Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Review

A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12

Author: David J Klinke II

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales.
Appendix
Available only for authorised users
Literature
1.
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999, 17: 2639-2648.PubMed
2.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001, 344: 783-792. 10.1056/NEJM200103153441101PubMedCrossRef
3.
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989, 244: 707-712. 10.1126/science.2470152PubMedCrossRef
4.
Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Leahy DJ: Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003, 421: 756-760. 10.1038/nature01392PubMedCrossRef
5.
Franklin MC, Carey KD, Vajdos FF, Leahy DJ, Vos AM, Sliwkowski MX: Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004, 5: 317-328. 10.1016/S1535-6108(04)00083-2PubMedCrossRef
6.
Yarden Y: Biology of HER2 and Its Importance in Breast Cancer. Oncology. 2001, 61: 1-13. 10.1159/000055396PubMedCrossRef
7.
Cardoso F, Piccart MJ, Durbecq V, DiLeo A: Resistance to trastuzumab: a necessary evil or a temporary challenge?. Clin Breast Cancer. 2002, 3: 247-257. 10.3816/CBC.2002.n.028PubMedCrossRef
8.
9.
Jones KL, Buzdar AU: Evolving novel anti-HER2 strategies. Lancet Oncol. 2009, 10: 1179-1187. 10.1016/S1470-2045(09)70315-8PubMedCrossRef
10.
11.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002, 3: 991-998. 10.1038/ni1102-991PubMedCrossRef
12.
Dunn GP, Old LJ, Schreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol. 2004, 22: 329-360. 10.1146/annurev.immunol.22.012703.104803PubMedCrossRef
13.
14.
Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, Presky DH: The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol. 1998, 16: 495-521. 10.1146/annurev.immunol.16.1.495PubMedCrossRef
15.
Trinchieri G: Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003, 3: 133-146. 10.1038/nri1001PubMedCrossRef
16.
Murphy FJ, Hayes MP, Burd PR: Disparate intracellular processing of human IL-12 preprotein subunits: atypical processing of the P35 signal peptide. J Immunol. 2000, 164: 839-847.PubMedCrossRef
17.
Heinzel FP, Hujer AM, Ahmed FN, Rerko RM: In vivo production and function of IL-12 p40 homodimers. J Immunol. 1997, 158: 4381-4388.PubMed
18.
Ha SJ, Chang J, Song MK, Suh YS, Jin HT, Lee CH, Nam GH, Choi G, Choi KY, Lee SH, Kim WB, Sung YC: Engineering N-glycosylation mutations in IL-12 enhances sustained cytotoxic T lymphocyte responses for DNA immunization. Nat Biotechnol. 2002, 20: 381-386. 10.1038/nbt0402-381PubMedCrossRef
19.
Ling P, Gately MK, Gubler U, Stern AS, Lin P, Hollfelder K, Su C, Pan YC, Hakimi J: Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J Immunol. 1995, 154: 116-127.PubMed
20.
Klinke DJ: The Ratio of P40 Monomer to Dimer is an Important Determinant of IL-12 Bioactivity. J Theor Biol. 2006, 240: 323-335. 10.1016/j.jtbi.2005.09.022PubMedCrossRef
21.
Colombo MP, Trinchieri G: Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 2002, 13: 155-168. 10.1016/S1359-6101(01)00032-6PubMedCrossRef
22.
Bekaii-Saab TS, Roda JM, Guenterberg KD, Ramaswamy B, Young DC, Ferketich AK, Lamb TA, Grever MR, Shapiro CL, W E, Carson I: A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies. Mol Cancer Ther. 2009, 8: 2983-2991. 10.1158/1535-7163.MCT-09-0820PubMedCentralPubMedCrossRef
23.
Parihar R, Nadella P, Lewis A, Jensen R, De HC, Dierksheide JE, VanBuskirk AM, Magro CM, Young DC, Shapiro CL, W E, Carson I: A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients. Clin Cancer Res. 2004, 10: 5027-5037. 10.1158/1078-0432.CCR-04-0265PubMedCrossRef
24.
Parihar R, Dierksheide J, Hu Y, Carson WE: IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells. J Clin Invest. 2002, 110: 983-992.PubMedCentralPubMedCrossRef
25.
26.
Ahn AC, Tewari M, Poon CS, Phillips RS: The limits of reductionism in medicine: Could systems biology offer an alternative?. PLoS Medicine. 2006, 3: 709-713.
27.
Ramkrishna D, Amundson NR: Mathematics in chemical engineering: A 50 year introspection. AIChE J. 2004, 50: 7-23. 10.1002/aic.10002.CrossRef
28.
Ottino JM: New Tools, New Outlooks, New Opportunities. AIChE J. 2005, 51: 1840-1845. 10.1002/aic.10616.CrossRef
29.
Vincenti WG: What Engineers Know and How They Know It. 1990, Baltimore: John Hopkins Press
30.
Lander ES, Weinberg RA: Genomics: Journey to the Center of Biology. Science. 2000, 287: 1777-1782. 10.1126/science.287.5459.1777PubMedCrossRef
31.
McGraw-Hill Concise Encyclopedia of Engineering. 2005, --- Either first page or author must be supplied. New York: McGraw-Hill Professional
32.
Okino MS, Mavrovouniotis ML: Simplification of chemical reaction systems by time-scale analysis. Chem Eng Commun. 1999, 176: 115-131. 10.1080/00986449908912149.CrossRef
33.
Haken H: Synergetics Introduction and Advanced Topics. 2004, New York, NY: Springer-Verlag
34.
Delgado J, Liao JC: Control of metabolic pathways by time-scale separation. Biosystems. 1995, 36: 55-70. 10.1016/0303-2647(95)01528-SPubMedCrossRef
35.
Jamshidi N, Palsson BO: Top-down analysis of temporal hierarchy in biochemical reaction networks. PLoS Comput Biol. 2008, 4: e1000177- 10.1371/journal.pcbi.1000177PubMedCentralPubMedCrossRef
36.
Weisz PB: Diffusion and chemical transformation. Science. 1973, 179: 433-440. 10.1126/science.179.4072.433PubMedCrossRef
37.
van Osdol W, Fujimori K, Weinstein JN: An analysis of monoclonal antibody distribution in microscopic tumor nodules: consequences of a "binding site barrier". Cancer Res. 1991, 51: 4776-4784.PubMed
38.
Thurber GM, Zajic SC, Wittrup KD: Theoretic criteria for antibody penetration into solid tumors and micrometastases. J Nucl Med. 2007, 48: 995-999. 10.2967/jnumed.106.037069PubMedCrossRef
39.
Anderson AR, Quaranta V: Integrative mathematical oncology. Nat Rev Cancer. 2008, 8: 227-234. 10.1038/nrc2329PubMedCrossRef
40.
Asthagiri AR, Lauffenburger DA: Bioengineering Models of Cell Signaling. Ann Rev Biomed Eng. 2000, 2: 31-53. 10.1146/annurev.bioeng.2.1.31.CrossRef
41.
Pawson T, Nash P: Assembly of Cell Regulatory Systems Through Protein Interaction Domains. Science. 2003, 300: 445-452. 10.1126/science.1083653PubMedCrossRef
42.
Hilser VJ: Biochemistry. An ensemble view of allostery. Science. 2010, 327: 653-654. 10.1126/science.1186121PubMedCrossRef
43.
Almlof M, Aqvist J, Smalas AO, Brandsdal BO: Probing the effect of point mutations at protein-protein interfaces with free energy calculations. Biophys J. 2006, 90: 433-442. 10.1529/biophysj.105.073239PubMedCentralPubMedCrossRef
44.
Jones RB, Gordus A, Krall JA, MacBeath G: A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature. 2006, 439: 168-174. 10.1038/nature04177PubMedCrossRef
45.
Kaushansky A, Gordus A, Chang B, Rush J, MacBeath G: A quantitative study of the recruitment potential of all intracellular tyrosine residues on EGFR, FGFR1 and IGF1R. Mol Biosyst. 2008, 4: 643-653. 10.1039/b801018hPubMedCentralPubMedCrossRef
46.
Gordus A, Krall JA, Beyer EM, Kaushansky A, Wolf-Yadlin A, Sevecka M, Chang BH, Rush J, MacBeath G: Linear combinations of docking affinities explain quantitative differences in RTK signaling. Mol Syst Biol. 2009, 5: 235- 10.1038/msb.2008.72PubMedCentralPubMedCrossRef
47.
van Gunsteren WF, Bakowies D, Baron R, Chandrasekhar I, Christen M, Daura X, Gee P, Geerke DP, Glattli A, Hunenberger PH, Kastenholz MA, Oostenbrink C, Schenk M, Trzesniak D, d van V, Yu HB: Biomolecular modeling: Goals, problems, perspectives. Angew Chem Int Ed Engl. 2006, 45: 4064-4092. 10.1002/anie.200502655PubMedCrossRef
48.
Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, Dupuis S, Soudais C, Al-Mohsen IZ, Genin E, Lammas D, Kumararatne DS, Leclerc T, Rafii A, Frayha H, Murugasu B, Wah LB, Sinniah R, Loubser M, Okamoto E, Al-Ghonaium A, Tufenkeji H, Abel L, Casanova JL: Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet. 2002, 70: 336-348. 10.1086/338625PubMedCentralPubMedCrossRef
49.
Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J, Breiman A, Altare F, Baretto R, Le DF, Kayal S, Koch H, Richter D, Brezina M, Aksu G, Wood P, Al-Jumaah S, Raspall M, Duarte AJDS, Tuerlinckx D, Virelizier JL, Fischer A, Enright A, Bernhoft J, Cleary AM, Vermylen C, Rodriguez-Gallego C, Davies G, Blutters-Sawatzki R, Siegrist CA, Ehlayel MS, Novelli V, Haas WH, Levy J, Freihorst J, Al-Hajjar S, Nadal D, M De V, Jeppsson O, Kutukculer N, Frecerova K, Caragol I, Lammas D, Kumararatne DS, Abel L, Casanova JL: Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications. J Exp Med. 2003, 197: 527-535. 10.1084/jem.20021769PubMedCentralPubMedCrossRef
50.
Kondo N, Matsui E, Kaneko H, Fukao T, Teramoto T, Inoue R, Watanabe M, Kasahara K, Morimoto N: Reduced interferon-gamma production and mutations of the interleukin-12 receptor beta(2) chain gene in atopic subjects. Int Arch Allergy Immunol. 2001, 124: 117-120. 10.1159/000053687PubMedCrossRef
51.
Matsui E, Kaneko H, Fukao T, Teramoto T, Inoue R, Watanabe M, Kasahara K, Kondo N: Mutations of the IL-12 receptor beta2 chain gene in atopic subjects. Biochem Biophys Res Commun. 1999, 266: 551-555. 10.1006/bbrc.1999.1859PubMedCrossRef
52.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005, 365: 1054-1061.PubMedCrossRef
53.
Hookham MB, Elliott J, Suessmuth Y, Staerk J, Ward AC, Vainchenker W, Percy MJ, McMullin MF, Constantinescu SN, Johnston JA: The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3. Blood. 2007, 109: 4924-4929. 10.1182/blood-2006-08-039735PubMedCrossRef
54.
Shaw MH, Boyartchuk V, Wong S, Karaghiosoff M, Ragimbeau J, Pellegrini S, Muller M, Dietrich WF, Yap GS: A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc Natl Acad Sci USA. 2003, 100: 11594-11599.PubMedCentralPubMedCrossRef
55.
Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G, Jonsen A, Rantapaa-Dahlqvist S, Moller B, Kere J, Koskenmies S, Widen E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, Ronnblom L, Syvanen AC: Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet. 2005, 76: 528-537. 10.1086/428480PubMedCentralPubMedCrossRef
56.
Hellquist A, Jarvinen TM, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L, Panelius J, Hasan T, Julkunen H, D'Amato M, Saarialho-Kere U, Kere J: Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. J Rheumatol. 2009, 36: 1631-1638. 10.3899/jrheum.081160PubMedCrossRef
57.
Shimoda K, Kato K, Aoki K, Matsuda T, Miyamoto A, Shibamori M, Yamashita M, Numata A, Takase K, Kobayashi S, Shibata S, Asano Y, Gondo H, Sekiguchi K, Nakayama K, Nakayama T, Okamura T, Okamura S, Niho Y, Nakayama K: Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity. 2000, 13: 561-571. 10.1016/S1074-7613(00)00055-8PubMedCrossRef
58.
Nakamura R, Shibata K, Yamada H, Shimoda K, Nakayama K, Yoshikai Y: Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by gammadelta T cells. J Immunol. 2008, 181: 2071-2075.PubMedCrossRef
59.
Sachs K, Perez O, er D, Lauffenburger DA, Nolan GP: Causal protein-signaling networks derived from multiparameter single-cell data. Science. 2005, 308: 523-529. 10.1126/science.1105809PubMedCrossRef
60.
Schlessinger J: Epidermal Growth Factor Receptor Pathway. Sci Signal (Connections Map in the Database of Cell Signaling, as seen 26 July 2010). --- Either ISSN or Journal title must be supplied.
61.
Bhalla US, Iyengar R: Emergent properties of networks of biological signaling pathways. Science. 1999, 283: 381-387. 10.1126/science.283.5400.381PubMedCrossRef
62.
Bhalla US: Models of cell signaling pathways. Curr Opin Genet Dev. 2004, 14: 375-381. 10.1016/j.gde.2004.05.002PubMedCrossRef
63.
Murray PJ: The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007, 178: 2623-2629.PubMedCrossRef
64.
Szabo SJ, Dighe AS, Gubler U, Murphy KM: Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med. 1997, 185: 817-824. 10.1084/jem.185.5.817PubMedCentralPubMedCrossRef
65.
Lawless VA, Zhang S, Ozes ON, Bruns HA, Oldham I, Hoey T, Grusby MJ, Kaplan MH: Stat4 regulates multiple components of IFN-gamma-inducing signaling pathways. J Immunol. 2000, 165: 6803-6808.PubMedCrossRef
66.
Becskei A, Grusby MJ: Contribution of IL-12R mediated feedback loop to Th1 cell differentiation. FEBS Lett. 2007, 581: 5199-5206. 10.1016/j.febslet.2007.10.007PubMedCentralPubMedCrossRef
67.
Fujimoto M, Tsutsui H, Yumikura-Futatsugi S, Ueda H, Xingshou O, Abe T, Kawase I, Nakanishi K, Kishimoto T, Naka T: A regulatory role for suppressor of cytokine signaling-1 in T(h) polarization in vivo. Int Immunol. 2002, 14: 1343-1350. 10.1093/intimm/dxf094PubMedCrossRef
68.
Eyles JL, Metcalf D, Grusby MJ, Hilton DJ, Starr R: Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1. J Biol Chem. 2002, 277: 43735-43740. 10.1074/jbc.M208586200PubMedCrossRef
69.
Yamamoto K, Yamaguchi M, Miyasaka N, Miura O: SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor beta2 subunit. Biochem Biophys Res Commun. 2003, 310: 1188-1193. 10.1016/j.bbrc.2003.09.140PubMedCrossRef
70.
Athie-Morales V, Smits HH, Cantrell DA, Hilkens CM: Sustained IL-12 signaling is required for Th1 development. J Immunol. 2004, 172: 61-69.PubMedCrossRef
71.
72.
Schmidt D, Muller S: PIAS/SUMO: new partners in transcriptional regulation. Cell Mol Life Sci. 2003, 60: 2561-2574. 10.1007/s00018-003-3129-1PubMedCrossRef
73.
Wormald S, Hilton DJ: Inhibitors of cytokine signal transduction. J Biol Chem. 2004, 279: 821-824. 10.1074/jbc.R300030200PubMedCrossRef
74.
Arora T, Liu B, He H, Kim J, Murphy TL, Murphy KM, Modlin RL, Shuai K: PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J Biol Chem. 2003, 278: 21327-21330. 10.1074/jbc.C300119200PubMedCrossRef
75.
Lazebnik Y: Can a biologist fix a radio? Or, what I learned while studying apoptosis. Cancer Cell. 2002, 2: 179-183. 10.1016/S1535-6108(02)00133-2PubMedCrossRef
76.
Huang CY, JEF : Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA. 1996, 93: 10078-10083. 10.1073/pnas.93.19.10078PubMedCentralPubMedCrossRef
77.
Westerhoff HV: Signalling control strength. J Theor Biol. 2008, 252: 555-567. 10.1016/j.jtbi.2007.11.035PubMedCrossRef
78.
79.
Mayr C, Bartel DP: Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell. 2009, 138: 673-684. 10.1016/j.cell.2009.06.016PubMedCentralPubMedCrossRef
80.
Lu TX, Munitz A, Rothenberg ME: MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J Immunol. 2009, 182: 4994-5002. 10.4049/jimmunol.0803560PubMedCentralPubMedCrossRef
81.
Navarro A, Diaz T, Martinez A, Gaya A, Pons A, Gel B, Codony C, Ferrer G, Martinez C, Montserrat E, Monzo M: Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma. Blood. 2009, 114: 2945-2951. 10.1182/blood-2009-02-204842PubMedCrossRef
82.
Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, Liu MF, Wang ED: MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010, 70: 3119-3127. 10.1158/0008-5472.CAN-09-4250PubMedCrossRef
83.
Cozen W, Gill PS, Salam MT, Nieters A, Masood R, Cockburn MG, Gauderman WJ, Martinez-Maza O, Nathwani BN, Pike MC, Berg DJVD, Hamilton AS, Deapen DM, Mack TM: Interleukin-2, interleukin-12, and interferon-gamma levels and risk of young adult Hodgkin lymphoma. Blood. 2008, 111: 3377-3382. 10.1182/blood-2007-08-106872PubMedCentralPubMedCrossRef
84.
Zhao B, Meng LQ, Huang HN, Pan Y, Xu QQ: A novel functional polymorphism, 16974 A/C, in the interleukin-12-3' untranslated region is associated with risk of glioma. DNA Cell Biol. 2009, 28: 335-341. 10.1089/dna.2008.0845PubMedCrossRef
85.
Wei YS, Lan Y, Luo B, Lu D, Nong HB: Association of variants in the interleukin-27 and interleukin-12 gene with nasopharyngeal carcinoma. Mol Carcinog. 2009, 48: 751-757. 10.1002/mc.20522PubMedCrossRef
86.
Han SS, Cho EY, Lee TS, Kim JW, Park NH, Song YS, Kim JG, Lee HP, Kang SB: Interleukin-12 p40 gene (IL12B) polymorphisms and the risk of cervical cancer in Korean women. Eur J Obstet Gynecol Reprod Biol. 2008, 140: 71-75. 10.1016/j.ejogrb.2008.02.007PubMedCrossRef
87.
Takeuchi-Hatanaka K, Ohyama H, Nishimura F, Kato-Kogoe N, Soga Y, Matsushita S, Nakasho K, Yamanegi K, Yamada N, Terada N, Takashiba S: Polymorphisms in the 5' flanking region of IL12RB2 are associated with susceptibility to periodontal diseases in the Japanese population. J Clin Periodontol. 2008, 35: 317-323. 10.1111/j.1600-051X.2008.01208.xPubMedCrossRef
88.
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007, 357: 977-986. 10.1056/NEJMoa073003PubMedCentralPubMedCrossRef
89.
Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, Gu X, Walker EJ, Jing K, Juran BD, Mason AL, Myers RP, Peltekian KM, Ghent CN, Coltescu C, Atkinson EJ, Heathcote EJ, Lazaridis KN, Amos CI, Siminovitch KA: Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009, 360: 2544-2555. 10.1056/NEJMoa0810440PubMedCentralPubMedCrossRef
90.
Sato K, Shiota M, Fukuda S, Iwamoto E, Machida H, Inamine T, Kondo S, Yanagihara K, Isomoto H, Mizuta Y, Kohno S, Tsukamoto K: Strong Evidence of a Combination Polymorphism of the Tyrosine Kinase 2 Gene and the Signal Transducer and Activator of Transcription 3 Gene as a DNA-Based Biomarker for Susceptibility to Crohn's Disease in the Japanese Population. J Clin Immunol. 2009, 29: 815-825. 10.1007/s10875-009-9320-xPubMedCentralPubMedCrossRef
91.
Rowley JD: Chromosome translocations: dangerous liaisons revisited. Nat Rev Cancer. 2001, 1: 245-250. 10.1038/35106108PubMedCrossRef
92.
Korbel JO, Urban AE, Grubert F, Du J, Royce TE, Starr P, Zhong GN, Emanuel BS, Weissman SM, Snyder M, Gerstein MB: Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome. Proc Natl Acad Sci USA. 2007, 104: 10110-10115. 10.1073/pnas.0703834104PubMedCentralPubMedCrossRef
93.
Korbel JO, Urban AE, Affourtit JP, Godwin B, Grubert F, Simons JF, Kim PM, Palejev D, Carriero NJ, Du L, Taillon BE, Chen ZT, Tanzer A, Saunders ACE, Chi JX, Yang FT, Carter NP, Hurles ME, Weissman SM, Harkins TT, Gerstein MB, Egholm M, Snyder M: Paired-end mapping reveals extensive structural variation in the human genome. Science. 2007, 318: 420-426. 10.1126/science.1149504PubMedCentralPubMedCrossRef
94.
Zhao X, Li C, Paez JG, Chin K, Janne PA, Chen TH, Girard L, Minna J, Christiani D, Leo C, Gray JW, Sellers WR, Meyerson M: An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res. 2004, 64: 3060-3071. 10.1158/0008-5472.CAN-03-3308PubMedCrossRef
95.
96.
Airoldi I, Cocco C, Di CE, Disaro S, Ognio E, Basso G, Pistoia V: Methylation of the IL-12Rbeta2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells. Cancer Res. 2006, 66: 3978-3980. 10.1158/0008-5472.CAN-05-4418PubMedCrossRef
97.
Suzuki M, Iizasa T, Nakajima T, Kubo R, Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T: Aberrant methylation of IL-12Rbeta2 gene in lung adenocarcinoma cells is associated with unfavorable prognosis. Ann Surg Oncol. 2007, 14: 2636-2642. 10.1245/s10434-006-9310-7PubMedCrossRef
98.
Schoeberl B, Eichler-Jonsson C, Gilles ED, Müller G: Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nature Biotech. 2002, 20: 370-376. 10.1038/nbt0402-370.CrossRef
99.
Kholodenko BN, Demin OV, Moehren G, Hoek JB: Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor. J Biol Chem. 1999, 274: 30169-30181. 10.1074/jbc.274.42.30169PubMedCrossRef
100.
Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, Kholodenko BN: Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol Syst Biol. 2007, 3: 144- 10.1038/msb4100188PubMedCentralPubMedCrossRef
101.
Forsythe R, Mavrovouniotis M: Model Reduction in the Computational Modeling of Reaction Systems. J Chem Inf Comput Sci. 1997, 37: 258-264.PubMedCrossRef
102.
Broadbelt LJ, Pfaendtner J: Lexicography of kinetic modeling of complex reaction networks. AIChE J. 2005, 51: 2112-2121. 10.1002/aic.10599.CrossRef
103.
Green WH: Predictive Kinetics: A New Approach for the 21st Century. Adv Chem Eng. 2007, 32: 1-50. 10.1016/S0065-2377(07)32001-2.CrossRef
104.
Ugi I, Bauer J, Brandt J, Freidrich J, Gasteiger J, Jochum C, Schubert W: New applications of computers in chemistry. Angew Chem Int Ed Engl. 1979, 18: 111-123. 10.1002/anie.197901111.CrossRef
105.
Klinke DJ, Broadbelt LJ: Mechanism Reduction during Computer Generation of Compact Reaction Models. AIChE J. 1997, 43: 1828-1837. 10.1002/aic.690430718.CrossRef
106.
Klinke DJ, Broadbelt LJ: Construction of a Mechanistic Model of Fischer-Tropsch Synthesis on Ni(111) and Co(0001) Surfaces. Chem Eng Sci. 1999, 54: 3379-3389. 10.1016/S0009-2509(98)00386-8.CrossRef
107.
Blinov ML, Faeder JR, Goldstein B, Hlavacek WS: BioNetGen: software for rule-based modeling of ignal transduction based on the interactions of molecular domains. Bioinform. 2004, 20: 3289-3291. 10.1093/bioinformatics/bth378.CrossRef
108.
Fages F, Soliman S, Chabrier-Rivier N: Modelling and querying interaction networks in the biochemical abstract machine BIOCHAM. J Biol Phys Chem. 2004, 4: 64-73. 10.4024/2040402.jbpc.04.02.CrossRef
109.
Lok L, Brent R: Automatic generation of cellular reaction networks with Moleculizer 1.0. Nat Biotechnol. 2005, 23: 131-136. 10.1038/nbt1054PubMedCrossRef
110.
Meier-Schellersheim M, Xu X, Angermann B, Kunkel EJ, Jin T, Germain RN: Key role of local regulation in chemosensing revealed by a new molecular interaction-based modeling method. PLoS Comput Biol. 2006, 2: e82- 10.1371/journal.pcbi.0020082PubMedCentralPubMedCrossRef
111.
Blinov ML, Faeder JR, Goldstein B, Hlavacek WS: A Network Model of Early Events in Epidermal Growth Factor Receptor Signaling That Accounts for Combinatorial Complexity. Biosystems. 2006, 83: 136-151. 10.1016/j.biosystems.2005.06.014PubMedCrossRef
112.
Hlavacek WS, Faeder JR, Blinov ML, Perelson AS, Goldstein B: The Complexity of Complexes in Signal Transduction. Biotech Bioeng. 2003, 84: 783-794. 10.1002/bit.10842.CrossRef
113.
Susnow RG, Dean AM, Green WH, Broadbelt LJ: Rate-Based Construction of Kinetic Models for Complex Systems. J Phys Chem A. 1997, 101: 3731-3740. 10.1021/jp9637690.CrossRef
114.
Klinke DJ: Signal transduction networks in cancer: quantitative parameters influence network topology. Cancer Res. 2010, 70: 1773-1782. 10.1158/0008-5472.CAN-09-3234PubMedCentralPubMedCrossRef
115.
Klinke DJ: An empirical Bayesian approach for model-based inference of cellular signaling networks. BMC Bioinformatics. 2009, 10: 371- 10.1186/1471-2105-10-371PubMedCentralPubMedCrossRef
116.
117.
Gelman A, Carlin JB, Stern HS, Rubin DB: Bayesian Data Analysis. 2004, Texts in Statistical Science, Boca Raton, FL: Chapman and Hall
118.
National Research Council (US) Committee on Learning, : How people learn: brain, mind, experience, and school. 2000, --- Either first page or author must be supplied. Washington, DC: National Academies Press
119.
Brown KS, Sethna JP: Statistical mechanical approaches to models with many poorly known parameters. Phys Rev E Stat Nonlin Soft Matter Phys. 2003, 68: 021904- 10.1103/PhysRevE.68.021904PubMedCrossRef
120.
Finley SD, Gupta D, Cheng N, Klinke DJ: Inferring Relevant Control Mechanisms for Interleukin-12 Signaling within Naive CD4+ T cells. Immunol Cell Biol.
121.
Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, J E Darnell J, Murphy KM: Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med. 1995, 181: 1755-1762. 10.1084/jem.181.5.1755PubMedCrossRef
122.
Nimmerjahn F, Ravetch JV: Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science. 2005, 310: 1510-1512. 10.1126/science.1118948PubMedCrossRef
123.
Hart DN: Dendritic cells: unique leukocyte populations which control the primary immune response. Blood. 1997, 90: 3245-3287.PubMed
124.
Moser M, Murphy KM: Dendritic cell regulation of TH1-TH2 development. Nat Immunol. 2000, 1: 199-205. 10.1038/79734PubMedCrossRef
125.
Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL: Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003, 278: 1910-1914. 10.1074/jbc.M207577200PubMedCrossRef
126.
Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ: IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005, 201: 233-240. 10.1084/jem.20041257PubMedCentralPubMedCrossRef
127.
Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA: Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000, 13: 715-725. 10.1016/S1074-7613(00)00070-4PubMedCrossRef
128.
Jang MS, Son YM, Kim GR, Lee YJ, Lee WK, Cha SH, Han SH, Yun CH: Synergistic production of interleukin-23 by dendritic cells derived from cord blood in response to costimulation with LPS and IL-12. J Leukoc Biol. 2009, 86: 691-699. 10.1189/JLB.1008639PubMedCrossRef
129.
Martin-Orozco N, Dong C: The IL-17/IL-23 axis of inflammation in cancer: friend or foe?. Curr Opin Investig Drugs. 2009, 10: 543-549.PubMed
130.
Seder RA, Paul WE: Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994, 12: 635-673. 10.1146/annurev.iy.12.040194.003223PubMedCrossRef
131.
Worschech A, Kmieciak M, Knutson KL, Bear HD, Szalay AA, Wang E, Marincola FM, Manjili MH: Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors. Cancer Res. 2008, 68: 2436-2446. 10.1158/0008-5472.CAN-07-6822PubMedCentralPubMedCrossRef
132.
Rizzuto GA, Merghoub T, Hirschhorn-Cymerman D, Liu C, Lesokhin AM, Sahawneh D, Zhong H, Panageas KS, Perales MA, tan Bonnet G, Wolchok JD, Houghton AN: Self-antigen-specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response. J Exp Med. 2009, 206: 849-866. 10.1084/jem.20081382PubMedCentralPubMedCrossRef
133.
Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, Jenkins MK: Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity. 2007, 27: 203-213. 10.1016/j.immuni.2007.07.007PubMedCentralPubMedCrossRef
134.
Murphy KM, Stockinger B: Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol. 2010, 11: 674-680. 10.1038/ni.1899PubMedCentralPubMedCrossRef
135.
Fidler IJ, Kripke ML: Metastasis Results from Preexisting Variant Cells Within a Malignant Tumor. Science. 1977, 197: 893-895. 10.1126/science.887927PubMedCrossRef
136.
Gangnus R, Langer S, Breit E, Pantel K, Speicher MR: Genomic Profiling of Viable and Proliferative Micrometastatic Cells from Early-Stage Breast Cancer Patients. Clin Cancer Res. 2004, 10: 3457-3464. 10.1158/1078-0432.CCR-03-0818PubMedCrossRef
137.
Weinberg RA: The Biology of Cancer. 2007, New York, NY: Garland Science
138.
Irish JM, Hovland R, Krutzik PO, Perez OD, Bruserud O, Gjertsen BT, Nolan GP: Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell. 2004, 118: 217-228. 10.1016/j.cell.2004.06.028PubMedCrossRef
139.
Swamy M, Kulathu Y, Ernst S, Reth M, Schamel WWA: Two dimensional Blue Native-/SDS-PAGE analysis of SLP family adaptor protein complexes. Immunol Letters. 2006, 104: 131-137. 10.1016/j.imlet.2005.11.004.CrossRef
140.
141.
Debnath J, Brugge JS: Modelling glandular epithelial cancers in three-dimensional cultures. Nat Rev Cancer. 2005, 5: 675-688. 10.1038/nrc1695PubMedCrossRef
142.
143.
Feinerman O, Veiga J, Dorfman JR, Germain RN, tan Bonnet G: Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science. 2008, 321: 1081-1084. 10.1126/science.1158013PubMedCentralPubMedCrossRef
144.
Elowitz MB, Levine AJ, Siggia ED, Swain PS: Stochastic gene expression in a single cell. Science. 2002, 297: 1183-1186. 10.1126/science.1070919PubMedCrossRef
145.
Herpen CMV, van der Laak JA, V de I, van Krieken JH, de Wilde PC, Balvers MG, Adema GJ, Mulder PHD: Intratumoral recombinant human interleukin-12 administration in head and neck squamous cell carcinoma patients modifies locoregional lymph node architecture and induces natural killer cell infiltration in the primary tumor. Clin Cancer Res. 2005, 11: 1899-1909. 10.1158/1078-0432.CCR-04-1524PubMedCrossRef
146.
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K: Immunobiology of dendritic cells. Annu Rev Immunol. 2000, 18: 767-811. 10.1146/annurev.immunol.18.1.767PubMedCrossRef
147.
Lanzavecchia A, Sallusto F: The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol. 2001, 13: 291-298. 10.1016/S0952-7915(00)00218-1PubMedCrossRef
148.
Klinke DJ: An Age-Structured Model of Dendritic Cell Trafficking in the Lung. Am J Physiol Lung Cell Mol Physiol. 2006, 291: 1038-1049. 10.1152/ajplung.00048.2006.CrossRef
149.
Klinke DJ: A Multi-scale Model of Dendritic Cell Education and Trafficking in the Lung: Implications for T Cell Polarization. Ann Biomed Eng. 2007, 35: 937-955. 10.1007/s10439-007-9318-6PubMedCrossRef
150.
Ebner S, Ratzinger G, Krosbacher B, Schmuth M, Weiss A, Reider D, Kroczek RA, Herold M, Heufler C, Fritsch P, Romani N: Production of IL-12 by human monocyte-derived dendritic cells is optimal when the stimulus Is given at the onset of maturation, and Is further enhanced by IL-4 [In Process Citation]. J Immunol. 2001, 166: 633-641.PubMedCrossRef
151.
Hochrein H, O'Keeffe M, Luft T, Vandenabeele S, Grumont RJ, Maraskovsky E, Shortman K: Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med. 2000, 192: 823-833. 10.1084/jem.192.6.823PubMedCentralPubMedCrossRef
152.
Nicolini A, Carpi A, Rossi G: Cytokines in breast cancer. Cytokine Growth Factor Rev. 2006, 17: 325-337. 10.1016/j.cytogfr.2006.07.002PubMedCrossRef
153.
Ben-Baruch A: Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Res. 2003, 5: 31-36. 10.1186/bcr554PubMedCentralPubMedCrossRef
154.
Bright JJ, Sriram S: TGF-beta inhibits IL-12-induced activation of Jak-STAT pathway in T lymphocytes. J Immunol. 1998, 161: 1772-1777.PubMed
155.
Sudarshan C, Galon J, Zhou Y, O'Shea JJ: TGF-beta does not inhibit IL-12- and IL-2-induced activation of Janus kinases and STATs. J Immunol. 1999, 162: 2974-2981.PubMed
156.
Airoldi I, Cocco C, Giuliani N, Ferrarini M, Colla S, Ognio E, Taverniti G, Di CE, Cutrona G, Perfetti V, Rizzoli V, Ribatti D, Pistoia V: Constitutive expression of IL-12R beta 2 on human multiple myeloma cells delineates a novel therapeutic target. Blood. 2008, 112: 750-759. 10.1182/blood-2008-02-139378PubMedCrossRef
157.
Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT: COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer. 2000, 89: 2637-2645. 10.1002/1097-0142(20001215)89:12<2637::AID-CNCR17>3.0.CO;2-BPubMedCrossRef
158.
Chan G, Boyle JO, Yang EK, Zhang F, Sacks PG, Shah JP, Edelstein D, Soslow RA, Koki AT, Woerner BM, Masferrer JL, Dannenberg AJ: Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res. 1999, 59: 991-994.PubMed
159.
Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M: Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res. 1997, 57: 1276-1280.PubMed
160.
Luft T, Jefford M, Luetjens P, Toy T, Hochrein H, Masterman KA, Maliszewski C, Shortman K, Cebon J, Maraskovsky E: Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets. Blood. 2002, 100: 1362-1372. 10.1182/blood-2001-12-0360PubMedCrossRef
161.
Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S: Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007, 67: 4507-4513. 10.1158/0008-5472.CAN-06-4174PubMedCrossRef
162.
Vanderlugt CL, Miller SD: Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol. 2002, 2: 85-95. 10.1038/nri724PubMedCrossRef
163.
Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, Coveler AL, Childs JS, Higgins DM, Fintak PA, dela RC, Tietje K, Link J, Waisman J, Salazar LG: Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol. 2009, 27: 4685-4692. 10.1200/JCO.2008.20.6789PubMedCentralPubMedCrossRef
164.
Wierecky J, Muller MR, Wirths S, Halder-Oehler E, Dorfel D, Schmidt SM, Hantschel M, Brugger W, Schroder S, Horger MS, Kanz L, Brossart P: Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. Cancer Res. 2006, 66: 5910-5918. 10.1158/0008-5472.CAN-05-3905PubMedCrossRef
165.
Adams GP, Weiner LM: Monoclonal antibody therapy of cancer. Nat Biotechnol. 2005, 23: 1147-1157. 10.1038/nbt1137PubMedCrossRef
166.
Khoo MCK: Physiological Control Systems: Analysis, Simulation, and Estimation IEEE Press Series on Biomedical Engineering. 2000, Piscataway, NJ: IEEE Press
167.
Bergman RN, Ider YZ, Bowden CR, Cobelli C: Quantitative estimation of insulin sensitivity. Am J Physiol. 1979, 236: 667-
168.
Catron DM, Itano AA, Pape KA, Mueller DL, Jenkins MK: Visualizing the first 50 hr of the primary immune response to a soluble antigen. Immunity. 2004, 21: 341-347. 10.1016/j.immuni.2004.08.007PubMedCrossRef
169.
170.
Abbas AK, C A, Janeway J: Immunology: improving on nature in the twenty-first century. Cell. 2000, 100: 129-138. 10.1016/S0092-8674(00)81689-XPubMedCrossRef
171.
Kirschner DE, Chang ST, Riggs TW, Perry N, Linderman JJ: Toward a multiscale model of antigen presentation in immunity. Immunol Rev. 2007, 216: 93-118.PubMedCrossRef
172.
Quaranta V, Rejniak KA, Gerlee P, Anderson AR: Invasion emerges from cancer cell adaptation to competitive microenvironments: quantitative predictions from multiscale mathematical models. Semin Cancer Biol. 2008, 18: 338-348. 10.1016/j.semcancer.2008.03.018PubMedCentralPubMedCrossRef
173.
Costa MN, Radhakrishnan K, Wilson BS, Vlachos DG, Edwards JS: Coupled stochastic spatial and non-spatial simulations of ErbB1 signaling pathways demonstrate the importance of spatial organization in signal transduction. PLoS One. 2009, 4: e6316- 10.1371/journal.pone.0006316PubMedCentralPubMedCrossRef
174.
Shoda L, Kreuwel H, Gadkar K, Zheng Y, Whiting C, Atkinson M, Bluestone J, Mathis D, Young D, Ramanujan S: The Type 1 Diabetes PhysioLab Platform: a validated physiologically based mathematical model of pathogenesis in the non-obese diabetic mouse. Clin Exp Immunol. 2010, 161: 250-267.PubMedCentralPubMed
175.
Klinke DJ: Integrating Epidemiological Data into a Mechanistic Model of Type 2 Diabetes: Validating the Prevalence of Virtual Patients. Ann Biomed Eng. 2008, 36: 321-324. 10.1007/s10439-007-9410-yPubMedCrossRef
176.
177.
American Association for the Advancement of Science, : Science for All Americans. 1990, --- Either first page or author must be supplied. New York: Oxford University Press
178.
Humphreys P: Extending Ourselves: Computational Science, Empiricism, and Scientific Method. 2007, New York, NY: Oxford University Press
Metadata
Title
A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12
Author
David J Klinke II
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-242

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue

Research

Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer

Short communication

Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo

Research

Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis

Research

Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression

Research

Differential expression of DKK-1 binding receptors on stromal cells and myeloma cells results in their distinct response to secreted DKK-1 in myeloma

Research

Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits