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  • American Association for Cancer Research (AACR)  (8)
  • 1
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    Online Resource
    Abstract A116: IgG antibody switching and clonal expansion in melanoma and normal skin microenvironments
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Immunology Research Vol. 4, No. 11_Supplement ( 2016-11-01), p. A116-A116
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 11_Supplement ( 2016-11-01), p. A116-A116
    Abstract: Antibodies have been detected against known melanoma-associated antigens in patients with malignant disease. While much is known about cancer-specific T cell responses, the nature of cancer-specific B cells and their antibody repertoires are less well understood. We investigated circulating skin-homing B cells (CD19+CD22+CLA+) in healthy volunteers (n = 24) and melanoma patients (n = 49) and examined the presence of CD22+ B cells in melanoma lesions (n = 173) and normal skins tissue (n = 16). We detected mature IgG mRNA in 13 of 27 normal skin and 9 of 21 cutaneous melanoma samples and we detected mRNA for the enzyme Activation-induced cytidine deaminase (AID). IgG variable heavy chain sequences from melanomas (n = 51) and normal skins (n = 29) featured lower IgG1/IgGtotal subclass representation compared with circulating B cell antibody sequences (n = 36). The presence of affinity-matured cutaneous antibody repertoires in malignant skin was supported by evidence of somatic hypermutation, class-switching and B cell clonal family trees in melanoma lesions and a subset of melanoma-associated clones featuring shorter CDR3 region lengths relative to circulating B cell sequences. Homology modelling also indicated differential putative binding site patterns in melanoma compared to normal skin-resident antibodies, suggesting distinct melanoma-associated repertoires and potentially, antigen recognition profiles. These findings support the presence of a mature tumor-resident B cell compartment with characteristics distinct to that of B cells in normal skin and the circulation. Citation Format: Louise Saul, Kristina M. Ilieva, Heather J. Bax, Panagiotis Karagiannis, Isabel Correa, Irene Rodriguez-Hernandez, Debra H. Josephs, Isabella Tosi, Isioma U. Egbuniwe, Sara Lombardi, Silvia Crescioli, Carl Hobbs, Federica Villanova, Anthony Cheung, Jenny LC Geh, Ciaran Healy, Mark Harries, Victoria Sanz-Moreno, David Fear, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG antibody switching and clonal expansion in melanoma and normal skin microenvironments [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A116.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.IMM2016-A116
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2732517-9
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  • 2
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    Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 5 ( 2017-03-01), p. 1127-1141
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 5 ( 2017-03-01), p. 1127-1141
    Abstract: IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen–specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcϵ receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFα+ and CD80+ macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG. Cancer Res; 77(5); 1127–41. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-1829
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Abstract B65: IgG4 subclass antibodies impair antitumor immunity in melanoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 1_Supplement ( 2013-01-01), p. B65-B65
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 1_Supplement ( 2013-01-01), p. B65-B65
    Abstract: Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 type immune responses in a range of inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. We found that CD22+ B cells and IgG4+ infiltrating cells accumulated in melanoma lesions. When compared to B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Consistent with modified Th2-biased inflammation and in situ production of IgG4, we detected IL-10 and IL-4 cytokine mRNA in melanoma lesions. Tumor cells enhanced IL-10, IL-4 and VEGF secretion and production of IgG4 by B cells ex vivo. Despite accumulation in tumors, and in contrast to IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro and in vivo. Furthermore, treatment with IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions by blocking of FcgammaRI against tumors, providing a novel perspective on tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches. Citation Format: Panagiotis Karagiannis, Amy E. Gilbert, Debra H. Josephs, Niwa Ali, Tihomir Dodev, Louise Saul, Luke Roberts, Emma Beddowes, Alexander Koers, Silvia Ferreira, Jenny L.C. Geh, Ciaran Healy, Mark Harries, Carl Hobbs, Philip J. Blower, Tracey Mitchell, David Fear, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG4 subclass antibodies impair antitumor immunity in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B65.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMIMM2012-B65
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Abstract A009: IgG4: a new tool to predict the risk of disease progression in melanoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Immunology Research Vol. 4, No. 1_Supplement ( 2016-01-01), p. A009-A009
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 1_Supplement ( 2016-01-01), p. A009-A009
    Abstract: Purpose: Novel findings point to a pathological and immunoregulatory function of IgG4 antibodies and IgG4+ B cells in inflammatory diseases and malignancies. It has been reported that IgG4 antibodies impair humoral responses and restrict activation of immune effector cells in melanoma and cholangiocarcinomas. Thus the biological function of IgG4 may also be accompanied with predictive potential. Experimental Design: We investigated IgG4 as a potential indicator of the risk of disease progression in human sera (n=271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n=71: 47 melanoma patients; 24 healthy volunteers). Results: The serum levels of IgG4 (IgG4/IgGtotal) were elevated in melanoma samples and high IgG4 levels correlated negatively with progression-free survival (hazard ratio (HR) 2.01, 95% confidence interval ([CI]) 1.34-3.35; P=0.0016) and overall survival (HR 1.90 95%[CI] 1.17-3.29; P=0.0116). IgG4 was an independently negative prognostic marker for progression-free survival (PFS; HR 2.46, 95%[CI] 1.01-6.02) in patients with stage I-II disease. Moreover in a similar cohort elevation of IgG4+ circulating B cells (CD45+CD22+CD19+CD3-CD14-) (P=0.014) was also negatively prognostic for progression-free survival. The marker LDH, which is already used in clinical practice, is associated with PFS in melanoma, especially in advanced stages. We found that by combining LDH and IgG4 the prognostic value was improved (AUC:0.67; P=0.0002) than either serum indicator alone. In tissues (n=256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) we found IgG4+ cell infiltrates in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases. These findings suggest biological involvement of IgG4 in Th2 tumour environments at the metastatic and local levels. Conclusion: Our data are consistent with emerging evidence for immunosuppressive roles for IgG4, further supporting prognostic utility in melanoma and potential to facilitate patient stratification. Citation Format: Panagiotis Karagiannis, Federica Villanova, Debra H. Josephs, Isabel Correa, Mieke Van Hemelrijck, Carl Hobbs, Louise Saul, Isioma U. Egbuniwe, Isabella Tosi, Kristina M. Ilieva, Emma Kent, Eduardo Calonje, Mark Harries, Ian Fentiman, Joyce Taylor-Papadimitriou, Joy Burchel, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG4: a new tool to predict the risk of disease progression in melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A009.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A009
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 5
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    Abstract 2524: Antibodies of the IgG and IgE classes against the melanoma-associated antigen HMW-MAA: Investigating a new therapeutic approach
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2524-2524
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2524-2524
    Abstract: Melanoma, the fastest rising cancer in the UK, is a major therapeutic challenge and effective treatments are urgently needed. The human high molecular weight melanoma associated antigen (HMW-MAA), a membrane-bound protein over-expressed in & gt; 90% of melanomas, is thought to contribute to melanoma growth and metastasis. A number of studies indicate the merit of blocking these tumor-promoting functions by antibodies. Most antibodies for cancer therapy in clinical use belong to the IgG class, the most prevalent class in blood. IgE antibodies, characterised for their role in allergic responses and protection against parasites, function through high-affinity Fc receptors. IgE antibodies, naturally reside in tissues where they exert immunological surveillance, a different spectrum of effector cells, and offer a novel therapeutic approach by targeting solid tumors such as melanoma. Previous studies, suggest that IgE antibodies are more effective than the corresponding IgGs in eliciting anti-tumural immune responses, with our lead antibody candidate against the tumour antigen Folate Receptor alpha (FRa) presently in clinical development. We wished to elucidate whether this concept can be applied to the treatment of melanoma. To test this, we engineered IgG1, IgG4 and IgE antibodies of the same specificity against HMW-MAA and examined their functionality in activating immune effector cells against cancer cells. IgG1 and IgE antibodies induced significant tumor cell death by two mechanisms: antibody-dependent cell-mediated phagocytosis and antibody-dependent cell-mediated cytotoxicity in vitro, using patient-derived monocytes and monocytes from healthy volunteers. These results suggest different antibody classes may harbor complementary functional properties against cancer cells, by activating different families of Fc receptors on immune effector cells. Furthermore, we compared the therapeutic efficacy of these antibodies in tumor-bearing NOD/SCID/IL-2 receptor ≤ chain-/- mice engrafted with human lymphocytes. We demonstrate, that IgE antibodies are superior compared to IgG1 (p & lt;0.05) and non-specific antibody controls (p & lt;0.001). Moreover, immunohistological and transcriptomic analyses revealed an increased lymphocyte infiltrate within the treatment groups. The data indicate, infiltrating immune cells interactions with the tumor microenviroment to reduce tumor growth. We are currently undertaking additional functional validation to identify the in vivo signaling mechanisms involved. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2524. doi:1538-7445.AM2012-2524
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-2524
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 410466-3
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  • 6
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    Effects of BRAF Mutations and BRAF Inhibition on Immune Responses to Melanoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Molecular Cancer Therapeutics Vol. 13, No. 12 ( 2014-12-01), p. 2769-2783
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 13, No. 12 ( 2014-12-01), p. 2769-2783
    Abstract: Malignant melanoma is associated with poor clinical prognosis; however, novel molecular and immune therapies are now improving patient outcomes. Almost 50% of melanomas harbor targetable activating mutations of BRAF that promote RAS–RAF–MEK–ERK pathway activation and melanoma proliferation. Recent evidence also indicates that melanomas bearing mutant BRAF may also have altered immune responses, suggesting additional avenues for treatment of this patient group. The small molecule inhibitors selective for mutant BRAF induce significant but short-lived clinical responses in a proportion of patients, but also lead to immune stimulatory bystander events, which then subside with the emergence of resistance to inhibition. Simultaneous BRAF and MEK inhibition, and especially combination of BRAF inhibitors with new immunotherapies such as checkpoint blockade antibodies, may further enhance immune activation, or counteract immunosuppressive signals. Preclinical evaluation and ongoing clinical trials should provide novel insights into the role of immunity in the therapy of BRAF-mutant melanoma. Mol Cancer Ther; 13(12); 2769–83. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-14-0290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 7
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    Anti-Folate Receptor Alpha–Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 20 ( 2018-10-15), p. 5098-5111
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 20 ( 2018-10-15), p. 5098-5111
    Abstract: Purpose: Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy. Experimental Design: We evaluated FRα expression in breast cancers by genomic (n = 3,414) and IHC (n = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro, and in human TNBC xenograft models. Results: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy–residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth. Conclusions: FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. Clin Cancer Res; 24(20); 5098–111. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0652
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 2036787-9
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  • 8
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    Abstract B46: Immunotherapy of solid tumors with IgE antibodies: Paradigm of a novel concept towards clinical application.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 1_Supplement ( 2013-01-01), p. B46-B46
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 1_Supplement ( 2013-01-01), p. B46-B46
    Abstract: Developing therapeutic antibodies with enhanced effector functions may be key to improving clinical outcomes in cancer. Our strategy to address this entails engineering antibodies directly targeting tumor antigens and bearing Fc regions of the IgE antibody class. Numerous attributes of this class, such as natural immune activatory functions in tissues and high affinity for cognate receptors on frequently tumor-resident effector cells can translate into effector cell activation and superior protection against solid tumors, compared to the conventionally-used antibodies with IgG Fc regions. We have developed a paradigm for this concept, the antibody MOv18 IgE, against the tumor antigen Folate Receptor α. This agent is presently prepared for first-in-man clinical studies, having demonstrated superior efficacy compared to the corresponding IgG1 antibody in three in vivo models of cancer, including one in an immunocompetent host. The antibody also yielded very promising safety profiles in in vivo evaluations, and also in ex vivo readouts normally applied in the field of allergy to examine sensitivity to allergens. The latter studies, conducted using cancer patient blood, suggest that this antibody is unlikely to trigger Type I hypersensitivity in patients. We have now extended the pathway to the design of similarly potent antibodies for the treatment of other solid tumors such as malignant melanoma and breast carcinoma. Two antibodies with Fc regions of the IgG1 and IgE classes and the same specificity for CSPG4, a tumor antigen expressed by 80% of melanomas, were tested in a xenograft model of human melanoma in a humanized host, with evident superior efficacy for the IgE counterpart. On-going evaluations and planned clinical studies in patients with cancer will constitute important metrics of the concept of IgE antibodies in cancer therapy, will inform the emerging field of AllergoOncology and will provide new scope for the design of novel cancer therapies. Citation Format: Sophia N. Karagiannis, Debra H. Josephs, Panagiotis Karagiannis, Louise Saul, Amy E. Gilbert, Tihomir Dodev, Alexander Koers, Philip J. Blower, Andrew J. Beavil, Frank O. Nestle, James F. Spicer, Hannah J. Gould. Immunotherapy of solid tumors with IgE antibodies: Paradigm of a novel concept towards clinical application. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B46.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMIMM2012-B46
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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