Title Page
Contents
ABSTRACT 11
Ⅰ. Introduction 12
Ⅱ. OV Models in Cancer 18
1. General Framework of the OV Basic Model 18
2. Application to Glioblastoma; BTZ Therapy 32
3. Multi-scale Hybrid Model for OV-BTZ Therapy in GBM 37
Ⅲ. Cytokine Shield 49
1. PDE Based Model 52
2. Multi-scale Hybrid Model 60
Ⅳ. Neutrophil Model in Lung Cancer Invasion 70
1. Materials and Methods 72
2. Results 81
Ⅴ. Chemo-brain 103
1. Materials and Method 104
2. Results 109
Ⅵ. Discussion 124
References 134
Abstract (in Korean) 167
Table 1. Parameters used in the OV therapy model. 24
Table 2. OV therapy model parameters for the intracellular dynamics. 46
Table 3. Reference values in the OV therapy model. 49
Table 4. Parameters used in the cytokine shield model. 56
Table 5. Parameters used in the cytokine shield model (Continued from Table 4). 57
Table 6. Reference values in the cytokine shield model. 58
Table 7. Parameters used in the neutrophil model. 79
Table 8. Parameters used in the neutrophil model (Continued from Table 7) 80
Table 9. Reference values in the neutrophil model. 81
Table 10. Parameters used in the chemo-brain model. 110
Table 11. Parameters used in the chemo-brain model (Continued from Table 10). 111
Table 12. Reference values used in the chemo-brain model. 112
Figure 1. A schematic illustration of OV therapy model. 19
Figure 2. Effect of OV on tumor growth. 25
Figure 3. Dynamics of OV infection and tumor growth for various infection rates (basic model). 26
Figure 4. Effect of the dissolution rate on OV infection and tumor growth (basic model). 27
Figure 5. Effect of the growth rate of tumor on OV infection and tumor growth (basic model). 29
Figure 6. Effect of the carrying capacity of the tumor on OV infection and tumor growth (basic model). 30
Figure 7. Sensitivity analysis of the basic OV model. 32
Figure 8. Synergistic effect of OV+BTZ combination therapy on tumor growth. 34
Figure 9. Effect of the injection rate of BTZ on OV infection and tumor growth. 35
Figure 10. Sensitivity analysis of the OV+BTZ model. 37
Figure 11. A schematic diagram of the cell's movement rules in agent based model. 41
Figure 12. A schematic diagram of the multi-scale hybrid model. 42
Figure 13. A schematic diagram of the role of BTZ and OVs in regulation of apoptosis and necroptosis. 43
Figure 14. Influence of dynamic BTZ fluctuations on the transition from Tt to Ta in the absence of OVs.[이미지참조] 47
Figure 15. Dynamics of tumor progression and OV+BTZ combination therapy. 48
Figure 16. Dynamics of tumor progression in each domain in OV+BTZ therapy. 50
Figure 17. A schematic diagram of cytokine shield model. 51
Figure 18. Dynamics of the system. 59
Figure 19. CXCL12-promoted T cell invasion. 60
Figure 20. CXCL12-mediated nonlinear regulation of T cell invasion. 61
Figure 21. Effect of the parameters in the CXCL12-CXCR4 binding kinetics on T cell invasion. 62
Figure 22. A schematic diagram of the T cell's movement rules in the agent based model. 63
Figure 23. A schematic diagram of the multi-scale hybrid model in cytokine shield. 66
Figure 24. Role of STCs in infiltration of T cells. 67
Figure 25. Effect of chemotaxis and random walk ratio on infiltration of T cells. 68
Figure 26. Effect of the TME on T cell infiltration and anti-CXCL12 therapy. 71
Figure 27. Network of interactions among tumor cells, immune cells, and cytokines/chemokines 72
Figure 28. Local N1/N2 dynamics. 83
Figure 29. Dynamics of the N1/N2 and NE system. 84
Figure 30. Effect of chemotaxis of neutrophils on the tumor system. 86
Figure 31. Effect of the NE-mediated enhancement parameter αE on the N2-to-N1 ratio and tumor growth.[이미지참조] 87
Figure 32. Effect of fluctuating TGF-ß on tumor growth. 89
Figure 33. Effect of NE inhibition on tumor growth. 91
Figure 34. Anti-chemotaxis therapy by injecting a TGF-ß inhibitor 93
Figure 35. Therapeutic effect of IFN-ß on tumor growth. 96
Figure 36. Therapeutic effect of a combination therapy (DNase + IFN-ß) on tumor growth. 97
Figure 37. Effect of the N21R distribution and δ on tumor growth. 101
Figure 38. Anti-tumor effect by negating chemotaxis through DNase I 102
Figure 39. A schematic diagram of TZB and ATV combination therapy. 104
Figure 40. A schematic diagram of the role of ATV and TZB in regulation of apoptosis. 113
Figure 41. Role of ATV and TZB in regulation of apoptosis. 114
Figure 42. Effect of TZB treatment on tumor growth and chemo-brain expression. 117
Figure 43. Apoptosis system in response to ATV infusion. 119
Figure 44. Optimized treatment strategy. 120
Figure 45. A schematic diagram of breast cancer-induced chemo-brain in brain tissue. 121
Figure 46. Dynamics of the intracellular system in response to onset of CSCs in either brain or breast. 123
Figure 47. Effect of the location of CSC expression on chemo-brain. 124
Figure 48. Anti-cancer and anti-chemo efficacy in TZB-ATV combination therapy. 125