2011, 8(2): 279-287. doi: 10.3934/mbe.2011.8.279

Questions from the fourth son: A clinician reflects on immunomonitoring, surrogate markers and systems biology

1. 

Wiseman Research Initiatives, LLC., 756 Fairfield Circle, Pasadena, CA 91106, United States

Received  May 2010 Revised  November 2010 Published  April 2011

The fourth son is the one who doesn't even know how to ask a question. Tumor immunology is challenged by the failure to identify reliable surrogate markers in vaccine and other experimental therapies for cancer; perhaps investigators haven't yet asked the right questions. Unlike prophylactic vaccines for infectious disease, where the development of antibody is considered a satisfactory endpoint, no such endpoint exists for human therapeutic vaccines. Why is this? Despite an extensive roster of in vitro assays that correlate immune responses to favorable clinical outcomes, no assay is sufficiently reliable to be usefully predictive for vaccine therapy. The discussion reviews some of the historical developments in tumor immunology and the problem of defining a causal relationship when strong correlations are identified. The development of mathematical models from empirical data may help inform the clinician/scientist about underlying mechanisms and help frame new testable hypotheses.
Citation: Charles Wiseman, M.D.. Questions from the fourth son: A clinician reflects on immunomonitoring, surrogate markers and systems biology. Mathematical Biosciences & Engineering, 2011, 8 (2) : 279-287. doi: 10.3934/mbe.2011.8.279
References:
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[2]

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[3]

M. M. Black, R. E. Zachrau, B. Shore, A. S. Dion and H. P. Leis Jr, Cellular emmunity to autologous breast cancer and R111-murine mammary tumor virus preparations,, Cancer Research, 38 (1978), 2068. Google Scholar

[4]

R. A. Blades, P. J. Keating, L. J. McWilliam, N. J. R. George and Peter L. Stern, Loss of HLA class 1 expression in prostrate cancer: implications for immunotherapy,, Urology, 46 (1995), 681. doi: 10.1016/S0090-4295(99)80301-X. Google Scholar

[5]

V. Bronte and S. Mocellin, Suppressive influences in the immune response to cancer,, Journal of Immunotherapy, 32 (2009), 1. doi: 10.1097/CJI.0b013e3181837276. Google Scholar

[6]

L. H. Butterfield, M. L. Disis, B. A. Fox, P. P. Lee, S. N. Khleif, M. Thurin, G. Trinchieri, E. Wang, J. Wigginton, D. Chaussabel, G. Coukos, M. Dhodapkar, L. H\aa kansson, S. Janetzki, T. O. Kleen, J. M. Kirkwood, C. Maccalli, H. Maecker, M. Maio, A. Malyguine, G. Masucci, A. K. Palucka, D. M. Potter, A. Ribas, L. Rivoltini, D. Schendel, B. Seliger, S. Selvan, C. L. Slingluff Jr, D. F. Stroncek, H. Streicher, X. Wu, B. Zeskind, Y. Zhao, M. B. Zocca, H. Zwierzina and F. M. Marincola, A systematic approach to biomarker discovery,, preamble to, 6 (2008). Google Scholar

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A. G. Dalgleish and B. R. Souberbielle, The development of therapeutic vaccines for the management of malignant melanoma,, Cancer Survey, 26 (1996), 289. Google Scholar

[9]

L. G. de Pillis, A. E. Radunskaya and C. L. Wiseman, A validated mathematical model of cell-mediated immune response to tumor growth,, Cancer Research, 65 (2005), 7950. Google Scholar

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A. Diefenbach, E. Jensen, A. Jamieson and D. Raulet, Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity,, Nature, 413 (2001), 165. doi: 10.1038/35093109. Google Scholar

[11]

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J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pagès, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoué, P. Bruneval, P-H Cugnenc, Z. Trajanoski, W-H Fridman and F. Pagès, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome,, Science, 313 (2006), 1960. doi: 10.1126/science.1129139. Google Scholar

[16]

A. M. Hicks, Transferable anticancer innate immunity in spontaneous regression/complete resistance mice,, PNAS, 103 (2006), 7753. doi: 10.1073/pnas.0602382103. Google Scholar

[17]

K. Klages, C. T. Mayer, K. Lahl, C. Loddenkemper, M. W. L. Teng, S. F. Ngiow, M. J. Smyth, A. Hamann, J. Huehn and T. Sparwasser, Selective depletion of Foxp3$^+$ regulatory T cells improves effective therapeutic vaccination against established melanoma,, Cancer Research, 70 (2010), 7788. doi: 10.1158/0008-5472.CAN-10-1736. Google Scholar

[18]

K. -H. Lee, E. Wang, M. B. Nielsen, J. Wunderlich, S. Migueles, M. Connors, S. M. Steinberg, S. A. Rosenberg and F. M. Marincola, Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility in in-vitro stimulation but does not lead to tumor regression,, J. Immunol., 163 (1999), 6292. Google Scholar

[19]

T. W. T. Leung, Y. Z. Patt, L. Wan-Yee, S. K. W. Ho, S. C. H. Yu, A. T. C. Chan, T. S. K. Mok, W. Yeo, Choong-tsek Liew, N. W. Y. Leung, A. M. Y. Tang and P. J. Johnson, Complete pathological remission is possible with septemic combination chemotherapy for inoperable hepatocellular carcinoma,, Clinical Cancer Research, 5 (1999), 1676. Google Scholar

[20]

K. S. S. D. Mandrekar, Clinical trial designs for predictive biomarker validation: Theoretical considerations and practical challenges,, JCO, 27 (2009), 4027. doi: 10.1200/JCO.2009.22.3701. Google Scholar

[21]

F. M. Marincola, L. Rivoltini, M. L. Salgaller, M. Player and S. A. Rosenberg, Differential anti-MART-1/MelanA CTL activity in peripheral blook of HLA-A2 melanoma patients in comparison to healthy donors: evidence for in-vivo priming by tumor cells,, J. Immunother. Emphasis Tumor Immunol, 19 (1996), 266. Google Scholar

[22]

, "Mathematical Methods in Systems Biology,", Tel Aviv University, (2010), 7. Google Scholar

[23]

A. F. Ochsenbein, S. Sierro, B. Odermatt, M. Pericin, U. Karrer, J. Hermans, S. Hemmi, H. Hengartner and R. M. Zinkernagel, Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction [Erratum appears in Nature 2001 Sep 13;413(6852):183],, Nature, 411 (2001), 1058. Google Scholar

[24]

V. Rom-Kedar, "Models of the Innate Immune System: Theory and Medical Implications,'', Presentation, (2010). Google Scholar

[25]

S. Rosenberg, R. M. Sherry, K. E. Morton, W. J. Scharfman, J. C. Yang, S. L. Topalian, R. E. Royal, U. Kammula, N. P. Restifo, M. S. Hughes, D. Schwartzentruber, D. M. Berman, S. L. Schwarz, L. T. Ngo, S. A. Mavroukakis, D. E. White and S. M. Steinberg, Tumor progression can occur despite the induction of very high levelsof Self/Tumor antigen-specific CD8+ t cells in Patiens w Melanoma,, J immunol, 175 (2005), 6175. Google Scholar

[26]

J. Schlom, P. M. Arlen, J. L. Gulley, Cancer vaccines: Moving beyond current paradigms,, Clinical Cancer Research, 13 (2007), 3776. doi: 10.1158/1078-0432.CCR-07-0588. Google Scholar

[27]

J. Schlom, J. L. Gulley, P. M. Arlen, Paradigm shifts in cancer vaccine therapy,, Experimental Biology and Medicine, 233 (2008), 522. doi: 10.3181/0708-MR-226. Google Scholar

[28]

, "Smoking and Health,'', Report of the Advisory Committee to the Surgeon General of the Public Health Service, (1103). Google Scholar

[29]

M. Susser, What is a cause and how do we know one? A grammar for pragmatic epidemiology,, Am. J. of Epidemiology, 133 (1991), 635. Google Scholar

[30]

P. Tieri, S. Valensin, V. Latora, G. C. Castellani, M. Marchiori, D. Remondini and C. Franceschi, Quantifying the relevance of different mediators in the human immune cell network,, Bioinformatics, 21 (2005), 1639. doi: 10.1093/bioinformatics/bti239. Google Scholar

[31]

E. Wang, A. Monaco, V. MonsurrÃ, M. Sabatino, Z. Pos, L. Uccellini, J. Wang, A. Worschech, D. F. Stroncek and F. M. Marincola, Antitumor vaccines, immunotherapy and the immunological constant of rejection,, Idrugs, 12 (2009), 297. Google Scholar

[32]

E. Wang, A. Worschech and F. M. Marincola, The immunologic constant of rejection,, Trends in Immunology, 29 (2008), 256. doi: 10.1016/j.it.2008.03.002. Google Scholar

[33]

T. L. Whiteside, Anti-tumor vaccines in head and neck cancer: Targeting immune responses to the tumor,, Current Cancer Drug Targets, 7 (2007), 633. doi: 10.2174/156800907782418310. Google Scholar

[34]

C. Wiseman, R. Cailleau, M. Olivé, G. R. Blumenschein and J. M. Bowen, Autologous and homologous immunofluorescent antibody to established breast cancer cell lines,, In Vitro, 16 (1980), 629. doi: 10.1007/BF02618388. Google Scholar

[35]

C. Wiseman, C. Presant, R. Rao and J. Smith, Clinical responses to intralymphatic whole-cell melanoma vaccine augmented by in vitro incubation with alpha-interferon,, Ann. N.Y. Acad. Sci., 690 (1993), 388. doi: 10.1111/j.1749-6632.1993.tb44040.x. Google Scholar

[36]

C. L. Wiseman and A. Kharazi, Objective clinical regression of metastatic breast cancer in disparate sites after use of whole-cell vaccine genetically modified to release sargramostim,, Breast Journal, 12 (2006), 475. doi: 10.1111/j.1075-122X.2006.00319.x. Google Scholar

[37]

J. D. Wolchok and P. B. Chapman, How can we tell when cancer vaccines vaccinate,, J. Clin. Oncol., 21 (2003), 586. doi: 10.1200/JCO.2003.12.065. Google Scholar

[38]

J. D. Wolchok, A. Hoos, S. O'Day, J. S. Weber, O. Hamid, C. Lebbé, M. Maio, M. Binder, O. Bohnsack, G. Nichol, R. Humphrey and F. S. Hodi, Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria,, Clinical Cancer Research, 15 (2009), 7412. doi: 10.1158/1078-0432.CCR-09-1624. Google Scholar

[39]

A. Worschech, M. Kmieciak, K. L. Knutson, H. D. Bear, A. A. Szalay, E. Wang, F. M. Marincola and M. H. Manjili, Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors,, Cancer Res., 68 (2008), 2436. doi: 10.1158/0008-5472.CAN-07-6822. Google Scholar

[40]

L. Zaritskaya, K. A. Shafer-Weaver, M. K. Gregory, S. L. Strobl, M. Baseler and A. Malyguine, Application of a flow cytometric cytotoxicity assay for monitoring cancer vaccine trials,, Journal of Immunotherapy, 32 (2009), 186. doi: 10.1097/CJI.0b013e318197b1b2. Google Scholar

show all references

References:
[1]

D. Berd, H. Maguire Jr. and M. Mastrangelo, Induction of cell mediated immunity to autologous melanomic cells and regression of metatases,, Cancer Research, 46 (1986), 2572. Google Scholar

[2]

D. Bernstein, G. E. Williams, H. Eisen, S. Mital, J. G. Wohlgemuth, T. M. Klingler, K. C. Fang, M. C. Deng and J. Kobashigawa, Gene expression profiling distinguishes a molecular signature for grade 1B mild acute cellular rejection in cardiac allograft recipients,, The Journal of Heart and Lung Transplantation, 26 (2007). doi: 10.1016/j.healun.2007.09.017. Google Scholar

[3]

M. M. Black, R. E. Zachrau, B. Shore, A. S. Dion and H. P. Leis Jr, Cellular emmunity to autologous breast cancer and R111-murine mammary tumor virus preparations,, Cancer Research, 38 (1978), 2068. Google Scholar

[4]

R. A. Blades, P. J. Keating, L. J. McWilliam, N. J. R. George and Peter L. Stern, Loss of HLA class 1 expression in prostrate cancer: implications for immunotherapy,, Urology, 46 (1995), 681. doi: 10.1016/S0090-4295(99)80301-X. Google Scholar

[5]

V. Bronte and S. Mocellin, Suppressive influences in the immune response to cancer,, Journal of Immunotherapy, 32 (2009), 1. doi: 10.1097/CJI.0b013e3181837276. Google Scholar

[6]

L. H. Butterfield, M. L. Disis, B. A. Fox, P. P. Lee, S. N. Khleif, M. Thurin, G. Trinchieri, E. Wang, J. Wigginton, D. Chaussabel, G. Coukos, M. Dhodapkar, L. H\aa kansson, S. Janetzki, T. O. Kleen, J. M. Kirkwood, C. Maccalli, H. Maecker, M. Maio, A. Malyguine, G. Masucci, A. K. Palucka, D. M. Potter, A. Ribas, L. Rivoltini, D. Schendel, B. Seliger, S. Selvan, C. L. Slingluff Jr, D. F. Stroncek, H. Streicher, X. Wu, B. Zeskind, Y. Zhao, M. B. Zocca, H. Zwierzina and F. M. Marincola, A systematic approach to biomarker discovery,, preamble to, 6 (2008). Google Scholar

[7]

D. L. Chao, M. P. Davenport, S. Forrest and A. S. Perelson, A stochastic model of cytotoxic T cell responses,, Journal of Theoretical Biology, 228 (2004), 227. doi: 10.1016/j.jtbi.2003.12.011. Google Scholar

[8]

A. G. Dalgleish and B. R. Souberbielle, The development of therapeutic vaccines for the management of malignant melanoma,, Cancer Survey, 26 (1996), 289. Google Scholar

[9]

L. G. de Pillis, A. E. Radunskaya and C. L. Wiseman, A validated mathematical model of cell-mediated immune response to tumor growth,, Cancer Research, 65 (2005), 7950. Google Scholar

[10]

A. Diefenbach, E. Jensen, A. Jamieson and D. Raulet, Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity,, Nature, 413 (2001), 165. doi: 10.1038/35093109. Google Scholar

[11]

M. L. Disis, V. Goodell, K. Schiffman and K. L. Knutson, Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients,, Journal of Clinical Immunology, 24 (2004), 571. doi: 10.1023/B:JOCI.0000040928.67495.52. Google Scholar

[12]

M. E. Dudley, J. R. Wunderlich, P. F. Robbins, J. C. Yang, P. Hwu, D. J. Schwartzentruber, S. L. Topalian, R. Sherry, N. P. Restifo, A. M. Hubicki, M. R. Robinson, M. Raffeld, P. Duray, C. A. Seipp, L. Rogers-Freezer, K. E. Morton, S. A. Mavroukakis, D. E. White and S. A. Rosenberg, Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes,, Science, 298 (2002), 850. doi: 10.1126/science.1076514. Google Scholar

[13]

B. Eibl, H. Schwaighofer, D. Nachbaur, C. Marth, A. Gächter, R. Knapp, G. Böck, C. Gassner, L. Schiller, F. Petersen and D. Niederwieser, Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer,, Blood, 88 (1996), 1501. Google Scholar

[14]

A. M. F. Fulton, A. Weise and Wei Wei-Zen, Prospects of controlling breast cancer metastasis by immune intervention,, Breast disease, 26 (2006), 115. Google Scholar

[15]

J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pagès, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoué, P. Bruneval, P-H Cugnenc, Z. Trajanoski, W-H Fridman and F. Pagès, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome,, Science, 313 (2006), 1960. doi: 10.1126/science.1129139. Google Scholar

[16]

A. M. Hicks, Transferable anticancer innate immunity in spontaneous regression/complete resistance mice,, PNAS, 103 (2006), 7753. doi: 10.1073/pnas.0602382103. Google Scholar

[17]

K. Klages, C. T. Mayer, K. Lahl, C. Loddenkemper, M. W. L. Teng, S. F. Ngiow, M. J. Smyth, A. Hamann, J. Huehn and T. Sparwasser, Selective depletion of Foxp3$^+$ regulatory T cells improves effective therapeutic vaccination against established melanoma,, Cancer Research, 70 (2010), 7788. doi: 10.1158/0008-5472.CAN-10-1736. Google Scholar

[18]

K. -H. Lee, E. Wang, M. B. Nielsen, J. Wunderlich, S. Migueles, M. Connors, S. M. Steinberg, S. A. Rosenberg and F. M. Marincola, Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility in in-vitro stimulation but does not lead to tumor regression,, J. Immunol., 163 (1999), 6292. Google Scholar

[19]

T. W. T. Leung, Y. Z. Patt, L. Wan-Yee, S. K. W. Ho, S. C. H. Yu, A. T. C. Chan, T. S. K. Mok, W. Yeo, Choong-tsek Liew, N. W. Y. Leung, A. M. Y. Tang and P. J. Johnson, Complete pathological remission is possible with septemic combination chemotherapy for inoperable hepatocellular carcinoma,, Clinical Cancer Research, 5 (1999), 1676. Google Scholar

[20]

K. S. S. D. Mandrekar, Clinical trial designs for predictive biomarker validation: Theoretical considerations and practical challenges,, JCO, 27 (2009), 4027. doi: 10.1200/JCO.2009.22.3701. Google Scholar

[21]

F. M. Marincola, L. Rivoltini, M. L. Salgaller, M. Player and S. A. Rosenberg, Differential anti-MART-1/MelanA CTL activity in peripheral blook of HLA-A2 melanoma patients in comparison to healthy donors: evidence for in-vivo priming by tumor cells,, J. Immunother. Emphasis Tumor Immunol, 19 (1996), 266. Google Scholar

[22]

, "Mathematical Methods in Systems Biology,", Tel Aviv University, (2010), 7. Google Scholar

[23]

A. F. Ochsenbein, S. Sierro, B. Odermatt, M. Pericin, U. Karrer, J. Hermans, S. Hemmi, H. Hengartner and R. M. Zinkernagel, Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction [Erratum appears in Nature 2001 Sep 13;413(6852):183],, Nature, 411 (2001), 1058. Google Scholar

[24]

V. Rom-Kedar, "Models of the Innate Immune System: Theory and Medical Implications,'', Presentation, (2010). Google Scholar

[25]

S. Rosenberg, R. M. Sherry, K. E. Morton, W. J. Scharfman, J. C. Yang, S. L. Topalian, R. E. Royal, U. Kammula, N. P. Restifo, M. S. Hughes, D. Schwartzentruber, D. M. Berman, S. L. Schwarz, L. T. Ngo, S. A. Mavroukakis, D. E. White and S. M. Steinberg, Tumor progression can occur despite the induction of very high levelsof Self/Tumor antigen-specific CD8+ t cells in Patiens w Melanoma,, J immunol, 175 (2005), 6175. Google Scholar

[26]

J. Schlom, P. M. Arlen, J. L. Gulley, Cancer vaccines: Moving beyond current paradigms,, Clinical Cancer Research, 13 (2007), 3776. doi: 10.1158/1078-0432.CCR-07-0588. Google Scholar

[27]

J. Schlom, J. L. Gulley, P. M. Arlen, Paradigm shifts in cancer vaccine therapy,, Experimental Biology and Medicine, 233 (2008), 522. doi: 10.3181/0708-MR-226. Google Scholar

[28]

, "Smoking and Health,'', Report of the Advisory Committee to the Surgeon General of the Public Health Service, (1103). Google Scholar

[29]

M. Susser, What is a cause and how do we know one? A grammar for pragmatic epidemiology,, Am. J. of Epidemiology, 133 (1991), 635. Google Scholar

[30]

P. Tieri, S. Valensin, V. Latora, G. C. Castellani, M. Marchiori, D. Remondini and C. Franceschi, Quantifying the relevance of different mediators in the human immune cell network,, Bioinformatics, 21 (2005), 1639. doi: 10.1093/bioinformatics/bti239. Google Scholar

[31]

E. Wang, A. Monaco, V. MonsurrÃ, M. Sabatino, Z. Pos, L. Uccellini, J. Wang, A. Worschech, D. F. Stroncek and F. M. Marincola, Antitumor vaccines, immunotherapy and the immunological constant of rejection,, Idrugs, 12 (2009), 297. Google Scholar

[32]

E. Wang, A. Worschech and F. M. Marincola, The immunologic constant of rejection,, Trends in Immunology, 29 (2008), 256. doi: 10.1016/j.it.2008.03.002. Google Scholar

[33]

T. L. Whiteside, Anti-tumor vaccines in head and neck cancer: Targeting immune responses to the tumor,, Current Cancer Drug Targets, 7 (2007), 633. doi: 10.2174/156800907782418310. Google Scholar

[34]

C. Wiseman, R. Cailleau, M. Olivé, G. R. Blumenschein and J. M. Bowen, Autologous and homologous immunofluorescent antibody to established breast cancer cell lines,, In Vitro, 16 (1980), 629. doi: 10.1007/BF02618388. Google Scholar

[35]

C. Wiseman, C. Presant, R. Rao and J. Smith, Clinical responses to intralymphatic whole-cell melanoma vaccine augmented by in vitro incubation with alpha-interferon,, Ann. N.Y. Acad. Sci., 690 (1993), 388. doi: 10.1111/j.1749-6632.1993.tb44040.x. Google Scholar

[36]

C. L. Wiseman and A. Kharazi, Objective clinical regression of metastatic breast cancer in disparate sites after use of whole-cell vaccine genetically modified to release sargramostim,, Breast Journal, 12 (2006), 475. doi: 10.1111/j.1075-122X.2006.00319.x. Google Scholar

[37]

J. D. Wolchok and P. B. Chapman, How can we tell when cancer vaccines vaccinate,, J. Clin. Oncol., 21 (2003), 586. doi: 10.1200/JCO.2003.12.065. Google Scholar

[38]

J. D. Wolchok, A. Hoos, S. O'Day, J. S. Weber, O. Hamid, C. Lebbé, M. Maio, M. Binder, O. Bohnsack, G. Nichol, R. Humphrey and F. S. Hodi, Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria,, Clinical Cancer Research, 15 (2009), 7412. doi: 10.1158/1078-0432.CCR-09-1624. Google Scholar

[39]

A. Worschech, M. Kmieciak, K. L. Knutson, H. D. Bear, A. A. Szalay, E. Wang, F. M. Marincola and M. H. Manjili, Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors,, Cancer Res., 68 (2008), 2436. doi: 10.1158/0008-5472.CAN-07-6822. Google Scholar

[40]

L. Zaritskaya, K. A. Shafer-Weaver, M. K. Gregory, S. L. Strobl, M. Baseler and A. Malyguine, Application of a flow cytometric cytotoxicity assay for monitoring cancer vaccine trials,, Journal of Immunotherapy, 32 (2009), 186. doi: 10.1097/CJI.0b013e318197b1b2. Google Scholar

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