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  1. Article ; Online: Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries.

    Montinaro, Antonella / Walczak, Henning

    Cell death and differentiation

    2022  Volume 30, Issue 2, Page(s) 237–249

    Abstract: Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in a wide variety of cancer cells, both in vitro and in vivo, importantly without killing any essential normal cells. These findings formed the basis for the ... ...

    Abstract Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in a wide variety of cancer cells, both in vitro and in vivo, importantly without killing any essential normal cells. These findings formed the basis for the development of TRAIL-receptor agonists (TRAs) for cancer therapy. However, clinical trials conducted with different types of TRAs have, thus far, afforded only limited therapeutic benefit, as either the respectively chosen agonist showed insufficient anticancer activity or signs of toxicity, or the right TRAIL-comprising combination therapy was not employed. Therefore, in this review we will discuss molecular determinants of TRAIL resistance, the most promising TRAIL-sensitizing agents discovered to date and, importantly, whether any of these could also prove therapeutically efficacious upon cancer relapse following conventional first-line therapies. We will also discuss the more recent progress made with regards to the clinical development of highly active non-immunogenic next generation TRAs. Based thereupon, we next propose how TRAIL resistance might be successfully overcome, leading to the possible future development of highly potent, cancer-selective combination therapies that are based on our current understanding of biology TRAIL-induced cell death. It is possible that such therapies may offer the opportunity to tackle one of the major current obstacles to effective cancer therapy, namely overcoming chemo- and/or targeted-therapy resistance. Even if this were achievable only for certain types of therapy resistance and only for particular types of cancer, this would be a significant and meaningful achievement.
    MeSH term(s) Humans ; Neoplasms/drug therapy ; Apoptosis ; TNF-Related Apoptosis-Inducing Ligand/pharmacology ; TNF-Related Apoptosis-Inducing Ligand/therapeutic use ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics ; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use
    Chemical Substances TNF-Related Apoptosis-Inducing Ligand ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; Antineoplastic Agents
    Language English
    Publishing date 2022-10-04
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/s41418-022-01059-z
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  2. Article ; Online: Sterile Inflammation Fuels Gastric Cancer.

    Montinaro, Antonella / Walczak, Henning

    Immunity

    2018  Volume 48, Issue 3, Page(s) 481–483

    Abstract: Constitutively activated NF-κB signaling has long been known to be oncogenic. In this issue of Immunity, O'Reilly et al. (2018) unveil a link between loss of NF-κB1, aberrant STAT1 signaling, sterile inflammation, and the increased expression of immune ... ...

    Abstract Constitutively activated NF-κB signaling has long been known to be oncogenic. In this issue of Immunity, O'Reilly et al. (2018) unveil a link between loss of NF-κB1, aberrant STAT1 signaling, sterile inflammation, and the increased expression of immune checkpoint molecules as cancer drivers.
    MeSH term(s) Carcinogenesis ; Humans ; Inflammation ; NF-kappa B ; Neoplasms ; Signal Transduction
    Chemical Substances NF-kappa B
    Language English
    Publishing date 2018-03-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2018.03.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy.

    von Karstedt, Silvia / Montinaro, Antonella / Walczak, Henning

    Nature reviews. Cancer

    2016  Volume 17, Issue 6, Page(s) 352–366

    Abstract: The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the ... ...

    Abstract The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL-TRAIL-R system to their own advantage. However, novel insight on two fronts - how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered - gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL-TRAIL-R system - as well as the gaps therein - and discuss the opportunities and challenges in effectively targeting this pathway.
    MeSH term(s) Humans ; Neoplasms/etiology ; Neoplasms/pathology ; Neoplasms/therapy ; Receptors, TNF-Related Apoptosis-Inducing Ligand/physiology ; Signal Transduction ; TNF-Related Apoptosis-Inducing Ligand/physiology
    Chemical Substances Receptors, TNF-Related Apoptosis-Inducing Ligand ; TNF-Related Apoptosis-Inducing Ligand
    Language English
    Publishing date 2016-10-13
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2062767-1
    ISSN 1474-1768 ; 1474-175X
    ISSN (online) 1474-1768
    ISSN 1474-175X
    DOI 10.1038/nrc.2017.28
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality.

    Albert, Marie-Christine / Uranga-Murillo, Iratxe / Arias, Maykel / De Miguel, Diego / Peña, Natacha / Montinaro, Antonella / Varanda, Ana Beatriz / Theobald, Sebastian J / Areso, Itziar / Saggau, Julia / Koch, Manuel / Liccardi, Gianmaria / Peltzer, Nieves / Rybniker, Jan / Hurtado-Guerrero, Ramón / Merino, Pedro / Monzón, Marta / Badiola, Juan J / Reindl-Schwaighofer, Roman /
    Sanz-Pamplona, Rebeca / Cebollada-Solanas, Alberto / Megyesfalvi, Zsolt / Dome, Balazs / Secrier, Maria / Hartmann, Boris / Bergmann, Michael / Pardo, Julián / Walczak, Henning

    Cell death and differentiation

    2024  

    Abstract: The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process ... ...

    Abstract The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.
    Language English
    Publishing date 2024-03-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/s41418-024-01278-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Adenosine receptors as potential targets in melanoma.

    Montinaro, Antonella / Iannone, Raffaella / Pinto, Aldo / Morello, Silvana

    Pharmacological research

    2013  Volume 76, Page(s) 34–40

    Abstract: Melanoma is one of the most aggressive types of cancer, that is difficult to manage clinically. A major feature of melanoma cells is their ability to escape immune surveillance. Adenosine receptors play a pivotal role in host immune-surveillance. A2a ( ... ...

    Abstract Melanoma is one of the most aggressive types of cancer, that is difficult to manage clinically. A major feature of melanoma cells is their ability to escape immune surveillance. Adenosine receptors play a pivotal role in host immune-surveillance. A2a (A2aR) and, partially, A2bR receptors mediate the adenosine-induced immune-suppression, which markedly facilitates tumor development/progression. On the contrary, A3R stimulation enhances the anti-tumor immune response and thus limits tumor growth. A3R also inhibits the proliferation of many cancer cells. Given that A2aR and A3R have profound effects on tumor growth and metastasis, they are attractive targets for novel therapeutic anti-cancer agents. Here, we review the role played by A2aR and A3R in regulating cancer pathogenesis, with a focus on melanoma, and the therapeutic potential of adenosine receptors pharmacological modulation.
    MeSH term(s) Adenosine/immunology ; Adenosine A2 Receptor Antagonists/pharmacology ; Adenosine A2 Receptor Antagonists/therapeutic use ; Adenosine A3 Receptor Agonists/pharmacology ; Adenosine A3 Receptor Agonists/therapeutic use ; Animals ; Humans ; Melanoma/drug therapy ; Melanoma/immunology ; Melanoma/pathology ; Molecular Targeted Therapy/methods ; Receptor, Adenosine A2A/immunology ; Receptor, Adenosine A3/immunology
    Chemical Substances Adenosine A2 Receptor Antagonists ; Adenosine A3 Receptor Agonists ; Receptor, Adenosine A2A ; Receptor, Adenosine A3 ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2013-10
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 1003347-6
    ISSN 1096-1186 ; 0031-6989 ; 1043-6618
    ISSN (online) 1096-1186
    ISSN 0031-6989 ; 1043-6618
    DOI 10.1016/j.phrs.2013.07.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Ubiquitin in the immune system.

    Zinngrebe, Julia / Montinaro, Antonella / Peltzer, Nieves / Walczak, Henning

    EMBO reports

    2013  Volume 15, Issue 1, Page(s) 28–45

    Abstract: Ubiquitination is a post-translational modification process that has been implicated in the regulation of innate and adaptive immune responses. There is increasing evidence that both ubiquitination and its reversal, deubiquitination, play crucial roles ... ...

    Abstract Ubiquitination is a post-translational modification process that has been implicated in the regulation of innate and adaptive immune responses. There is increasing evidence that both ubiquitination and its reversal, deubiquitination, play crucial roles not only during the development of the immune system but also in the orchestration of an immune response by ensuring the proper functioning of the different cell types that constitute the immune system. Here, we provide an overview of the latest discoveries in this field and discuss how they impact our understanding of the ubiquitin system in host defence mechanisms as well as self-tolerance.
    MeSH term(s) Adaptor Proteins, Signal Transducing/physiology ; Animals ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; Proteolysis ; Self Tolerance ; Signal Transduction ; Toll-Like Receptors/physiology ; Tumor Necrosis Factor-alpha/physiology ; Ubiquitin/physiology ; Ubiquitination
    Chemical Substances Adaptor Proteins, Signal Transducing ; Toll-Like Receptors ; Tumor Necrosis Factor-alpha ; Ubiquitin
    Language English
    Publishing date 2013-12-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.1002/embr.201338025
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  7. Article: Adenosine receptors as potential targets in melanoma

    Montinaro, Antonella / Iannone, Raffaella / Pinto, Aldo / Morello, Silvana

    Pharmacological research. 2013 Oct., v. 76

    2013  

    Abstract: Melanoma is one of the most aggressive types of cancer, that is difficult to manage clinically. A major feature of melanoma cells is their ability to escape immune surveillance. Adenosine receptors play a pivotal role in host immune-surveillance. A2a ( ... ...

    Abstract Melanoma is one of the most aggressive types of cancer, that is difficult to manage clinically. A major feature of melanoma cells is their ability to escape immune surveillance. Adenosine receptors play a pivotal role in host immune-surveillance. A2a (A2aR) and, partially, A2bR receptors mediate the adenosine-induced immune-suppression, which markedly facilitates tumor development/progression. On the contrary, A3R stimulation enhances the anti-tumor immune response and thus limits tumor growth. A3R also inhibits the proliferation of many cancer cells. Given that A2aR and A3R have profound effects on tumor growth and metastasis, they are attractive targets for novel therapeutic anti-cancer agents. Here, we review the role played by A2aR and A3R in regulating cancer pathogenesis, with a focus on melanoma, and the therapeutic potential of adenosine receptors pharmacological modulation.
    Keywords adenosine ; antineoplastic agents ; immune response ; melanoma ; metastasis ; monitoring ; neoplasm cells ; pathogenesis ; receptors
    Language English
    Dates of publication 2013-10
    Size p. 34-40.
    Publishing place Elsevier Ltd
    Document type Article
    ISSN 1043-6618
    DOI 10.1016/j.phrs.2013.07.002
    Database NAL-Catalogue (AGRICOLA)

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  8. Article ; Online: Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers.

    Montinaro, Antonella / Areso Zubiaur, Itziar / Saggau, Julia / Kretz, Anna-Laura / Ferreira, Rute M M / Hassan, Omar / Kitzig, Ella / Müller, Ines / El-Bahrawy, Mona A / von Karstedt, Silvia / Kulms, Dagmar / Liccardi, Gianmaria / Lemke, Johannes / Walczak, Henning

    Cell death and differentiation

    2021  Volume 29, Issue 3, Page(s) 492–503

    Abstract: Primary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in ... ...

    Abstract Primary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis ; Cell Line, Tumor ; Mitochondria ; Neoplasms/drug therapy ; TNF-Related Apoptosis-Inducing Ligand/pharmacology
    Chemical Substances Antineoplastic Agents ; TNF-Related Apoptosis-Inducing Ligand
    Language English
    Publishing date 2021-09-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/s41418-021-00869-x
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  9. Article ; Online: A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets.

    Li, Xiang / Huang, Chun-Hao / Sánchez-Rivera, Francisco J / Kennedy, Margaret C / Tschaharganeh, Darjus F / Morris, John P / Montinaro, Antonella / O'Rourke, Kevin P / Banito, Ana / Wilkinson, John E / Chen, Chi-Chao / Ho, Yu-Jui / Dow, Lukas E / Tian, Sha / Luan, Wei / de Stanchina, Elisa / Zhang, Tinghu / Gray, Nathanael S / Walczak, Henning /
    Lowe, Scott W

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 17, Page(s) e2110557119

    Abstract: Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a ... ...

    Abstract Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile preclinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9—a cancer target whose clinical development has been hampered by compounds with poorly understood target specificity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve significant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cyclin-Dependent Kinase 9/metabolism ; Mice ; Neoplasms/drug therapy ; Neoplasms/genetics ; RNA Interference
    Chemical Substances Antineoplastic Agents ; Cdk9 protein, mouse (EC 2.7.11.22) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22)
    Language English
    Publishing date 2022-04-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2110557119
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  10. Article ; Online: Cl-IB-MECA enhances TNF-α release in peritoneal macrophages stimulated with LPS.

    Forte, Giovanni / Sorrentino, Rosalinda / Montinaro, Antonella / Pinto, Aldo / Morello, Silvana

    Cytokine

    2011  Volume 54, Issue 2, Page(s) 161–166

    Abstract: Adenosine receptor A3 (A3R) belongs to the Gi/Gq-coupled receptor family, that leads to the intracellular cAMP reduction and intracellular calcium increase, respectively. A3R is widely expressed and it can play a crucial role in many patho-physiological ... ...

    Abstract Adenosine receptor A3 (A3R) belongs to the Gi/Gq-coupled receptor family, that leads to the intracellular cAMP reduction and intracellular calcium increase, respectively. A3R is widely expressed and it can play a crucial role in many patho-physiological conditions, including inflammation. Here we investigate the effect of Cl-IB-MECA, A3R agonist, on the production of TNF-α. We found that Cl-IB-MECA enhances LPS-induced TNF-α release in peritoneal macrophages. This effect is reduced by MRS1191, A3R antagonist and by forskolin, activator of adenylyl cyclase. pIκBα increased in LPS+Cl-IB-MECA-treated macrophages, while total IκB kinase-β (IKKβ) reduced. Indeed, p65NF-κB nuclear translocation increased in cells treated with LPS+Cl-IB-MECA. Moreover, IMD 0354, IKKβ inhibitor, significantly abrogated the effect of Cl-IB-MECA on TNF-α release. Inhibition of protein kinase C (PKC) significantly reduced Cl-IB-MECA-induced TNF-α release in LPS-stimulated macrophages. Furthermore, LY-294002, PI3K inhibitor, reduced the TNF-α production enhanced by Cl-IB-MECA, although the phosphorylation status of Akt did not change in cells treated with LPS+Cl-IB-MECA than LPS alone. In summary, these data show that Cl-IB-MECA is able to enhance TNF-α production in LPS-treated macrophages in an NF-κB- dependent manner.
    MeSH term(s) Adenosine/analogs & derivatives ; Adenosine/pharmacology ; Animals ; Blotting, Western ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Lipopolysaccharides/pharmacology ; Macrophages, Peritoneal/drug effects ; Macrophages, Peritoneal/metabolism ; Mice ; Mice, Inbred C57BL ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Kinase C/metabolism ; Receptors, Purinergic P1/drug effects ; Receptors, Purinergic P1/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription, Genetic
    Chemical Substances Lipopolysaccharides ; NF-kappa B ; Receptors, Purinergic P1 ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein Kinase C (EC 2.7.11.13) ; Adenosine (K72T3FS567) ; 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Z07JR07J6C)
    Language English
    Publishing date 2011-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1018055-2
    ISSN 1096-0023 ; 1043-4666
    ISSN (online) 1096-0023
    ISSN 1043-4666
    DOI 10.1016/j.cyto.2011.02.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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