/gmaa155 |
17 |
CHAVARRIA-SMITH J, VANCE R E. The NLRP1 inflammasomes[J]. Immunol Rev, 2015,265(1):22-34. doi:10.1111/imr.12283
doi: 10.1111/imr.12283 |
18 |
DEVI S, STEHLIK C, DORFLEUTNER A. An Update on CARD Only Proteins (COPs) and PYD Only Proteins (POPs) as Inflammasome Regulators[J]. Int J Mol Sci, 2020, 21(18):6901. doi:10.3390/ijms21186901
doi: 10.3390/ijms21186901 |
19 |
LU A, WU H. Structural mechanisms of inflammasome assembly[J]. FEBS J, 2015, 282(3):435-444. doi:10.1111/febs.13133
doi: 10.1111/febs.13133 |
20 |
BARNETT K C, LI S, LIANG K, et al. A 360 degrees view of the inflammasome: Mechanisms of activation, cell death, and diseases[J]. Cell, 2023, 186(11):2288-2312. doi:10.1016/j.cell.2023.04.025
doi: 10.1016/j.cell.2023.04.025 |
21 |
MATIKAINEN S, NYMAN T A, CYPRYK W. Function and Regulation of Noncanonical Caspase-4/5/11 Inflammasome[J]. J Immunol, 2020, 204(12):3063-3069. doi:10.4049/jimmunol.2000373
doi: 10.4049/jimmunol.2000373 |
22 |
WANG D, ZHANG B, LIU X, et al. Agree to disagree: The contradiction between IL-18 and IL-37 reveals shared targets in cancer[J]. Pharmacol Res, 2024, 200:107072. doi:10.1016/j.phrs.2024.107072
doi: 10.1016/j.phrs.2024.107072 |
23 |
MOHAMMED T F, QADIR F A. Detection of IL-1beta, VEGF and IL-4 with their novel genetic variations in breast cancer patients[J]. Saudi J Biol Sci, 2023, 30(2):103544. doi:10.1016/j.sjbs.2022.103544
doi: 10.1016/j.sjbs.2022.103544 |
24 |
WANG F, LI G, NING J, et al. Alcohol accumulation promotes esophagitis via pyroptosis activation[J]. Int J Biol Sci, 2018,14(10):1245-1255. doi:10.7150/ijbs.24347
doi: 10.7150/ijbs.24347 |
25 | GAO J, QIU X, XI G, et al. Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in non‑small cell lung cancer[J]. Oncol Rep, 2018,40(4):1971-1984. |
26 |
LI S, YUE M, XU H, et al. Chemotherapeutic drugs-induced pyroptosis mediated by gasdermin E promotes the progression and chemoresistance of pancreatic cancer[J]. Cancer Lett, 2023, 564:216206. doi:10.1016/j.canlet.2023.216206
doi: 10.1016/j.canlet.2023.216206 |
27 | YU S, YIN J J, MIAO J X, et al. Activation of NLRP3 inflammasome promotes the proliferation and migration of esophageal squamous cell carcinoma[J]. Oncol Rep, 2020, 43(4):1113-1124. |
28 |
JIANG X, ZHU Z, DING L, et al. ALKBH4 impedes 5-FU Sensitivity through suppressing GSDME induced pyroptosis in gastric cancer[J]. Cell Death Dis, 2024,15(6):435. doi:10.1038/s41419-024-06832-1
doi: 10.1038/s41419-024-06832-1 |
29 |
GUO J, YE F, XIE W, et al. The HOXC-AS2/miR-876-5p/HKDC1 axis regulates endometrial cancer progression in a high glucose-related tumor microenvironment[J]. Cancer Sci, 2022, 113(7):2297-2310. doi:10.1111/cas.15384
doi: 10.1111/cas.15384 |
30 |
LIU Y, FANG Y, CHEN X, et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome[J]. Sci Immunol, 2020, 5(43):eaax7969. doi:10.1126/sciimmunol.aax7969
doi: 10.1126/sciimmunol.aax7969 |
31 |
DING Y, YAN Y, DONG Y, et al. NLRP3 promotes immune escape by regulating immune checkpoints: A pan-cancer analysis[J]. Int Immunopharmacol, 2022, 104:108512. doi:10.1016/j.intimp.2021.108512
doi: 10.1016/j.intimp.2021.108512 |
32 |
DENG M, SUN S, ZHAO R, et al. The pyroptosis-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma[J]. Mol Med, 2022, 28(1):16. doi:10.1186/s10020-022-00445-0
doi: 10.1186/s10020-022-00445-0 |
33 |
HU Y, LIU Y, ZONG L, et al. The multifaceted roles of GSDME-mediated pyroptosis in cancer: Therapeutic strategies and persisting obstacles[J]. Cell Death Dis, 2023, 14(12):836. doi:10.1038/s41419-023-06382-y
doi: 10.1038/s41419-023-06382-y |
34 |
XIA J, CHU C, LI W, et al. Mitochondrial Protein UCP1 Inhibits the Malignant Behaviors of Triple-negative Breast Cancer through Activation of Mitophagy and Pyroptosis[J]. Int J Biol Sci, 2022, 18(7):2949-2961. doi:10.7150/ijbs.68438
doi: 10.7150/ijbs.68438 |
35 |
YANG C, WANG Z Q, ZHANG Z C, et al. CBL0137 activates ROS/BAX signaling to promote caspase-3/GSDME-dependent pyroptosis in ovarian cancer cells[J]. Biomed Pharmacother, 2023, 161:114529. doi:10.1016/j.biopha.2023.114529
doi: 10.1016/j.biopha.2023.114529 |
36 |
YU D, WANG S, WANG J, et al. EZH2-STAT3 signaling pathway regulates GSDMD-mediated pyroptosis in glioblastoma[J]. Cell Death Discov, 2024, 10(1):341. doi:10.1038/s41420-024-02105-0
doi: 10.1038/s41420-024-02105-0 |
37 |
TENG J F, MEI Q B, ZHOU X G, et al. Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-kappaB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer[J]. Cancers (Basel), 2020, 12(1):193. doi:10.3390/cancers12010193
doi: 10.3390/cancers12010193 |
38 |
CAI J, YI M, TAN Y, et al. Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-IotaIota[J]. J Exp Clin Cancer Res, 2021, 40(1):190. doi:10.1186/s13046-021-01995-7
doi: 10.1186/s13046-021-01995-7 |
39 |
YAN H, LUO B, WU X, et al. Cisplatin Induces Pyroptosis via Activation of MEG3/NLRP3/caspase-1/GSDMD Pathway in Triple-Negative Breast Cancer[J]. Int J Biol Sci, 2021, 17(10):2606-2621. doi:10.7150/ijbs.60292
doi: 10.7150/ijbs.60292 |
40 |
ZHANG Z, ZHANG H, LI D, et al. Caspase-3-mediated GSDME induced Pyroptosis in breast cancer cells through the ROS/JNK signalling pathway[J]. J Cell Mol Med, 2021, 25(17):8159-8168. doi:10.1111/jcmm.16574
doi: 10.1111/jcmm.16574 |
41 |
WANG Y, YIN B, LI D, et al. GSDME mediates caspase-3-dependent pyroptosis in gastric cancer[J]. Biochem Biophys Res Commun, 2018, 495(1):1418-1425. doi:10.1016/j.bbrc.2017.11.156
doi: 10.1016/j.bbrc.2017.11.156 |
42 |
YU J, LI S, QI J, et al. Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells[J]. Cell Death Dis, 2019, 10(3):193. doi:10.1038/s41419-019-1441-4
doi: 10.1038/s41419-019-1441-4 |
43 |
HAGE C, HOVES S, STRAUSS L, et al. Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell-Mediated Cytotoxicity Against Hepatocellular Carcinoma[J]. Hepatology, 2019,70(4):1280-1297. doi:10.1002/hep.30666
doi: 10.1002/hep.30666 |
44 |
HAN Z, LIANG Y, LI Y, et al. Programmed Cascade Polydopamine Nanoclusters for Pyroptosis-Based Tumor Immunotherapy[J]. Small, 2024, 20(42):e2401397. doi:10.1002/smll.202401397
doi: 10.1002/smll.202401397 |
45 |
REN Y, FENG M, HAO X, et al. USP48 Stabilizes Gasdermin E to Promote Pyroptosis in Cancer[J]. Cancer Res, 2023, 83(7):1074-1093. doi:10.1158/0008-5472.can-22-1812
doi: 10.1158/0008-5472.can-22-1812 |
46 |
ERKES D A, CAI W, SANCHEZ I M, et al. Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis[J]. Cancer Discov, 2020, 10(2):254-269. doi:10.1158/2159-8290.cd-19-0672
doi: 10.1158/2159-8290.cd-19-0672 |
47 |
JIANG Y, YANG Y, HU Y, et al. Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade[J]. Cell Rep, 2022, 41(4):111553. doi:10.1016/j.celrep.2022.111553
doi: 10.1016/j.celrep.2022.111553 |
48 | SANG R, FAN R, DENG A, et al. Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy[J]. J Med Chem, 2023, 66(13):8464-8483. |
49 |
FONTANA P, DU G, ZHANG Y, et al. Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity[J]. Cell, 2024, 187(22):6165-6181.e22. doi:10.1016/j.cell.2024.08.007
doi: 10.1016/j.cell.2024.08.007 |
50 |
AI Y L, WANG W J, LIU F J, et al. Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P[J]. Cell Res, 2023, 33(12):904-922. doi:10.1038/s41422-023-00848-6
doi: 10.1038/s41422-023-00848-6 |
51 |
DI M, MIAO J, PAN Q, et al. OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis[J]. J Exp Clin Cancer Res, 2022, 41(1):328. doi:10.1186/s13046-022-02533-9
doi: 10.1186/s13046-022-02533-9 |
52 |
SU L, CHEN Y, HUANG C, et al. Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models[J]. Sci Transl Med, 2023, 15(678):eabl7895. doi:10.1126/scitranslmed.abl7895
doi: 10.1126/scitranslmed.abl7895 |
53 |
LI Y T, TAN X Y, MA L X, et al. Targeting LGSN restores sensitivity to chemotherapy in gastric cancer stem cells by triggering pyroptosis[J]. Cell Death Dis, 2023, 14(8):545. doi:10.1038/s41419-023-06081-8
doi: 10.1038/s41419-023-06081-8 |
54 | 韩蓉,吴东明,邓任华,等. X线辐照激活NLRP3灰性体引起损伤肺组织细胞焦亡(pyroptosis)[J]. 细胞与分子免疫学杂志, 2017, 33(9):1206-1211. |
55 |
YANG C, SONG C, WANG Y, et al. Re-Du-Ning injection ameliorates radiation-induced pneumonitis and fibrosis by inhibiting AIM2 inflammasome and epithelial-mesenchymal transition[J]. Phytomedicine, 2022, 102:154184. doi:10.1016/j.phymed.2022.154184
doi: 10.1016/j.phymed.2022.154184 |
56 |
QIU H, WANG W, HU K, et al. EuHD1 protects against inflammatory injury driven by NLRP3 inflammasome[J]. Int Immunopharmacol, 2023, 115:109712. doi:10.1016/j.intimp.2023.109712
doi: 10.1016/j.intimp.2023.109712 |
57 |
ZHANG L, BAI H, ZHOU J, et al. Role of tumor cell pyroptosis in anti-tumor immunotherapy[J]. Cell Insight, 2024, 3(3):100153. doi:10.1016/j.cellin.2024.100153
doi: 10.1016/j.cellin.2024.100153 |
58 |
LI M, JIANG P, YANG Y, et al. The role of pyroptosis and gasdermin family in tumor progression and immune microenvironment[J]. Exp Hematol Oncol, 2023, 12(1):103. doi:10.1186/s40164-023-00464-5
doi: 10.1186/s40164-023-00464-5 |
59 |
NING H, HUANG S, LEI Y, et al. Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity[J]. Nat Commun, 2022, 13(1):6578. doi:10.1038/s41467-022-34253-1
doi: 10.1038/s41467-022-34253-1 |
60 |
WU F, WANG M, ZHONG T, et al. Inhibition of CDC20 potentiates anti-tumor immunity through facilitating GSDME-mediated pyroptosis in prostate cancer[J]. Exp Hematol Oncol, 2023, 12(1):67. doi:10.1186/s40164-023-00428-9
doi: 10.1186/s40164-023-00428-9 |
61 |
WU L, BAI S, HUANG J, et al. Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer[J]. Cancers (Basel), 2023, 15(12):3221. doi:10.3390/cancers15123221
doi: 10.3390/cancers15123221 |
62 |
ZHANG Z, ZHANG Y, XIA S, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity[J]. Nature, 2020, 579(7799):415-420. doi:10.1038/s41586-020-2071-9
doi: 10.1038/s41586-020-2071-9 |
63 |
SONG X, HUANG H, XIA L, et al. Engineering 2D Multienzyme-Mimicking Pyroptosis Inducers for Ultrasound-Augmented Catalytic Tumor Nanotherapy[J]. Adv Sci (Weinh), 2023, 10(24):e2301279. doi:10.1002/advs.202301279
doi: 10.1002/advs.202301279 |
64 |
CHANG M, WANG Z, DONG C, et al. Ultrasound-Amplified Enzyodynamic Tumor Therapy by Perovskite Nanoenzyme-Enabled Cell Pyroptosis and Cascade Catalysis[J]. Adv Mater, 2023, 35(7):e2208817. doi:10.1002/adma.202208817
doi: 10.1002/adma.202208817 |
65 |
XU K, CHANG M, WANG Z, et al. Multienzyme-Mimicking LaCoO(3) Nanotrigger for Programming Cancer-Cell Pyroptosis[J]. Adv Mater, 2023, 35(35):e2302961. doi:10.1002/adma.202302961
doi: 10.1002/adma.202302961 |
66 |
LI F, ZHANG X Q, HO W, et al. mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy[J]. Nat Commun, 2023, 14(1):4223. doi:10.1038/s41467-023-39938-9
doi: 10.1038/s41467-023-39938-9 |
67 |
CHEN B, YAN Y, YANG Y, et al. A pyroptosis nanotuner for cancer therapy[J]. Nat Nanotechnol, 2022, 17(7):788-798. doi:10.1038/s41565-022-01125-0
doi: 10.1038/s41565-022-01125-0 |
68 |
DING B, CHEN H, TAN J, et al. ZIF-8 Nanoparticles Evoke Pyroptosis for High-Efficiency Cancer Immunotherapy[J]. Angew Chem Int Ed Engl, 2023, 62(10):e202215307. doi:10.1002/anie.202215307
doi: 10.1002/anie.202215307 |
69 |
WANG M, WU M, LIU X, et al. Pyroptosis Remodeling Tumor Microenvironment to Enhance Pancreatic Cancer Immunotherapy Driven by Membrane Anchoring Photosensitizer[J]. Adv Sci (Weinh), 2022, 9(29):e2202914. doi:10.1002/advs.202202914
doi: 10.1002/advs.202202914 |
[1] | Yujun YI,Xiaoming ZHAI,Huiling LIU,Jin. TAO. The role of PTTG1 in colonic inflammation by regulating intestinal epithelial cells pyroptosis [J]. The Journal of Practical Medicine, 2024, 40(5): 632-638. |
[2] | Zhenghao ZHANG,Fang MA,Qing ZHANG,Tongtong XIA,Honglin LIU,Zhigang BAI,Guanjun LU,Jingwen ZHANG,Hongjian PENG,Yideng JIANG,Shengchao. MA. Effect of LncRNA SNHG1 on homocysteine⁃induced podocytespyrophosis [J]. The Journal of Practical Medicine, 2024, 40(4): 476-482. |
[3] | Xiuli SHI,Jiaqi CHEN,Fan ZHU,Juan ZENG,Na. WU. The effect of miR⁃143⁃3p on pyroptosis of ulcerative colitis cells by regulating TLR2/NF⁃κB/NLRP3 [J]. The Journal of Practical Medicine, 2024, 40(15): 2056-2062. |
[4] | Di WANG,Jian YANG,Xiang HE. Dexmedetomidine alleviates propofol induced learning and memory impairment in rats at developmental stage by regulating AKAP150 [J]. The Journal of Practical Medicine, 2024, 40(12): 1619-1624. |
[5] | Xuan QIU,Yishajiang SHAREZATI,Yulan CHEN,Mengmeng WANG,Yu LI,Tulahong GULINAZI,Abuhan ZUBAIDAN,Abulizi ALIYA,Xingchen WANG. Effect of transient receptor potential channel 5 on myocardial pyroptosis in intermittent hypoxia [J]. The Journal of Practical Medicine, 2024, 40(12): 1637-1642. |
[6] | Dan XIE,Shi. OUYANG. Effect of Yinchenhao Decoction combined with exosomes derived from umbilical cord mesenchymal stem cells on acute liver failure and hepatocyte pyroptosis [J]. The Journal of Practical Medicine, 2023, 39(23): 3034-3042. |
[7] | Jiashan LI,Debin YANG,Zhifeng. PENG. Effect of chronic high fat diet on brain injury in ischemia/reperfusion rats and its mechanisms [J]. The Journal of Practical Medicine, 2023, 39(20): 2579-2583. |
[8] | Sha YI,Nan HU,Yue LI,Lin YANG,Yuting ZHANG,Xia XIONG,Guishu ZHONG,Yan. CHEN. Role of peroxisome proliferator⁃activated receptors⁃γ in modulating P. acnes⁃induced pyroptosis, cell proliferation and apoptosis in human keratinocytes [J]. The Journal of Practical Medicine, 2023, 39(16): 2043-2049. |
[9] | . Amygdalin reduces coronary endothelial pyroptosis and ameliorates atherosclerotic plaque formation in ApoE-/- mice [J]. The Journal of Practical Medicine, 2023, 39(14): 1746-1755. |
Viewed | ||||||
Full text |
|
|||||
Abstract |
|
|||||