scholarly journals Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade

2020 ◽  
Vol 8 (1) ◽  
pp. e000610 ◽  
Author(s):  
Rui Yang ◽  
Samah Elsaadi ◽  
Kristine Misund ◽  
Pegah Abdollahi ◽  
Esten Nymoen Vandsemb ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Stromal Cells ◽  
Adenosine Receptor ◽  
Immune Checkpoints ◽  
Incurable Cancer ◽  
Myeloma Cells ◽  
Hematological Cancers ◽  
Adenosine Receptor A2a

BackgroundPD1/PDL1-directed therapies have been unsuccessful for multiple myeloma (MM), an incurable cancer of plasma cells in the bone marrow (BM). Therefore, other immune checkpoints such as extracellular adenosine and its immunosuppressive receptor should be considered. CD39 and CD73 convert extracellular ATP to adenosine, which inhibits T-cell effector functions via the adenosine receptor A2A (A2AR). We set out to investigate whether blocking the adenosine pathway could be a therapy for MM.MethodsExpression of CD39 and CD73 on BM cells from patients and T-cell proliferation were determined by flow cytometry and adenosine production by Liquid chromatograpy-mass spectrometry (HPCL/MS). ENTPD1 (CD39) mRNA expression was determined on myeloma cells from patients enrolled in the publicly available CoMMpass study. Transplantable 5T33MM myeloma cells were used to determine the effect of inhibiting CD39, CD73 and A2AR in mice in vivo.ResultsElevated level of adenosine was found in BM plasma of MM patients. Myeloma cells from patients expressed CD39, and high gene expression indicated reduced survival. CD73 was found on leukocytes and stromal cells in the BM. A CD39 inhibitor, POM-1, and an anti-CD73 antibody inhibited adenosine production and reduced T-cell suppression in vitro in coculture of myeloma and stromal cells. Blocking the adenosine pathway in vivo with a combination of Sodium polyoxotungstate (POM-1), anti-CD73, and the A2AR antagonist AZD4635 activated immune cells, increased interferon gamma production, and reduced the tumor load in a murine model of MM.ConclusionsOur data suggest that the adenosine pathway can be successfully targeted in MM and blocking this pathway could be an alternative to PD1/PDL1 inhibition for MM and other hematological cancers. Inhibitors of the adenosine pathway are available. Some are in clinical trials and they could thus reach MM patients fairly rapidly.

Prosurvival and Immunosuppressive Functions of CD28 in the Myeloma Tumor Microenvironment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 473-473
Author(s):  
Jayakumar R Nair ◽  
Megan Murray ◽  
Chandana Koorella ◽  
Cheryl H Rozanski ◽  
Louise M Carlson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Stromal Cells ◽  
Kinase Activity ◽  
T Cell Proliferation ◽  
Myeloma Cells ◽  
Survival Signal ◽  
Cellular Components

Abstract Abstract 473 Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable for most patients. Myeloma cells are the transformed counterpart of the normal, bone marrow-resident long lived plasma cells (LLPC) that can survive for years to decades and are also responsible for long-term production of protective antibody titers. Critical interactions between MM and their bone marrow stromal cells (BMSC), that are important for their long term survival and chemotherapy resistance (in MM) identifies potential therapeutic targets, and are often the target for many IMIDs (thalidomide, lenalidomide). However, the specific molecular and cellular components of these interactions remain poorly characterized. These interactions directly transduce pro-survival signals to the myeloma cells as well as induce niche production of supportive soluble factors, the prototypic example being MM induction of stromal IL-6 - a key pro-MM survival cytokine. Despite this importance, the specific molecular and cellular components involved in these interactions remain poorly characterized. We have previously shown that CD28 expressed on human myeloma cells directly transduces a survival signal to MM cells upon binding its CD80/CD86 ligands on conventional (myeloid) dendritic cells (DC), and that DC preferentially co-localize with myeloma cells in the patient bone marrow niche. In our previous presentation at ASH (2010), we showed that myeloma cells interact with DCs to produce immunosuppressive factors such as IDO, and protects myeloma cells against cell death via a CD28-B7 mediated interaction. We now show that DC-IDO not only suppresses T-cell proliferation in invitro assays, but also contributes to the immunosuppressive milieu by inducing naïve T-cells to form T-regs (Fig 1). We hypothesize that while IDO activity by itself can suppress T-cell proliferation and induce T-cell growth arrest and apoptosis, the generation of T-regs by these immunosuppressive DCs (previous studies have shown a close association of T-regs with myeloma cells) form two facets of an immunosuppressive defense that myeloma cells mount against the body's anti-myeloma immune response.Figure 1Figure 1. As we have shown in our earlier presentations at ASH, on the myeloma side, the activation of CD28 induces pro-survival responses that can be extinguished by blocking CD28-B7 interactions between myeloma cells and DCs. Now we show that CD28 activation is accompanied by rapid tyrosine phosphorylation of CD28, association of p85 (PI3K), activation of Vav-1 and increase in CD28 associated tyrosine kinase activity, as shown by immunoprecipitation, western and kinase activity assays. Our data suggests a role for SLP76 downstream of Vav1 in CD28 mediated survival of myeloma cells. Immunoassays with protein extracts from myeloma cells that were previously co-cultured with DCs and isolated using positive magnetic selection show a decrease in BLIMP1 expression (Fig 2) that correlates with published data by other groups that indicates that DC mediated increase in myeloma clonogenicity/tumorigenicity is accompanied by increases in BCL6 (a negative regulator of BLIMP1). Blocking CD28-B7 interactions between myeloma and dendritic cells reversed this decrease in BLIMP1 expression. The implications of this to myeloma survival is currently under study in our lab.Figure 2Figure 2. In summary, we propose that CD28 expressed by myeloma cells serves as a central molecular bridge within a complex and integrated cellular and soluble factor microenvironment necessary for MM cell survival. CD28 directly delivers a pro-survival signal to the myeloma cell, and by ligating CD80/CD86 on conventional DC backsignals to these stromal cells to elicit immunosuppressive enzyme IDO and inducing immunosuppressive T-regulatory cells. Although undoubtedly incomplete, this model begins to point to novel therapeutic targets for the treatment of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bispecific T-Cell Engager (BiTE) Antibody Based Immunotherapy for Treatment of Relapsed Refractory Multiple Myeloma (RRMM): A Systematic Review of Preclinical and Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5567-5567
Author(s):  
Zunairah Shah ◽  
Mustafa Nadeem Malik ◽  
Syeda Sabeeka Batool ◽  
Sravanthi Kotapati ◽  
Aisha Akhtar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
T Cell ◽  
Adverse Events ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Myeloma Cells ◽  
Preclinical Trials ◽  
Bispecific T Cell Engager

Introduction Bispecific T-cell engager (BiTE) antibodies represent a novel therapeutic option for patients with multiple myeloma (MM). BiTE antibodies lack Fc region, and have variable domain only, they can simultaneously bind to two different epitopes i.e. cluster of differentiation 3 (CD3) molecules on tumor-specific T cells, and a specific antigen on myeloma cells, which leads to T-cell dependent destruction of myeloma cells. Currently, blinatumomab, specific for CD3 and CD19 is the only Food and Drug Administration FDA approved BiTE antibody for clinical use in patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia, several similar BiTE antibodies are under development. Methods Following PRISMA guidelines, we performed comprehensive literature on 4/15/19 cross-referencing the terms "bispecific antibodies" and "multiple myeloma" using PubMed, Embase, Web of Science, Cochrane Library, Clinicaltrials.gov and review of international medical meeting abstracts. Initially, 256 articles were identified and after detailed scrutiny, one phase 1 clinical trial with prelim results, 4 preclinical and 4 ongoing clinical trials were included. Results Preclinical trials: Anti-BCMA x Anti-CD3 Bispecific Antibody: BiTE antibodies are still in early development in MM, and most of the published data is about the pre-clinical phase. In preclinical trials, Hipp et al. 2017 and Cho et al. 2018 reported that AMG 420 (BI 836909) and AMG 701, which are anti CD3 and B-cell maturation antigen (BCMA), are highly efficacious in vitro in the killing of myeloma cells and potently induces autologous tumor cell lysis in patients with both newly diagnosed and RRMM regardless of their disease status. In mouse xenograft models reconstituted with human T cells, in vivo efficacy of AMG 420 was reported with an overall response in 6 of 10 animals, with all 6 responders became tumor-free at the end of the study. In an orthotopic L-363 xenograft model, treatment with AMG 420 resulted in prolonged median survival of 43-43.5 days. Dilillo et al. 2018 and Ji Li et al. 2017 reported similar in vivo results for REGN5458 and BFCR4350A respectively. Clinical trials: Currently, there are 5 phase 1 ongoing clinical trials (Table 1). Updated results of only first in human phase I AMG 420 are available. Forty-two MM patients with a high tumor burden and four prior lines of therapy were given 2.5 treatment cycles with AMG 420. Overall thirteen (31%) patients responded to AMG 420 therapy, with complete response (CR) in 6 (14.2%) patients, very good partial response (VGPR) in 2 (5%) patients and partial response (PR) in 2(5%) patients. Eleven of these patients responded in the first treatment cycle, with a median response time of 1 month. Twenty-five (57.1%) patients discontinued treatment due to progressive disease. Four deaths were reported; 2 from disease progression and 2 due to adverse events; neither of them was treatment-related. Serious adverse events were reported in twenty-one (50%) patients, the infection was reported in twelve (29%) and polyneuropathy in three (7%), eighteen (43%) required hospitalization. Treatment-related serious adverse events included three (7%) patients with grade 2-3 cytokine release syndrome, three (7%) with polyneuropathy and one (2.3%) with edema. Conclusion After the success of naked antibodies like daratumumab and elotuzumab for MM, there is a need to develop immunotherapy using conjugated antibodies and BiTE antibodies to overcome the challenge of MM resistance and relapse to prior therapies. Preclinical data with BiTE antibodies are promising; AMG 420 anti-CD3/BCMA BiTE has already been granted fast track status by the FDA. We anticipate that drug will enter phase 2 clinical trials for drug development against RRMM Other BiTE antibodies with strong preclinical efficacy are under development and data from larger prospective clinical trials is needed to explore their efficacy in the treatment of multiple myeloma. Table 1 Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Identification of Novel Immune-Checkpoint Molecules on Multiple Myeloma Cells Using a High-Throughput Discovery Platform

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 380-380
Author(s):  
Valentina Volpin ◽  
Till Michels ◽  
Antonio Sorrentino ◽  
Dirk Hose ◽  
Anthony D. Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Board Of Directors ◽  
High Throughput ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Immune Checkpoints ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
Immune Checkpoint Molecules

Abstract Introduction: Multiple myeloma (MM) is a B-cell malignancy, characterized by accumulation of plasma cell clones in the bone marrow. While novel therapeutic agents like immunomodulatory drugs and proteasome inhibitors have improved overall survival of MM patients, the disease remains incurable in most patients. Several studies showed that immune-checkpoint molecules are expressed by myeloma cells and induce tumor-related immune suppression. Despite the promising results achieved by blocking CTLA4 and the PD-1/PD-L1 axis in the treatment of various solid tumors and Hodgkin's lymphoma, targeting these checkpoints did not induce objective responses in Phase I/II trials in MM patients. Therefore, identification of novel immune-checkpoints and defining the subsequent molecular mechanisms of inhibition are essential for further improvement. Methods: Our main goal is to identify novel MM-related immune-checkpoint molecules by taking advantage of a high-throughput (HT) RNAi screen and sequentially validate the role of candidate molecules, whose blockade could potentially induce anti-tumor immunity in MM patients. Methods: High-throughput RNAi screens offer a possibility to systemically search for immune-checkpoint molecules. Therefore, we established a high-throughput screening system to discern candidate molecules and evaluate their use as potential targets for multiple myeloma immunotherapy. We established a luciferase based read-out system by generating a stable luciferase expressing MM cell line (KMM-1-luc). To test the effect of immune-checkpoint molecules, KMM-1-luc cells were transfected with a siRNAs library targeting 2514 genes encoding for cell surface proteins, kinases and GPCRs. Transfected tumor cells were subsequently co-cultured with patient-derived HLA-matched Myeloma Infiltrating T Lymphocytes (MILs) and the effect of gene knock-down on T-cell mediated tumor lysis was measured. Results: Based on our primary HT-screening, we have identified 132 candidate molecules (hits) whose knockdown increased T-cell mediated killing more efficiently than the established checkpoint genes CCR9. To confirm the hits and the robustness of the screening, we re-tested the identified candidates in a secondary screening. Among these potential immune-checkpoints we selected 10 hits for further validation. So far, we were able to confirm expression of the hits at mRNA level and to validate siRNAs on-target effect by qPCR and luciferase-based cytotoxicity assay. Detailed results will be presented at the meeting. Conclusion: Altogether we optimized a high-throughput RNAi screen to discover novel immune-checkpoints that are potential immunotherapeutic targets for the treatment of multiple myeloma. We are currently investigating the mode of action of the candidate hits in vitro. Further in vivo validation of these immune-checkpoint molecules is still required for clinical studies. Disclosures Goldschmidt: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Cytotoxic T Cell Responses Induced by CS1/CRT Fusion DNA Vaccine in a Human Plasmacytoma Model

2020 ◽  
Vol 10 ◽  
Author(s):  
Xueshi Ye ◽  
Wanli Li ◽  
Jinwen Huang ◽  
Lifei Zhang ◽  
Ye Zhang
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Dna Vaccine ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Myeloma Cells ◽  
Cell Responses ◽  
Incurable Disease ◽  
Cytotoxic T Cell Responses

To date, multiple myeloma remains an incurable disease. Immunotherapy is an encouraging option in the development of multiple myeloma (MM) therapy. CS1 is a specific myeloma antigen, which is highly expressed in myeloma cells. Calreticulin (CRT) is a key determinant of cell death, which can influence antigen presentation and promote cellular phagocytic uptake. In the current study, we constructed a DNA vaccine encoding both CS1 and CRT. Our results show that the PcDNA3.1-CS1/CRT vaccine was able to induce cytotoxic T cell responses against myeloma cells in vivo, and the tumor growth was significantly suppressed in mice immunized with this vaccine. Therefore, our findings indicate that the CS1/CRT fusion DNA vaccine may represent a promising novel myeloma therapy, and the potential for combining the CS1/CRT vaccine with other myeloma treatments.

scholarly journals Loss of Stromal Galectin-1 Enhances Multiple Myeloma Development: Emphasis on a Role in Osteoclasts

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 261 ◽  
Author(s):  
Joséphine Muller ◽  
Elodie Duray ◽  
Margaux Lejeune ◽  
Sophie Dubois ◽  
Erwan Plougonven ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stromal Cells ◽  
Tumour Progression ◽  
Microarray Data Analysis ◽  
Wild Type ◽  
Micro Computed Tomography ◽  
Myeloma Cells ◽  
Osteoclast Activity ◽  
Myeloma Bone Disease

Multiple myeloma osteolytic disease is caused by an uncoupled bone-remodelling process with an increased osteoclast activity. Disease development relies on interactions between myeloma cells and bone marrow stromal cells. Recent findings suggest a role for glycan-binding proteins in myeloma microenvironment. Here, we investigated lectins involved in osteoclastogenesis and their role in myeloma bone disease. Microarray data analysis showed a lower expression of galectin-1 (gal-1) in mature osteoclasts compared to monocytic progenitor cells, confirmed at the RNA and protein levels in osteoclast cultures. Confocal microscopy showed that gal-1 localised predominantly in the sealing zone of mature osteoclasts. Although equal differentiated-osteoclast numbers, gal-1−/− osteoclasts showed a higher resorption activity compared to wild-type controls. Micro-computed tomography showed an aberrant bone phenotype with decreased bone densities in gal-1−/− mice. In vivo, tumour progression was faster in gal-1−/− mice and associated with a marked bone loss. Additionally, myeloma cells were found to decrease gal-1 expression in osteoclasts. Our results demonstrate that galectin-1 regulates osteoclast activity with an increased resorption by gal-1−/− osteoclasts and decreased bone densities in gal-1−/− mice. We observed an enhanced tumour development in gal-1−/− mice compared to wild-type mice, suggesting that galectin-1 has a functional role in stromal cells in myeloma microenvironment.

scholarly journals Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 4451
Author(s):  
Coralia Cotoraci ◽  
Alina Ciceu ◽  
Alciona Sasu ◽  
Eftimie Miutescu ◽  
Anca Hermenean
Keyword(s):  
Multiple Myeloma ◽  
Survival Rate ◽  
Plasma Cells ◽  
Inhibition Of Proliferation ◽  
In Vivo Experiments ◽  
Clonal Proliferation ◽  
Hematological Cancers ◽  
Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

scholarly journals Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche

2021 ◽  
Vol 9 (3) ◽  
pp. e001803
Author(s):  
Louise M E Müller ◽  
Gemma Migneco ◽  
Gina B Scott ◽  
Jenny Down ◽  
Sancha King ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Immune Responses ◽  
Stromal Cells ◽  
Tumor Burden ◽  
Effector Memory ◽  
In Vivo Model ◽  
Bm Niche

BackgroundMultiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported.MethodsThis study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment.ResultsUsing the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+ T cell numbers; (ii) activated NK cells and CD8+ T cells and (iii) upregulated effector-memory CD8+ T cells. Moreover, increased effector-memory CD8+ T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes.ConclusionThese data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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