Immune Infiltration in Human Cancer: Prognostic Significance and Disease Control (original) (raw)
References
Akasaki Y, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS (2004) Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol 173:4352–4359 PubMedCAS Google Scholar
Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H, Mosseri V, Laccourreye O, Bruneval P, Fridman WH, Brasnu DF, Tartour E (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12:465–472 ArticlePubMedCAS Google Scholar
Badoual C, Bouchaud G, Agueznay Nel H, Mortier E, Hans S, Gey A, Fernani F, Peyrard S, -Puig PL, Bruneval P, Sastre X, Plet A, Garrigue-Antar L, Quintin-Colonna F, Fridman WH, Brasnu D, Jacques Y, Tartour E (2008) The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res 68:3907–3914 ArticlePubMedCAS Google Scholar
Badoual C, Hans S, Fridman WH, Brasnu D, Erdman S, Tartour E (2009) Revisiting the prognostic value of regulatory T cells in patients with cancer. J Clin Oncol 27:e5–e6, author reply e7 ArticlePubMed Google Scholar
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545, Review ArticlePubMedCAS Google Scholar
Baratelli F, Lin Y, Zhu L, Yang SC, Heuze-Vourc'h N, Zeng G, Reckamp K, Dohadwala M, Sharma S, Dubinett SM (2005) Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 175:1483–1490 PubMedCAS Google Scholar
Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL (2007) Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res 67:8865–8873 ArticlePubMedCAS Google Scholar
Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pagès F, Trajanoski Z, Galon J (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25:1091–1093 ArticlePubMedCAS Google Scholar
Birkeland Sa, Hamilton-Dutoit S, Sandvej K, Andersen Hm, Bendtzen K, Møller B, Jørgensen Ka (1995) EBV-induced post-transplant lymphoproliferative disorder (PTLD). Transplant Proc 27:3467–3472 PubMedCAS Google Scholar
Burnet FM (1970) The concept of immunological surveillance. Prog Exp Tumor Res 13:1–27 PubMedCAS Google Scholar
Camus M, Tosolini M, Mlecnik B, Pages F, Kirilovsky A, Berger A, Costes A, Bindea G, Charoentong P, Bruneval P, Trajanoski Z, Fridman W-H, Galon J (2009) Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res 69:2685–2693 ArticlePubMedCAS Google Scholar
Cassoux N, Giron A, Bodaghi B, Tran TH, Baudet S, Davy F, Chan CC, Lehoang P, Merle-Béral H (2007) IL-10 measurement in aqueous humor for screening patients with suspicion of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 48:3253–3259 ArticlePubMed Google Scholar
Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R, Magdeleinat P, Mami-Chouaib F, Dieu-Nosjean MC, Fridman WH, Damotte D, Sautès-Fridman C, Cremer I (2010) Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 120(4):1285–1297 ArticlePubMedCAS Google Scholar
Ciree A, Michel L, Camilleri-Broet S, Jean Louis F, Oster M, Flageul B, Senet P, Fossiez F, Fridman WH, Bachelez H, Tartour E (2004) Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Int J Cancer 112:113–120 ArticlePubMedCAS Google Scholar
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949 ArticlePubMedCAS Google Scholar
Dalerba P, Maccalli C, Casati C, Castelli C, Parmiani G (2003) Immunology and immunotherapy of colorectal cancer. Crit Rev Oncol Hematol 46:33–57 ArticlePubMed Google Scholar
Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531 ArticlePubMedCAS Google Scholar
Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, De Chaisemartin L, Lebecque S, Fridman Wh, Cadranel J (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410–4417 ArticlePubMedCAS Google Scholar
Droemann D, Goldmann T, Branscheid D, Clark R, Dalhoff K, Zabel P, Vollmer E (2003) Toll-like receptor 2 is expressed by alveolar epithelial cells type II and macrophages in the human lung. Histochem Cell Biol 119:103–108 PubMedCAS Google Scholar
Droemann D, Albrecht D, Gerdes J, Ulmer AJ, Branscheid D, Vollmer E, Dalhoff K, Zabel P, Goldmann T (2005) Human lung cancer cells express functionally active Toll-like receptor 9. Respir Res 6:1 ArticlePubMed Google Scholar
Dudek AZ, Yunis C, Harrison LI, Kumar S, Hawkinson R, Cooley S, Vasilakos JP, Gorski KS, Miller JS (2007) First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Clin Cancer Res 13:7119–7125 ArticlePubMedCAS Google Scholar
Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6:836–848 ArticlePubMedCAS Google Scholar
Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, Horwitz BH, Fox JG (2003) CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol 162:691–702 ArticlePubMedCAS Google Scholar
Erdman SE, Sohn JJ, Rao VP, Nambiar PR, Ge Z, Fox JG, Schauer DB (2005) CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 65:3998–4004 ArticlePubMedCAS Google Scholar
Erdman SE, Rao VP, Poutahidis T, Ihrig MM, Ge Z, Feng Y, Tomczak M, Rogers AB, Horwitz BH, Fox JG (2006) CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res 63:6042–6050 Google Scholar
Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339 ArticlePubMed Google Scholar
Gajewska BU, Alvarez D, Vidric M, Goncharova S, Stämpfli MR, Coyle AJ, Gutierrez-Ramos JC, Jordana M (2001) Generation of experimental allergic airways inflammation in the absence of draining lymph nodes. J Clin Invest 108:577–583 PubMedCAS Google Scholar
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Berger A, Camus M, Mlecnik B, Bruneval P, Molidor R, Cugnenc P-H, Trajanoski Z, Fridman WH, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predicts clinical outcome. Science 313:1960–1964 ArticlePubMedCAS Google Scholar
Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886 ArticlePubMedCAS Google Scholar
Gould SJ, Isaacson PG (1993) Bronchus-associated lymphoid tissue (BALT) in human fetal and infant lung. J Pathol 169:229–234 ArticlePubMedCAS Google Scholar
Greene FL, Sobin LH (2009) A worldwide approach to the TNM staging system: collaborative efforts of the AJCC and UICC. J Surg Oncol 99:269–272 ArticlePubMed Google Scholar
Gribar SC, Anand RJ, Sodhi CP, Hackam DJ (2008) The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation. J Leukoc Biol 83:493–498 ArticlePubMedCAS Google Scholar
Halle S, Dujardin HC, Bakocevic N, Fleige H, Danzer H, Willenzon S, Suezer Y, Hämmerling G, Garbi N, Sutter G, Worbs T, Förster R (2009) Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells. J Exp Med 206:2593–2601 ArticlePubMedCAS Google Scholar
Harizi H, Juzan M, Pitard V, Moreau JF, Gualde N (2002) Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. J Immunol 168:2255–2263 PubMedCAS Google Scholar
Hart OM, Athie-Morales V, O'Connor GM, Gardiner CM (2005) TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol 175:1636–1642 PubMedCAS Google Scholar
He W, Liu Q, Wang L, Chen W, Li N, Cao X (2007) TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol 44:2850–2859 ArticlePubMedCAS Google Scholar
Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529 ArticlePubMedCAS Google Scholar
Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434 ArticlePubMedCAS Google Scholar
Johnson B, Osada T, Clay T, Lyerly H, Aorse M (2009) Physiology and therepeutics of vascular endothelial growth factor in tumor immuno-suppression. Curr nol ned 9:702–707 Google Scholar
Kawamata N, Xu B, Nishijima H, Aoyama K, Kusumoto M, Takeuchi T, Tei C, Michie SA, Matsuyama T (2009) Expression of endothelia and lymphocyte adhesion molecules in bronchus-associated lymphoid tissue (BALT) in adult human lung. Respir Res 10:97 ArticlePubMed Google Scholar
Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, Grewal N, Spiess PJ, Antony PA, Palmer DC, Tagaya Y, Rosenberg SA, Waldmann TA, Restifo NP (2004) IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA 101:1969–1974 ArticlePubMedCAS Google Scholar
Kobayashi H, Dubois S, Sato N, Sabzevari H, Sakai Y, Waldmann TA, Tagaya Y (2005) Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance. Blood 105:721–727 ArticlePubMedCAS Google Scholar
Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–907 ArticlePubMedCAS Google Scholar
Kortylewski M, Yu H (2008) Role of Stat3 in suppressing anti-tumor immunity. Curr Opin Immunol 20:228–233 ArticlePubMedCAS Google Scholar
Kumar H, Kawai T, Akira S (2009) Toll-like receptors and innate immunity. Biochem Biophys Res Commun 388:621–625 ArticlePubMedCAS Google Scholar
Lamm DL (1992) Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 19:573–580 PubMedCAS Google Scholar
Larangé A, Antonios D, Pallardy M, Kerdine-Römer S (2009) TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation. J Leukoc Biol 85:673–683 ArticlePubMed Google Scholar
Lebel-Binay S, Berger A, Zinzindohoué F, Cugnenc P, Thiounn N, Fridman WH, Pagès F (2000) Interleukin-18: biological properties and clinical implications. Eur Cytokine Netw 11:15–26 PubMedCAS Google Scholar
Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR (2008) Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science 320:379–381 ArticlePubMedCAS Google Scholar
Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, Camus M, Gillard M, Bruneval P, Fridman Wh, Pagès F, Trajanoski Z, Galon J (2010) Biomolecular network reconstruction reveals mechanisms of immune reaction associated with improved prognosis in colorectal cancer. Gastroenterology 138:1429–1440 Google Scholar
Mochizuki M (2009) Regional Immunity of the Eye. Acta Ophthalmol, Nov 7, Epub ahead of print Google Scholar
Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, Woodland DL, Lund FE, Randall TD (2004) Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10:927–934 ArticlePubMedCAS Google Scholar
Nagpal JK, Mishra R, Das BR (2002) Activation of Stat-3 as one of the early events in tobacco chewing-mediated oral carcinogenesis. Cancer 94:2393–2400 ArticlePubMedCAS Google Scholar
Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A (2005) Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 6:769–776 ArticlePubMedCAS Google Scholar
Nguyen ST, Hasegawa S, Tsuda H, Tomioka H, Ushijima M, Noda M, Omura K, Miki Y (2007) Identification of a predictive gene expression signature of cervical lymph node metastasis in oral squamous cell carcinoma. Cancer Sci 98:740–746 ArticlePubMedCAS Google Scholar
Nussenblatt RB, Chan CC, Wilson WH, Hochman J, Gottesman M and the CNS and Ocular Lymphoma Workshop Group (2006) International Central Nervous System and Ocular Lymphoma Workshop: recommendations for the future. Ocul Immunol Inflamm 14:139–144. Google Scholar
O'Connell JB, Maggard MA, Ko CY (2004) Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96:1420–1425 ArticlePubMed Google Scholar
Ohteki T, Tada H, Ishida K, Sato T, Maki C, Yamada T, Hamuro J, Koyasu S (2006) Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J Exp Med 203:2329–2338 ArticlePubMedCAS Google Scholar
Pagès F, Berger A, Henglein B, Piqueras B, Danel C, Zinzindohoue F, Thiounn N, Cugnenc PH, Fridman WH (1999) Modulation of interleukin-18 expression in human colon carcinoma: consequences for tumor immune surveillance. Int J Cancer 84:326–330 ArticlePubMed Google Scholar
Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666 ArticlePubMed Google Scholar
Pagès F, Galon J, Fridman WH (2008) The essential role of the in situ immune reaction in human colorectal cancer. J Leukoc Biol 84:981–987 ArticlePubMed Google Scholar
Pagès F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH (2010) Immune infiltration in human tumors, a prognostic factor that should not be ignored_._ Oncogene 29:1093–1102 Google Scholar
Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman Wh, Galon J (2009) In situ Cytotoxic and Memory T Cells Predict Outcome in Early-Stage Colorectal Cancer Patients. J Clin Oncol 35:5944–5951 Article Google Scholar
Ren T, Xu L, Jiao S, Wang Y, Cai Y, Liang Y, Zhou Y, Zhou H, Wen Z (2009) TLR9 signaling promotes tumor progression of human lung cancer cell in vivo. Pathol Oncol Res 15:623–630 Google Scholar
Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192 ArticlePubMed Google Scholar
Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176:4894–4901 PubMedCAS Google Scholar
Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P (2007) Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res 13:4565–4574 ArticlePubMedCAS Google Scholar
Sato Y, Goto Y, Narita N, Hoon DS (2009) Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment. Cancer Microenviron 2(Suppl 1):205–214 Google Scholar
Seike M, Yanaihara N, Bowman ED, Zanetti KA, Budhu A, Kumamoto K, Mechanic LE, Matsumoto S, Yokota J, Shibata T, Sugimura H, Gemma A, Kudoh S, Wang XW, Harris CC (2007) Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier. J Natl Cancer Inst 99:1257–1269 ArticlePubMedCAS Google Scholar
Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111 ArticlePubMedCAS Google Scholar
Smyth MJ, Dunn GP, Schreiber RD (2006) Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90:1–50 ArticlePubMedCAS Google Scholar
Tartour E, Gey A, Sastre-Garau X, Lombard Surin I, Mosseri V, Fridman WH (1998) Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas. J Natl Cancer Inst 90:287–294 ArticlePubMedCAS Google Scholar
Tartour E, Mosseri V, Jouffroy T, Deneux L, Jaulerry C, Brunin F, Fridman WH, Rodriguez J (2001) Serum soluble interleukin-2 receptor concentrations as an independent prognostic marker in head and neck cancer. Lancet 357:1263–1264 ArticlePubMedCAS Google Scholar
Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X, Sutton SE, Cooke MP, Ohlén C, Greenberg PD (2006) Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med 12:335–341 ArticlePubMedCAS Google Scholar
Tesar BM, Chalasani G, Smith-Diggs L, Baddoura FK, Lakkis FG, Goldstein DR (2004) Direct antigen presentation by a xenograft induces immunity independently of secondary lymphoid organs. J Immunol 173:4377–4386 PubMedCAS Google Scholar
Thaunat O, Hanf W, Dubois V, McGregor B, Perrat G, Chauvet C, Touraine JL, Morelon E (2009) Chronic humoral rejection mediated by anti-HLA-DP alloantibodies: insights into the role of epitope sharing in donor-specific and non-donor specific alloantibodies generation. Transpl Immunol 20:209–211 ArticlePubMedCAS Google Scholar
Tillman DK Jr, Carroll MT (2008) A 36-month clinical experience of the effectiveness of curettage and imiquimod 5% cream in the treatment of basal cell carcinoma. J Drugs Dermatol 7:s7–s14 PubMed Google Scholar
Tissari J, Sirén J, Meri S, Julkunen I, Matikainen S (2005) IFN-alpha enhances TLR3-mediated antiviral cytokine expression in human endothelial and epithelial cells by up-regulating TLR3 expression. J Immunol 174:4289–4294 PubMedCAS Google Scholar
Touitou V, Daussy C, Bodaghi B, Camelo S, de Kozak Y, Lehoang P, Naud MC, Varin A, Thillaye-Goldenberg B, Merle-Béral H, Fridman WH, Sautès-Fridman C, Fisson S (2007) Impaired th1/tc1 cytokine production of tumor-infiltrating lymphocytes in a model of primary intraocular B-cell lymphoma. Invest Ophthalmol Vis Sci 48:3223–3229 ArticlePubMed Google Scholar
Tschernig T, Pabst R (2000) Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology 68:1–8, Review ArticlePubMedCAS Google Scholar
Van der Meer JW, Weening RS, Schellekens PT, van Munster IP, Nagengast FM (1993) Colorectal cancer in patients with X-linked agammaglobulinaemia. Lancet 341:1439–1440 ArticlePubMed Google Scholar
Waldmann TA (2006) The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6:595–601, Review ArticlePubMedCAS Google Scholar
Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957 ArticlePubMedCAS Google Scholar
Yajima T, Nishimura H, Wajjwalku W, Harada M, Kuwano H, Yoshikai Y (2002) Overexpression of interleukin-15 in vivo enhances antitumor activity against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response. Int J Cancer 99:573–578 ArticlePubMedCAS Google Scholar