von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

Abstract

Small interfering RNAs (siRNAs) are widely used in biomedical research and in clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. Genetically targeting mitochondrial antiviral-signaling protein (MAVS) reversed the siRNA-mediated sensitizing effect, but no activation of canonical MAVS signaling, which involves phosphorylation of IkBα and interferon regulatory transcription factor 3 (IRF3), was observed. In contrast, MAVS mediated a noncanonical signal resulting in a prominent increase in mitochondrial ROS levels, and increase in the BACH1/pNRF2 transcription factor ratio and GPX4 up-regulation, which was associated with a 50% decrease in intracellular glutathione levels. We conclude that siRNAs commonly sensitize to ferroptosis and may severely compromise the conclusions drawn from silencing approaches in biomedical research. Finally, as ferroptosis contributes to a variety of pathophysiological processes, we cannot exclude side effects in human siRNA-based therapeutical concepts that should be clinically tested.

People
von Mässenhausen, Anne
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Schlecht, Marlena Nastassja
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Beer, Kristina
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Maremonti, Francesca
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Tonnus, Wulf
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Belavgeni, Alexia
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Gavali, Shubhangi
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Flade, Karolin
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Riley, Joel S.
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

Vringer, Esmee and Heilig, Rosalie and Riley, Joel S. and Black, Annabel and Cloix, Catherine and Skalka, George and Montes-Gómez, Alfredo E. and Aguado, Aurore and Lilla, Sergio and Walczak, Henning and Gyrd-Hansen, Mads and Murphy, Daniel J. and Huang, Danny T. and Zanivan, Sara and Tait, Stephen W.G. (2024) Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response. EMBO Journal, 43 (6). pp. 904-930. ISSN 0261-4189

Victorelli, Stella and Salmonowicz, Hanna and Chapman, James and Martini, Helene and Vizioli, Maria Grazia and Riley, Joel S. and Cloix, Catherine and Hall-Younger, Ella and Espindola-Netto, Jair Machado and Jurk, Diana and Lagnado, Anthony B. and Gomez, Lilian Sales and Farr, Joshua N. and Saul, Dominik and Reed, Rebecca and Kelly, George and Eppard, Madeline and Greaves, Laura C. and Dou, Zhixun and Pirius, Nicholas and Szczepanowska, Karolina and Porritt, Rebecca A. and Huang, Huijie and Huang, Timothy Y. and Mann, Derek A. and Masuda, Claudio Akio and Khosla, Sundeep and Dai, Haiming and Kaufmann, Scott H. and Zacharioudakis, Emmanouil and Gavathiotis, Evripidis and LeBrasseur, Nathan K. and Lei, Xue and Sainz, Alva G. and Korolchuk, Viktor I. and Adams, Peter D. and Shadel, Gerald S. and Tait, Stephen W.G. and Passos, João F. (2023) Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature, 622 (7983). pp. 627-636. ISSN 0028-0836

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Zamora Gonzalez, Nadia
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Brucker, Anne
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Becker, Jorunn Naila
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Tmava, Mirela
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Meyer, Claudia
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Peitzsch, Mirko
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Hugo, Christian
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Gembardt, Florian
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Angeli, Jose Pedro Friedmann
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Bornstein, Stefan R.
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Tait, Stephen W. G.
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Linkermann, Andreas
Author

von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548

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Title:
Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis
Creators:
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas
Identification Number:
10.1126/sciadv.adk7329
Date:
15 March 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
American Association for the Advancement of Science
Additional Information:
Funding: Work in the linkermann lab was funded by the German ResearchFoundation SFB-tRR205, SFB-tRR 127, and SPP3206, and a heisenberg-Professorship to A.l.,project number 324141047, the international research training group (iRtG) 2251, and thedFG grant 522190184. it was further supported by the BMBF (FeRROPath consortium). SWGt issupported by a cancer Research UK Programme Grant (dRcnPG-Jun22\100011).
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https://pub.demo35.eprints-hosting.org/id/eprint/332
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Article
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Unnamed user with email ejo1f20@soton.ac.uk
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Date Deposited:
11 Jun 2025 16:37
Revision:
11
Last Modified:
12 Jun 2025 10:13
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