Overcoming tumor immune evasion with an unique arbovirus

Journal of Translational Medicine

Boris Minev¹  Santosh Kesari³  Tony Chen²  Bruce Lyday² 

[1] Genelux Corporation, San Diego Science Center, San Diego 92109, CA, USA;PrimeVax, LLC, Garden Grove, USA;Moores UCSD Cancer Center, UC San Diego, La Jolla 92093, CA, USA

关键词: Soluble TRAIL;    Spontaneous Regression;    Immune Evasion;    Immunotherapy;    Hyperthermia;    Dengue fever;    Dendritic cell;    Death Receptors;   

Others  :  1146395
DOI  :  10.1186/s12967-014-0349-0

 received in 2014-09-20, accepted in 2014-12-01,  发布年份 2015

【 摘 要 】

Combining dendritic cell vaccination with the adjuvant effect of a strain of dengue virus may be a way to overcome known tumor immune evasion mechanisms. Dengue is unique among viruses as primary infections carry lower mortality than the common cold, but secondary infections carry significant risk of hypovolemic shock. While current immuno-therapies rely on a single axis of attack, this approach combines physiological (hyperthermic reduction of tumor perfusion), immunological (activation of effector cells of the adaptive and innate immune system), and apoptosis-inducing pathways (sTRAIL) to destroy tumor cells. The premise of using multiple mechanisms of action in synergy with a decline in the ability of the tumor cells to employ resistance methods suggests the potential of this combination approach in cancer immunotherapy.

【 授权许可】

   
2015 Lyday et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Gubler DJ: Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998, 11:480-96.
• [2]Wald TG, Shult P, Krause P, Miller BA, Drinka P, Gravenstein S: A rhinovirus outbreak among residents of a long-term care facility. Ann Intern Med 1995, 123:588-93.
• [3]Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013, 369:122-33.
• [4]Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F: Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013, 98:1361-75.
• [5]Fellner C: Ipilimumab (yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. P T 2012, 37:503-30.
• [6]Gardner TA, Elzey BD, Hahn NM: Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. Hum Vaccin Immunother 2012, 8:534-9.
• [7]Patel SP, Woodman SE: Profile of ipilimumab and its role in the treatment of metastatic melanoma. Drug Des Devel Ther 2011, 5:489-95.
• [8]Liechtenstein T, Dufait I, Bricogne C, Lanna A, Pen J, Breckpot K, Escors D: PD-L1/PD-1 Co-Stimulation, a Brake for T cell Activation and a T cell Differentiation Signal. J Clin Cell Immunol 2012, S12:Pii:006.
• [9]Chmielewski M, Hombach AA, Abken H: Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells. Front Immunol 2013, 4:371.
• [10]Aris M, Barrio MM, Mordoh J: Lessons from cancer immunoediting in cutaneous melanoma. Clin Dev Immunol 2012, 2012:192719.
• [11]Algarra I, Garcia-Lora A, Cabrera T, Ruiz-Cabello F, Garrido F: The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape. Cancer Immunol Immunother 2004, 53:904-10.
• [12]Ellem KA, Schmidt CW, Li CL, Misko I, Kelso A, Sing G, Macdonald G, O’Rourke MG: The labyrinthine ways of cancer immunotherapy–T cell, tumor cell encounter: “how do I lose thee? Let me count the ways”. Adv Cancer Res 1998, 75:203-49.
• [13]Iancu EM, Baumgaertner P, Wieckowski S, Speiser DE, Rufer N: Profile of a serial killer: cellular and molecular approaches to study individual cytotoxic T-cells following therapeutic vaccination. J Biomed Biotechnol 2011, 2011:452606.
• [14]Jessy T: Immunity over inability: The spontaneous regression of cancer. J Nat Sci Biol Med 2011, 2:43-9.
• [15]McCarthy EF: The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J 2006, 26:154-8.
• [16]Bai XF, Bender J, Liu J, Zhang H, Wang Y, Li O, Du P, Zheng P, Liu Y: Local costimulation reinvigorates tumor-specific cytolytic T lymphocytes for experimental therapy in mice with large tumor burdens. J Immunol 2001, 167:3936-43.
• [17]Durand RE: Intermittent blood flow in solid tumours–an under-appreciated source of ‘drug resistance’. Cancer Metastasis Rev 2001, 20:57-61.
• [18]Vaupel P, Kallinowski F: Physiological effects of hyperthermia. Recent Results Cancer Res 1987, 104:71-109.
• [19]Dudar TE, Jain RK: Differential response of normal and tumor microcirculation to hyperthermia. Cancer Res 1984, 44:605-12.
• [20]Chan N, Bristow RG: “Contextual” synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair. Clin Cancer Res 2010, 16:4553-60.
• [21]Watanabe N, Niitsu Y, Umeno H, Kuriyama H, Neda H, Yamauchi N, Maeda M, Urushizaki I: Toxic effect of tumor necrosis factor on tumor vasculature in mice. Cancer Res 1988, 48:2179-83.
• [22]Hober D, Delannoy AS, Benyoucef S, De Groote D, Wattre P: High levels of sTNFR p75 and TNF alpha in dengue-infected patients. Microbiol Immunol 1996, 40:569-73.
• [23]Ganss R, Ryschich E, Klar E, Arnold B, Hammerling GJ: Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 2002, 62:1462-70.
• [24]Simmons CP, Farrar JJ, Nguyen VV, Wills B: Dengue. N Engl J Med 2012, 366:1423-32.
• [25]Bedognetti D, Wang E, Sertoli MR, Marincola FM: Gene-expression profiling in vaccine therapy and immunotherapy for cancer. Expert Rev Vaccines 2010, 9:555-65.
• [26]Niakan B: A mechanism of the spontaneous remission and regression of cancer. Cancer Biother Radiopharm 1998, 13:209-10.
• [27]Clancy T, Pedicini M, Castiglione F, Santoni D, Nygaard V, Lavelle TJ, Benson M, Hovig E: Immunological network signatures of cancer progression and survival. BMC Med Genomics 2011, 4:28. BioMed Central Full Text
• [28]Butz EA, Bevan MJ: Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity 1998, 8:167-75.
• [29]Kaufman HL, Bines SD: OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol 2010, 6:941-9.
• [30]Prestwich RJ, Errington F, Diaz RM, Pandha HS, Harrington KJ, Melcher AA, Vile RG: The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon. Hum Gene Ther 2009, 20:1119-32.
• [31]Wong HH, Lemoine NR, Wang Y: Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles. Viruses 2010, 2:78-106.
• [32]Kim DW, Krishnamurthy V, Bines SD, Kaufman HL: TroVax, a recombinant modified vaccinia Ankara virus encoding 5 T4: lessons learned and future development. Hum Vaccin 2010, 6:784-91.
• [33]Leitmeyer KC, Vaughn DW, Watts DM, Salas R, Villalobos I, De C, Ramos C, Rico-Hesse R: Dengue virus structural differences that correlate with pathogenesis. J Virol 1999, 73:4738-47.
• [34]Manson A: Manson’s Tropical Diseases. Saunders, Ltd., London; 2014.
• [35]Chang DM, Shaio MF: Production of interleukin-1 (IL-1) and IL-1 inhibitor by human monocytes exposed to dengue virus. J Infect Dis 1994, 170:811-7.
• [36]Chen YC, Wang SY: Activation of terminally differentiated human monocytes/macrophages by dengue virus: productive infection, hierarchical production of innate cytokines and chemokines, and the synergistic effect of lipopolysaccharide. J Virol 2002, 76:9877-87.
• [37]Kurane I, Innis BL, Nimmannitya S, Nisalak A, Meager A, Janus J, Ennis FA: Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J Clin Invest 1991, 88:1473-80.
• [38]Dalrymple NA, Mackow ER: Endothelial cells elicit immune-enhancing responses to dengue virus infection. J Virol 2012, 86:6408-15.
• [39]Pacsa AS, Agarwal R, Elbishbishi EA, Chaturvedi UC, Nagar R, Mustafa AS: Role of interleukin-12 in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol 2000, 28:151-5.
• [40]Azeredo EL, De Oliveira-Pinto LM, Zagne SM, Cerqueira DI, Nogueira RM, Kubelka CF: NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease. Clin Exp Immunol 2006, 143:345-56.
• [41]Gandini M, Gras C, Azeredo EL, Pinto LM, Smith N, Despres P, da Cunha RV, de Souza LJ, Kubelka CF, Herbeuval JP: Dengue Virus activates membrane TRAIL localizatoin and IFN-alpha production by human plasmacytoid dendritic cells in vitro and in vivo. PLoS Negl Trop Dis 2013, 7(6):e2257.
• [42]Kurane I, Janus J, Ennis FA: Dengue virus infection of human skin fibroblasts in vitro production of IFN-beta, IL-6 and GM-CSF. Arch Virol 1992, 124:21-30.
• [43]Copier J, Bodman-Smith M, Dalgleish A: Current status and future applications of cellular therapies for cancer. Immunotherapy 2011, 3:507-16.
• [44]Rosenberg SA, Yang JC, Restifo NP: Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004, 10:909-15.
• [45]Bozza FA, Cruz OG, Zagne SM, Azeredo EL, Nogueira RM, Assis EF, Bozza PT, Kubelka CF: Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis 2008, 8:86. BioMed Central Full Text
• [46]Chen J, Ng MM, Chu JJ: Molecular profiling of T-helper immune genes during dengue virus infection. Virol J 2008, 5:165. BioMed Central Full Text
• [47]Wills BA, Nguyen MD, Ha TL, Dong TH, Tran TN, Le TT, Tran VD, Nguyen TH, Nguyen VC, Stepniewska K, White NJ, Farrar JJ: Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005, 353:877-89.
• [48]da Rosa AP T, Vasconcelos PF, Travassos Da Rosa ES, Rodrigues SG, Mondet B, Cruz AC, Sousa MR, Travassos Da Rosa JF: Dengue epidemic in Belem, Para, Brazil, 1996-97. Emerg Infect Dis 2000, 6:298-301.
• [49]Lee IK, Liu JW, Yang KD: Clinical characteristics, risk factors, and outcomes in adults experiencing dengue hemorrhagic fever complicated with acute renal failure. Am J Trop Med Hyg 2009, 80:651-5.
• [50]Wang CC, Liu SF, Liao SC, Lee IK, Liu JW, Lin AS, Wu CC, Chung YH, Lin MC: Acute respiratory failure in adult patients with dengue virus infection. Am J Trop Med Hyg 2007, 77:151-8.
• [51]Overwijk WW, Theoret MR, Finkelstein SE, Surman DR, de Jong LA, Vyth-Dreese FA, Dellemijn TA, Antony PA, Spiess PJ, Palmer DC, Heimann DM, Klebanoff CA, Yu Z, Hwang LN, Feigenbaum L, Kruisbeek AM, Rosenberg SA, Restifo NP: Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 2003, 198:569-80.
• [52]Ubol S, Masrinoul P, Chaijaruwanich J, Kalayanarooj S, Charoensirisuthikul T, Kasisith J: Differences in global gene expression in peripheral blood mononuclear cells indicate a significant role of the innate responses in progression of dengue fever but not dengue hemorrhagic fever. J Infect Dis 2008, 197:1459-67.
• [53]Librarty D: Human dendritic cells are activated by Dengue Virus infection: enhancement by Gamma Interferon and implications for disease pathogenesis. J Virology 2001, 75:3501-8.
• [54]Green S, Pichyangkul S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Nisalak A, Kurane I, Rothman AL, Ennis FA: Early CD69 expression on peripheral blood lymphocytes from children with dengue hemorrhagic fever. J Infect Dis 1999, 180:1429-35.
• [55]Wagner SN, Schultewolter T, Wagner C, Briedigkeit L, Becker JC, Kwasnicka HM, Goos M: Immune response against human primary malignant melanoma: a distinct cytokine mRNA profile associated with spontaneous regression. Lab Invest 1998, 78:541-50.
• [56]Sinkovics JG, Horvath JC: Human natural killer cells: a comprehensive review. Int J Oncol 2005, 27:5-47.
• [57]Kelley JF, Kaufusi PH, Nerurkar VR: Dengue hemorrhagic fever-associated immunomediators induced via maturation of dengue virus nonstructural 4B protein in monocytes modulate endothelial cell adhesion molecules and human microvascular endothelial cells permeability. Virology 2012, 422:326-37.
• [58]Kovalovich K, Li W, DeAngelis R, Greenbaum LE, Ciliberto G, Taub R: Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J Biol Chem 2001, 276:26605-13.
• [59]von Russum A, Krall R, Escalante NK, Choy JC: Inflammatory cytokines determine the susceptibility of human CD8 T cells to Fas-mediated activation-induced cell death through modulation of FasL and c-FLIP(S) expression. J Biol Chem 2011, 286:21137-44.
• [60]West EJ, Scott KJ, Jennings VA, Melcher AA: Immune activation by combination human lymphokine-activated killer and dendritic cell therapy. Br J Cancer 2011, 105:787-95.
• [61]Lindau D: The Immunosuppressive tumor network: Myeloid-Derived Suppressor Cells, regulatory T cells and Natural Killer Cells. J Immunol 2013, 138:102-15.
• [62]Suwannasaen D, Romphruk A, Leelayuwat C, Lertmemongkolchai G: Bystander T cells in human immune responses to dengue antigens. BMC Immunol 2010, 11:47. BioMed Central Full Text
• [63]Medema JP, de Jong J, Peltenburg LT, Verdegaal EM, Gorter A, Bres SA, Franken KL, Hahne M, Albar JP, Melief CJ, Offringa R: Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc Natl Acad Sci U S A 2001, 98:11515-20.
• [64]Hamai A, Meslin F, Benlalam H, Jalil A, Mehrpour M, Faure F, Lecluse Y, Vielh P, Avril MF, Robert C, Chouaib S: ICAM-1 has a critical role in the regulation of metastatic melanoma tumor susceptibility to CTL lysis by interfering with PI3K/AKT pathway. Cancer Res 2008, 68:9854-64.
• [65]Becerra A, Warke RV, Martin K, Xhaja K, de Bosch N, Rothman AL, Bosch I: Gene expression profiling of dengue infected human primary cells identifies secreted mediators in vivo. J Med Virol 2009, 81:1403-11.
• [66]Turcotte S, Rosenberg SA: Immunotherapy for metastatic solid cancers. Adv Surg 2011, 45:341-60.
• [67]Becquart P, Wauquier N, Nkoghe D, Ndjoyi-Mbiguino A, Padilla C, Souris M, Leroy EM: Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production. BMC Infect Dis 2010, 10:356. BioMed Central Full Text
• [68]Yong X, Xiao YF, Luo G, He B, Lu MH, Hu CJ, Guo H, Yang SM: Strategies for enhancing vaccine-induced CTL antitumor immune responses. J Biomed Biotechnol 2012, 2012:605045.
• [69]Mesiano G, Todorovic M, Gammaitoni L, Leuci V, Giraudo Diego L, Carnevale-Schianca F, Fagioli F, Piacibello W, Aglietta M, Sangiolo D: Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors. Expert Opin Biol Ther 2012, 12:673-84.
• [70]Weishaupt C, Munoz KN, Buzney E, Kupper TS, Fuhlbrigge RC: T-cell distribution and adhesion receptor expression in metastatic melanoma. Clin Cancer Res 2007, 13:2549-56.
• [71]Wolf B, Schwarzer A, Cote AL, Hampton TH, Schwaab T, Huarte E, Tomlinson CR, Gui J, Fisher JL, Fadul CE, Hamilton JW, Ernstoff MS: Gene expression profile of peripheral blood lymphocytes from renal cell carcinoma patients treated with IL-2, interferon-alpha and dendritic cell vaccine. PLoS One 2012, 7:e50221.
• [72]Disis ML: Immunologic biomarkers as correlates of clinical response to cancer immunotherapy. Cancer Immunol Immunother 2011, 60:433-42.
• [73]Chakraborty NG, Li L, Sporn JR, Kurtzman SH, Ergin MT, Mukherji B: Emergence of regulatory CD4+ T cell response to repetitive stimulation with antigen-presenting cells in vitro: implications in designing antigen-presenting cell-based tumor vaccines. J Immunol 1999, 162:5576-83.
• [74]Steinbrink K, Jonuleit H, Muller G, Schuler G, Knop J, Enk AH: Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 1999, 93:1634-42.
• [75]Pasca A: Role of Interleukin-12 in patients with Dengue Hemorrhagic Fever. FEMS Immunol Med Microbiol 2012, 28:5.
• [76]Creusot RJ, Yaghoubi SS, Chang P, Chia J, Contag CH, Gambhir SS, Fathman CG: Lymphoid-tissue-specific homing of bone-marrow-derived dendritic cells. Blood 2009, 113:6638-47.
• [77]Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK: Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res 1999, 59:56-8.
• [78]Verdijk P, Aarntzen EH, Lesterhuis WJ, Boullart AC, Kok E, van Rossum MM, Strijk S, Eijckeler F, Bonenkamp JJ, Jacobs JF, Blokx W, Vankrieken JH, Joosten I, Boerman OC, Oyen WJ, Adema G, Punt CJ, Figdor CG, de Vries IJ: Limited amounts of dendritic cells migrate into the T-cell area of lymph nodes but have high immune activating potential in melanoma patients. Clin Cancer Res 2009, 15:2531-40.
• [79]Azeredo EL, Zagne SM, Alvarenga AR, Nogueira RM, Kubelka CF, de Oliveira-Pinto LM: Activated peripheral lymphocytes with increased expression of cell adhesion molecules and cytotoxic markers are associated with dengue fever disease. Mem Inst Oswaldo Cruz 2006, 101:437-49.
• [80]Waldmann T: The contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for the immunotherapy of rheumatological diseases. Arthritis Res 2002, 4(Suppl 3):S161-7. BioMed Central Full Text
• [81]Lapteva N, Huang XF: CCL5 as an adjuvant for cancer immunotherapy. Expert Opin Biol Ther 2010, 10:725-33.
• [82]Mellier G, Pervaiz S: The three Rs along the TRAIL: resistance, re-sensitization and reactive oxygen species (ROS). Free Radic Res 2012, 46:996-1003.
• [83]Chiba Y, Mizoguchi I, Mitobe K, Higuchi K, Nagai H, Nishigori C, Mizuguchi J, Yoshimoto T: IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperation with a TLR3 agonist poly(I:C) partly in a TRAIL-dependent manner. PLoS One 2013, 8:e76159.
• [84]Palacios C, Yerbes R, Sanchez-Perez T, Martin-Perez R, Cano-Gonzalez A, Lopez-Rivas A: The long and winding road to cancer treatment: the trail system. Curr Pharm Des 2014, 20(17):2819-33.
• [85]Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Screaton G, Hersey P: Progression in melanoma is associated with decreased expression of death receptors for tumor necrosis factor-related apoptosis-inducing ligand. Hum Pathol 2006, 37:1286-94.
• [86]Dai Y: A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-KappaB. BMC Cancer 2009, 9:392-416. BioMed Central Full Text
• [87]Wong KL, Chen W, Balakrishnan T, Toh YX, Fink K, Wong SC: Susceptibility and response of human blood monocyte subsets to primary dengue virus infection. PLoS One 2012, 7:e36435.
• [88]Dokouhaki P, Schuh NW, Joe B, Allen CA, Der SD, Tsao MS, Zhang L: NKG2D regulates production of soluble TRAIL by ex vivo expanded human gammadelta T cells. Eur J Immunol 2013, 43:3175-82.
• [89]Correia DV, Fogli M, Hudspeth K, da Silva MG, Mavilio D, Silva-Santos B: Differentiation of human peripheral blood Vdelta1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 2011, 118:992-1001.
• [90]Wang T, Welte T: Role of natural killer and Gamma-delta T cells in West Nile virus infection. Viruses 2013, 5:2298-310.
• [91]Neves-Souza PC, Azeredo EL, Zagne SM, Valls-de-Souza R, Reis SR, Cerqueira DI, Nogueira RM, Kubelka CF: Inducible nitric oxide synthase (iNOS) expression in monocytes during acute Dengue Fever in patients and during in vitro infection. BMC Infect Dis 2005, 5:64. BioMed Central Full Text
• [92]Huerta-Yepez S, Vega M, Escoto-Chavez SE, Murdock B, Sakai T, Baritaki S, Bonavida B: Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1. Nitric Oxide 2009, 20:39-52.
• [93]Vignesweran N: Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not its receptors during oral cancer progression. BMC Cancer 2007, 7:108-22. BioMed Central Full Text
• [94]Nasirudeen AM, Wong HH, Thien P, Xu S, Lam KP, Liu DX: RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. PLoS Negl Trop Dis 2011, 5:e926.
• [95]Leng CH, Chen HW, Chang LS, Liu HH, Liu HY, Sher YP, Chang YW, Lien SP, Huang TY, Chen MY, Chou AH, Chong P, Liu SJ: A recombinant lipoprotein containing an unsaturated fatty acid activates NF-kappaB through the TLR2 signaling pathway and induces a differential gene profile from a synthetic lipopeptide. Mol Immunol 2010, 47:2015-21.
• [96]Quast SA, Berger A, Buttstadt N, Friebel K, Schonherr R, Eberle J: General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC. PLoS One 2012, 7:e39290.
• [97]Caraglia M, Marra M, Tagliaferri P, Lamberts SW, Zappavigna S, Misso G, Cavagnini F, Facchini G, Abbruzzese A, Hofland LJ, Vitale G: Emerging strategies to strengthen the anti-tumour activity of type I interferons: overcoming survival pathways. Curr Cancer Drug Targets 2009, 9:690-704.
• [98]Tiwari AK, Roy HK: Progress against cancer (1971-2011): how far have we come? J Intern Med 2012, 271:392-9.
• [99]Rigau-Perez JG, Clark GG: Dengue activity in Puerto Rico, 1990. P R Health Sci J 1992, 11:65-8.