Login Register Cart 0
Review Article

干细胞分化阶段因素及其在癌症发展过程中触发对称性破坏过程中的作用：将癌细胞重编程为健康表型的量子场理论模型

卷 26, 期 6, 2019

页: [988 - 1001] 页: 14

弟呕挨: 10.2174/0929867324666170920142609

价格: $65

conference banner
摘要

长期的研究历史追求使用在细胞分化过程中分离的胚胎因子，用于将癌细胞转化回健康表型的明确目的。最近的结果澄清了存在于细胞分化的不同阶段的物质 - 我们称之为干细胞分化阶段因子（SCDSF） - 是具有低分子量的蛋白质和调节基因组表达的核酸。本综述总结了在细胞成熟的不同阶段采取的这些物质如何能够阻止许多人肿瘤细胞系的增殖，从而将癌细胞重编程为健康表型。这里提出的模型是量子场论（QFT）模型，其中SCDSF能够在癌症发展期间触发对称性破坏过程。这些对称破缺过程是基本粒子物理学和凝聚态物理学中许多现象的根源，它控制着全能细胞向更高程度的多样性和有序性的相变，从而导致细胞分化。在与胚胎干细胞具有许多基因组和代谢相似性的癌症中，刺激的再分化通常意味着表型逆转回到健康和不扩散。除了作用于细胞周期的关键组分外，SCDSF还能够通过微妙地影响癌症微环境，调节电化学以及生物大分子和间质水域中偶极网络之间的集体电动力行为来重编程癌细胞。源自耗散QFT框架的生物水中的相干效应可在肿瘤实例化发生在特定组织或器官中之前在系统水平上提供新的诊断和治疗靶标。因此，通过将环境作为我们模型的重要组成部分，我们可以将突变驱动的肿瘤发生的普遍范式推向更接近现实的描述。

关键词: 干细胞，癌症干细胞，胚胎，细胞分化，癌细胞重编程，遗传和表观遗传景观，表型逆转，量子场理论，自发对称破缺，电动力学，电磁，微环境，芳香网络，水偶极场，相干水，禁区 ，fractallike自相似性。

« Previous Next »
[1]
Biava, P.M.; Canaider, S.; Facchin, F.; Bianconi, E.; Ljungberg, L.; Rotilio, D.; Burigana, F.; Ventura, C. Stem cell differentiation stage factors from zebrafish embryo: A novel strategy to modulate the fate of normal and pathological human (stem) cells. Curr. Pharm. Biotechnol., 2015, 16(9), 782-792.
[2]
Biava, P.M.; Bonsignorio, D.; Hoxa, M. Life-protecting factor (LPF): An anti-cancer low molecular weight fraction isolated from pregnant uterine mucosa during embryo organogenesis. J. Tumor Marker Oncol., 2000, 15, 223-233.
[3]
Livraghi, T.; Meloni, F.; Frosi, A.; Lazzaroni, S.; Bizzarri, T.M.; Frati, L.; Biava, P.M. Treatment with stem cell differentiation stage factors of intermediate-advanced hepatocellular carcinoma: an open randomized clinical trial. Oncol. Res., 2005, 15(7-8), 399-408.
[4]
Livraghi, T.; Ceriani, R.; Palmisano, A.; Pedicini, V.; Pich, M.G.; Tommasini, M.A.; Torzilli, G. Complete response in 5 out of 38 patients with advanced hepatocellular carcinoma treated with stem cell differentiation stage factors: case reports from a single centre. Curr. Pharm. Biotechnol., 2011, 12(2), 254-260.
[5]
Biava, P.M.; Bonsignorio, D. Cancer and cell differentiation: a model to explain malignancy. J. Tumor Marker Oncol., 2002, 17, 47-54.
[6]
Pierce, G.B. The cancer cell and its control by the embryo. Rous-Whipple Award lecture. Am. J. Pathol., 1983, 113(1), 117-124.
[7]
Biava, P.M.; Nicolini, A.; Ferrari, P.; Carpi, A.; Sell, S. A systemic approach to cancer treatment: Tumor cell reprogramming focused on endocrine-related cancers. Curr. Med. Chem., 2014, 21(9), 1072-1081.
[8]
Mosoyan, G.; Nagi, C.; Marukian, S.; Teixeira, A.; Simonian, A.; Resnick-Silverman, L.; DiFeo, A.; Johnston, D.; Reynolds, S.R.; Roses, D.F.; Mosoian, A. Multiple breast cancer cell-lines derived from a single tumor differ in their molecular characteristics and tumorigenic potential. PLoS One, 2013, 8(1), e55145.
[9]
Botchkina, I.L.; Rowehl, R.A.; Rivadeneira, D.E.; Karpeh, M.S., Jr; Crawford, H.; Dufour, A.; Ju, J.; Wang, Y.; Leyfman, Y.; Botchkina, G.I. Phenotypic subpopulations of metastatic colon cancer stem cells: genomic analysis. Cancer Genomics Proteomics, 2009, 6(1), 19-29.
[10]
Pérez-Caro, M.; Cobaleda, C.; González-Herrero, I.; Vicente-Dueñas, C.; Bermejo-Rodríguez, C.; Sánchez-Beato, M.; Orfao, A.; Pintado, B.; Flores, T.; Sánchez-Martín, M.; Jiménez, R.; Piris, M.A.; Sánchez-García, I. Cancer induction by restriction of oncogene expression to the stem cell compartment. EMBO J., 2009, 28(1), 8-20.
[11]
Plaks, V.; Kong, N.; Werb, Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell, 2015, 16(3), 225-238.
[12]
Itzykson, C.; Zuber, J. Quantum field theory; McGraw-Hill: New York, 1980.
[13]
Umezawa, H. Advanced field theory: micro, macro and thermal concepts., 1993.
[14]
Umezawa, H.; Matsumoto, H.; Tachiki, M. Thermo field dynamics and condensed states., 1982.
[15]
Blasone, M.; Jizba, P.; Vitiello, G. Quantum field theory and its macroscopic manifestations., 2011.
[16]
Vitiello, G. My Double Unveiled; John Benjamins Publishing Company: Amsterdam, 2001.
[17]
Del Giudice, E.; Manka, R.; Milani, M.; Vitiello, G. Non-constant order parameter and vacuum evolution. Phys. Lett. B, 1988, 206, 661-664.
[18]
Preparata, G.; Vitiello, G.; Vitiello, G. Water as a free electric dipole laser. Phys. Rev. Lett., 1988, 61(9), 1085-1088.
[19]
Del Giudice, E.; Vitiello, G. The role of the electromagnetic field in the formation of domains in the process of symmetry breaking phase transitions. Phys. Rev. A, 2006, 74, 022105.
[20]
Alfinito, E.; Vitiello, G. Domain formation in non-instantaneous symmetry-breaking phase transitions. Phys. Rev. B, 2002, 65, 054105.
[21]
Vitiello, G. Coherent states, fractals and brain waves. New Mathematics and Natural Computation, 2009, 5, 245-264.
[22]
Vitiello, G. Fractals, coherent states and self-similarity induced noncommutative geometry. Phys. Lett. A, 2012, 376, 2527-2532.
[23]
Vitiello, G. On the isomorphism between dissipative systems, fractal self-similarity and electrodynamics. Toward an integrated vision of nature. Systems, 2014, 2, 203-216.
[24]
Goldstone, J. Field theories with superconductor solutions. Nuovo Cim., 1961, 19, 154-164.
[25]
Matsumoto, H.; Umezawa, H.; Vitiello, G.; Wyly, J.K. Spontaneous breakdown of a non-Abelian symmetry. Phys. Rev. D Part. Fields, 1974, 9, 2806-2813.
[26]
Shah, M.N.; Umezawa, H.; Vitiello, G. Relation among spin operators and magnons. Phys. Rev. B, 1974, 10, 4724-4736.
[27]
Del Giudice, E.; Doglia, S.; Milani, M.; Vitiello, G. Spontaneous symmetry breakdown and boson condensation in biology. Phys. Lett. A, 1983, 95, 508-510.
[28]
Del Giudice, E.; Doglia, S.; Milani, M.; Vitiello, G. A quantum field theoretical approach to the collective behavior of biological systems., Nucl. Phys. B.,. 1985. 251(FS 13),375-400
[29]
Del Giudice, E.; Doglia, S.; Milani, M.; Vitiello, G. Electromagnetic field and spontaneous symmetry breaking in biological matter., . Nucl. Phys. B. 1986. 275(FS 17), 185-199
[30]
Celeghini, E.; Rasetti, M.; Vitiello, G. Quantum Dissipation. Ann. Phys., 1992, 215, 156-170.
[31]
Peitgen, H.O.; Jürgens, H.; Saupe, D. Chaos and fractals.new frontiers of science; Springer-Verlag: Berlin, 1986.
[32]
Iliopoulos, D.; Hirsch, H.A.; Wang, G.; Struhl, K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc. Natl. Acad. Sci. USA, 2011, 108(4), 1397-1402.
[33]
Cheng, L.; Ramesh, A.V.; Flesken-Nikitin, A.; Choi, J.; Nikitin, A.Y. Mouse models for cancer stem cell research. Toxicol. Pathol., 2010, 38(1), 62-71.
[34]
Welte, Y.; Adjaye, J.; Lehrach, H.R.; Regenbrecht, C.R.A. Cancer stem cells in solid tumors: Elusive or illusive? Cell Commun. Signal., 2010, 8(1), 6.
[35]
Dontu, G.; Liu, S.; Wicha, M.S. Stem cells in mammary development and carcinogenesis: implications for prevention and treatment. Stem Cell Rev., 2005, 1(3), 207-213.
[36]
Cobaleda, C.; Sánchez-García, I. B-cell acute lymphoblastic leukaemia: Towards understanding its cellular origin. BioEssays, 2009, 31(6), 600-609.
[37]
Nagl, W.; Popp, F.A. A physical (electromagnetic) model of differentiation. 1. Basic considerations. Cytobios, 1983, 37(145), 45-62.
[38]
Szent-Györgyi, A. The living state and cancer. Physiol. Chem. Phys., 1980, 12(2), 99-110.
[39]
Preto, J.; Nardecchia, I.; Jaeger, S.; Ferrier, P.; Pettini, M. Investigating encounter dynamics of biomolecular reactions:Long-range resonant interactions versus Brownian collisions. Fields of the Cell., 2015, 215-228.
[40]
Kurian, P.; Dunston, G.; Lindesay, J. How quantum entanglement in DNA synchronizes double-strand breakage by type II restriction endonucleases. J. Theor. Biol., 2016, 391, 102-112.
[41]
Kurian, P.; Capolupo, A.; Craddock, T.J.A.; Vitiello, G. Water-mediated correlations in DNA-enzyme interactions. Phys. Lett. A, 2018, 382(1), 33-43.
[42]
Chernet, B.; Levin, M. Endogenous voltage potentials and the microenvironment: bioelectric signals that reveal, induce and normalize cancer. J. Clin. Exp. Oncol., 2013(Suppl. 1), S1-S002.
[43]
Chang, F.; Minc, N. Electrochemical control of cell and tissue polarity. Annu. Rev. Cell Dev. Biol., 2014, 30, 317-336.
[44]
Rossen, N.S.; Tarp, J.M.; Mathiesen, J.; Jensen, M.H.; Oddershede, L.B. Long-range ordered vorticity patterns in living tissue induced by cell division. Nat. Commun., 2014, 5, 5720.
[45]
Tanner, K.; Mori, H.; Mroue, R.; Bruni-Cardoso, A.; Bissell, M.J. Coherent angular motion in the establishment of multicellular architecture of glandular tissues. Proc. Natl. Acad. Sci. USA, 2012, 109(6), 1973-1978.
[46]
Lineweaver, C.H.; Davies, P.C.W.; Vincent, M.D. Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model. BioEssays, 2014, 36(9), 827-835.
[47]
Arani, R.; Bono, I.; Del Giudice, E.; Preparata, G. QED coherence and the thermodynamics of water. Int. J. Mod. Phys. B, 1995, 139, 1813-1841.
[48]
Landau, L.D. The theory of superfluidity of helium II. J. Phys. (USSR), 1941, 5, 71.
[49]
Germano, R.; Del Giudice, E.; De Ninno, A.; Elia, V.; Hison, C.; Napoli, E.; Tontodonato, V.; Tuccinardi, F.P.; Vitiello, G. Oxhydroelectric effect in bi-distilled water. Key Eng. Mater., 2013, 543, 455-459.
[50]
Germano, R.; Tontodonato, V.; Hison, C.; Cirillo, D.; Tuccinardi, F.P. Oxhydroelectric effect: electricity from water by twin electrodes. Key Eng. Mater., 2012, 495, 100-103.
[51]
Verzegnassi, C. Int. J. Mod. Phys, 2016, 1, 14.
[52]
Kurian, P.; Verzegnassi, C. Quantum field theory treatment of magnetic effects on the spin and orbital angular momentum of a free electron. Phys. Lett. A, 2016, 380(3), 380-, 394-396.
[53]
Blokzijl, F.; de Ligt, J.; Jager, M.; Sasselli, V.; Roerink, S.; Sasaki, N.; Huch, M.; Boymans, S.; Kuijk, E.; Prins, P.; Nijman, I.J.; Martincorena, I.; Mokry, M.; Wiegerinck, C.L.; Middendorp, S.; Sato, T.; Schwank, G.; Nieuwenhuis, E.E.S.; Verstegen, M.M.; van der Laan, L.J.W.; de Jonge, J.; IJzermans, J.N.M.; Vries, R.G.; van de Wetering, M.; Stratton, M.R.; Clevers, H.; Cuppen, E.; van Boxtel, R. Tissue-specific mutation accumulation in human adult stem cells during life. Nature, 2016, 538(7624), 260-264.
[54]
Shackleton, M.; Quintana, E.; Fearon, E.R.; Morrison, S.J. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell, 2009, 138(5), 822-829.
[55]
Visvader, J.E.; Lindeman, G.J. Cancer stem cells: current status and evolving complexities. Cell Stem Cell, 2012, 10(6), 717-728.
[56]
Biava, P.M.; Monguzzi, A.; Bonsignorio, D.; Frosi, A.; Sell, S.; Klavins, J.V. Xenopus laevis embryos share antigens with zebrafish embryos and with human malignant neoplasms J. Tumor Marker Oncol, 2001, 16, 203-206.
[57]
Chen, J.; Chen, Z.L. Technology update for the sorting and identification of breast cancer stem cells. Chin. J. Cancer, 2010, 29(3), 265-269.
[58]
Roesler, R.; Cornelio, D.B.; Abujamra, A.L.; Schwartsmann, G. HER2 as a cancer stem-cell target. Lancet Oncol., 2010, 11(3), 225-226.
[59]
Wu, W. Patents related to cancer stem cell research. Recent Pat. DNA Gene Seq., 2010, 4(1), 40-45.
[60]
Park, S.Y.; Lee, H.E.; Li, H.; Shipitsin, M.; Gelman, R.; Polyak, K. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin. Cancer Res., 2010, 16(3), 876-887.
[61]
Lawson, J.C.; Blatch, G.L.; Edkins, A.L. Cancer stem cells in breast cancer and metastasis. Breast Cancer Res. Treat., 2009, 118(2), 241-254.
[62]
Luo, J.; Yin, X.; Ma, T.; Lu, J. Stem cells in normal mammary gland and breast cancer. Am. J. Med. Sci., 2010, 339(4), 366-370.
[63]
Spiro, S.G.; Tanner, N.T.; Silvestri, G.A.; Janes, S.M.; Lim, E.; Vansteenkiste, J.F.; Pirker, R. Lung cancer: progress in diagnosis, staging and therapy. Respirology, 2010, 15(1), 44-50.
[64]
Gorelik, E.; Lokshin, A.; Levina, V. Lung cancer stem cells as a target for therapy. Anticancer. Agents Med. Chem., 2010, 10(2), 164-171.
[65]
Sullivan, J.P.; Minna, J.D.; Shay, J.W. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer Metastasis Rev., 2010, 29(1), 61-72.
[66]
Westhoff, B.; Colaluca, I.N.; D’Ario, G.; Donzelli, M.; Tosoni, D.; Volorio, G.; Pelosi, G.; Spaggiari, L.; Mazzarol, G.; Viale, G.; Pece, S.; Di Fiore, P.P. Alteration of the notch pathway in lung cancer. Proc. Natl. Acad. Sci. USA, 2010, 87, 457-466.
[67]
Lawson, D.A.; Zong, Y.; Memarzadeh, S.; Xin, L.; Huang, J.; Witte, O.N. Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc. Natl. Acad. Sci. USA, 2010, 107(6), 2610-2615.
[68]
Lang, S.H.; Anderson, E.; Fordham, R.; Collins, A.T. Modeling the prostate stem cell niche: an evaluation of stem cell survival and expansion in vitro. Stem Cells Dev., 2010, 19(4), 537-546.
[69]
Joung, J.Y.; Cho, K.S.; Kim, J.E.; Seo, H.K.; Chung, J.; Park, W.S.; Choi, M.K.; Lee, K.H. Prostate stem cell antigen mRNA in peripheral blood as a potential predictor of biochemical recurrence in high-risk prostate cancer. J. Surg. Oncol., 2010, 101(2), 145-148.
[70]
Liu, T.; Cheng, W.; Lai, D.; Huang, Y.; Guo, L. Characterization of primary ovarian cancer cells in different culture systems. Oncol. Rep., 2010, 23(5), 1277-1284.
[71]
Fong, M.Y.; Kakar, S.S. The role of cancer stem cells and the side population in epithelial ovarian cancer. Histol. Histopathol., 2010, 25(1), 113-120.
[72]
Murphy, S.K. Targeting ovarian cancer-initiating cells. Anticancer. Agents Med. Chem., 2010, 10(2), 157-163.
[73]
Peng, S.; Maihle, N.J.; Huang, Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene, 2010, 29(14), 2153-2159.
[74]
Tomuleasa, C.; Soritau, O.; Rus-Ciuca, D.; Pop, T.; Todea, D.; Mosteanu, O.; Pintea, B.; Foris, V.; Susman, S.; Kacsó, G.; Irimie, A. Isolation and characterization of hepatic cancer cells with stem-like properties from hepatocellular carcinoma. J. Gastrointestin. Liver Dis., 2010, 19(1), 61-67.
[75]
Zou, G.M. Liver cancer stem cells as an important target in liver cancer therapies. Anticancer. Agents Med. Chem., 2010, 10(2), 172-175.
[76]
Lee, T.K.; Castilho, A.; Ma, S.; Ng, I.O. Liver cancer stem cells: Implications for a new therapeutic target. Liver Int., 2009, 29(7), 955-965.
[77]
Marquardt, J.U.; Thorgeirsson, S.S. Stem cells in hepatocarcinogenesis: Evidence from genomic data. Semin. Liver Dis., 2010, 30(1), 26-34.
[78]
Kung, J.W.; Currie, I.S.; Forbes, S.J.; Ross, J.A. Liver development, regeneration, and carcinogenesis. J. Biomed. Biotechnol., 2010, 2010, 984248.
[79]
Gai, H.; Nguyen, D.M.; Moon, Y.J.; Aguila, J.R.; Fink, L.M.; Ward, D.C.; Ma, Y. Generation of murine hepatic lineage cells from induced pluripotent stem cells. Differentiation, 2010, 79(3), 171-181.
[80]
Correia, M.; Machado, J.C.; Ristimäki, A. Basic aspects of gastric cancer. Helicobacter, 2009, 14(Suppl. 1), 36-40.
[81]
Takaishi, S.; Okumura, T.; Tu, S.; Wang, S.S.; Shibata, W.; Vigneshwaran, R.; Gordon, S.A.; Shimada, Y.; Wang, T.C. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells, 2009, 27(5), 1006-1020.
[82]
Nishii, T.; Yashiro, M.; Shinto, O.; Sawada, T.; Ohira, M.; Hirakawa, K. Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma. Cancer Sci., 2009, 100(8), 1397-1402.
[83]
Chen, Z.; Xu, W.R.; Qian, H.; Zhu, W.; Bu, X.F.; Wang, S.; Yan, Y.M.; Mao, F.; Gu, H.B.; Cao, H.L.; Xu, X.J. Oct4, a novel marker for human gastric cancer. J. Surg. Oncol., 2009, 99(7), 414-419.
[84]
Kang, D.H.; Han, M.E.; Song, M.H.; Lee, Y.S.; Kim, E.H.; Kim, H.J.; Kim, G.H.; Kim, D.H.; Yoon, S.; Baek, S.Y.; Kim, B.S.; Kim, J.B.; Oh, S.O. The role of hedgehog signaling during gastric regeneration. J. Gastroenterol., 2009, 44(5), 372-379.
[85]
Yeung, T.M.; Gandhi, S.C.; Wilding, J.L.; Muschel, R.; Bodmer, W.F. Cancer stem cells from colorectal cancer-derived cell lines. Proc. Natl. Acad. Sci. USA, 2010, 107(8), 3722-3727.
[86]
Gulino, A.; Ferretti, E.; De Smaele, E. Hedgehog signalling in colon cancer and stem cells. EMBO Mol. Med., 2009, 1(6-7), 300-302.
[87]
Thenappan, A.; Li, Y.; Shetty, K.; Johnson, L.; Reddy, E.P.; Mishra, L. New therapeutics targeting colon cancer stem cells. Curr. Colorectal Cancer Rep., 2009, 5(4), 209.
[88]
Rasheed, Z.A.; Yang, J.; Wang, Q.; Kowalski, J.; Freed, I.; Murter, C.; Hong, S.M.; Koorstra, J.B.; Rajeshkumar, N.V.; He, X.; Goggins, M.; Iacobuzio-Donahue, C.; Berman, D.M.; Laheru, D.; Jimeno, A.; Hidalgo, M.; Maitra, A.; Matsui, W. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J. Natl. Cancer Inst., 2010, 102(5), 340-351.
[89]
Puri, S.; Hebrok, M. Cellular plasticity within the pancreas--lessons learned from development. Dev. Cell, 2010, 18(3), 342-356.
[90]
Quante, M.; Wang, T.C. Stem cells in gastroenterology and hepatology. Nat. Rev. Gastroenterol. Hepatol., 2009, 6(12), 724-737.
[91]
Sato, A.; Sakurada, K.; Kumabe, T.; Sasajima, T.; Beppu, T.; Asano, K.; Ohkuma, H.; Ogawa, A.; Mizoi, K.; Tominaga, T.; Kitanaka, C.; Kayama, T. Association of stem cell marker CD133 expression with dissemination of glioblastomas. Neurosurg. Rev., 2010, 33(2), 175-183.
[92]
Di Tomaso, T.; Mazzoleni, S.; Wang, E.; Sovena, G.; Clavenna, D.; Franzin, A.; Mortini, P.; Ferrone, S.; Doglioni, C.; Marincola, F.M.; Galli, R.; Parmiani, G.; Maccalli, C. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin. Cancer Res., 2010, 16(3), 800-813.
[93]
Ji, J.; Black, K.L.; Yu, J.S. Glioma stem cell research for the development of immunotherapy. Neurosurg. Clin. N. Am., 2010, 21(1), 159-166.
[94]
Ailles, L.; Prince, M. Cancer stem cells in head and neck squamous cell carcinoma. Methods Mol. Biol., 2009, 568, 175-193.
[95]
Zhang, P.; Zhang, Y.; Mao, L.; Zhang, Z.; Chen, W. Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Lett., 2009, 277(2), 227-234.
[96]
Brunner, M.; Thurnher, D.; Heiduschka, G.; Grasl, M.Ch.; Brostjan, C.; Erovic, B.M. Elevated levels of circulating endothelial progenitor cells in head and neck cancer patients. J. Surg. Oncol., 2008, 98(7), 545-550.

Rights & Permissions Print Cite
Article Metrics
115
7
1
1
© 2024 Bentham Science Publishers | Privacy Policy