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2. Using Stable Distributions to Characterize Proton Pencil Beams

Author

Heuvel, Frank Van den, Fiorini, Francesca, Schreuder, Niek, and George, Ben

Subjects
Physics - Medical Physics
Abstract

Purpose: To introduce and evaluate the use of stable distributions as a means of describing the behavior of charged particle pencil beams in a medium, with specific emphasis on proton beam scanning (PBS). Methods: The proton pencil beams of a clinically commissioned proton treatment facility are replicated in a Monte Carlo simulation system (FLUKA). For each available energy the beam deposition in water medium is characterized by the dose deposition. Using an alpha--stable distribution methodology each beam with a nominal energy $E$ is characterized by the lateral spread at depth $z$: $S(z;\alpha,\gamma,E)$ and a total energy deposition $I_D(z)$. The beams are then described as a function of the variation of the parameters at depth. Finally, an implementation in a freely available open source dose calculation suite (matRad, DKFZ, Heidelberg, Germany) is proposed. Results: Quantitatively, the fit of the stable distributions, compared to those implemented in standard treatment planning systems, are equivalent. The efficiency of the representation is better (2 compared to 3 and more parameters needed). The meta--parametrization (i.e. the description of the dose deposition by only providing the fitted parameters) allows for interpolation of non--measured data. In the case of the clinical data used in this paper, it was possible to only commission 1 out of 5 nominal energies to obtain a viable data set. Conclusions: Alpha--stable distributions are intrinsically suited to describe charged particle pencil beams in a medium and can be easily implemented in existing treatment planning systems. The use of alpha-distributions can easily be extended to other particles.

Published
2016
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3. SAMD9L acts as an antiviral factor against HIV-1 and primate lentiviruses by restricting viral and cellular translation.

Author

Legrand, Alexandre, Dahoui, Clara, De La Myre Mory, Clément, Noy, Kodie, Guiguettaz, Laura, Versapuech, Margaux, Loyer, Clara, Pillon, Margaux, Wcislo, Mégane, Guéguen, Laurent, Berlioz-Torrent, Clarisse, Cimarelli, Andrea, Mateo, Mathieu, Fiorini, Francesca, Ricci, Emiliano P., and Etienne, Lucie

Subjects
GENETIC translation, LENTIVIRUSES, HIV, VIRUS diseases, RNA viruses, RHABDOVIRUSES, SIMIAN immunodeficiency virus
Abstract

Sterile alpha motif domain-containing proteins 9 and 9-like (SAMD9/9L) are associated with life-threatening genetic diseases in humans and are restriction factors of poxviruses. Yet, their cellular function and the extent of their antiviral role are poorly known. Here, we found that interferon-stimulated human SAMD9L restricts HIV-1 in the late phases of replication, at the posttranscriptional and prematuration steps, impacting viral translation and, possibly, endosomal trafficking. Surprisingly, the paralog SAMD9 exerted an opposite effect, enhancing HIV-1. More broadly, we showed that SAMD9L restricts primate lentiviruses, but not a gammaretrovirus (MLV), nor 2 RNA viruses (arenavirus MOPV and rhabdovirus VSV). Using structural modeling and mutagenesis of SAMD9L, we identified a conserved Schlafen-like active site necessary for HIV-1 restriction by human and a rodent SAMD9L. By testing a gain-of-function constitutively active variant from patients with SAMD9L-associated autoinflammatory disease, we determined that SAMD9L pathogenic functions also depend on the Schlafen-like active site. Finally, we found that the constitutively active SAMD9L strongly inhibited HIV, MLV, and, to a lesser extent, MOPV. This suggests that the virus-specific effect of SAMD9L may involve its differential activation/sensing and the virus ability to evade from SAMD9L restriction. Overall, our study identifies SAMD9L as an HIV-1 antiviral factor from the cell autonomous immunity and deciphers host determinants underlying the translational repression. This provides novel links and therapeutic avenues against viral infections and genetic diseases. SAMD9 and SAMD9L are known restriction factors of poxviruses, but it is currently unknown if the SAMD9 gene family can restrict other viruses. This study demonstrates that SAMD9L, but not SAMD9, inhibits HIV-1 and other primate lentiviruses through a conserved Schlafen-like active site, thereby disrupting viral translation. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Experimental and computational dosimetry of laser-driven radiation beams

Author

Fiorini, Francesca

Subjects
535, QC Physics
Abstract

Laser-driven particle acceleration is an area of increasing research interest given the recent development of short pulse high intensity lasers. A significant difficulty in this field is given by the exceptionally large instantaneous dose rates which such particle beams can produce. This represents a challenge for standard dosimetry techniques and more sophisticated procedures need to be explored. In this thesis I present novel detection and characterisation methods using a combination of GafChromic films, TLD chips, nuclear activation and Monte Carlo simulations, applicable to laser-driven beams. Part of the work is focused on the detection of laserdriven protons used to irradiate V79 cells in order to determine the feasibility of laser-driven proton therapy. A dosimetry method involving GafChromic films and numerical simulations has been appositely developed and used to obtain cell survival results, which are in agreement with those obtained by conventionally accelerated proton beams. Another part is dedicated to the detection and characterisation of laser-driven electron and X-ray beams. An innovative simulation method to obtain the temperature of the electrons accelerated by the laser, and predict the subsequently generated X-ray beam, has been developed and compared with the acquired experimental data.

Published
2012

7. The inflammatory and tumor suppressor SAMD9L acts through a Schlafen-like box to restrict HIV and inhibit cell translation in SAAD/ATXPC

Author

Legrand, Alexandre, primary, Dahoui, Clara, additional, De La Myre Mory, Clément, additional, Loyer, Clara, additional, Noy, Kodie, additional, Guiguettaz, Laura, additional, Pillon, Margaux, additional, Wcislo, Mégane, additional, Guéguen, Laurent, additional, Cimarelli, Andrea, additional, Mateo, Mathieu, additional, Fiorini, Francesca, additional, Ricci, Emiliano, additional, and Etienne, Lucie, additional

Published
2023
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12. Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer: Results from eight European centres

Author

Hoffmann, Lone, primary, Mortensen, Hanna, additional, Shamshad, Muhammad, additional, Berbee, Maaike, additional, Bizzocchi, Nicola, additional, Bütof, Rebecca, additional, Canters, Richard, additional, Defraene, Gilles, additional, Ehmsen, Mai Lykkegaard, additional, Fiorini, Francesca, additional, Haustermans, Karin, additional, Hulley, Ryan, additional, Korevaar, Erik W., additional, Clarke, Matthew, additional, Makocki, Sebastian, additional, Muijs, Christina T., additional, Murray, Luke, additional, Nicholas, Owen, additional, Nordsmark, Marianne, additional, Radhakrishna, Ganesh, additional, Thomas, Melissa, additional, Troost, Esther G.C., additional, Vilches-Freixas, Gloria, additional, Visser, Sabine, additional, Weber, Damien C., additional, and Møller, Ditte Sloth, additional

Published
2022
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19. Two-long terminal repeat (LTR) DNA circles are a substrate for HIV-1 integrase

Author

Chaignepain, Stephane, Maillot, Benoit, Oladosu, Oyindamola, Robert, Xavier, Fiorini, Francesca, Kieffer, Bruno, Bouaziz, Serge, Gouet, Patrice, Ruff, Marc, Lee, Ga-Eun, Mauro, Eric, Shin, Cha-Gyun, Richetta, Clémence, Thierry, Sylvain, Thierry, Eloise, Lesbats, Paul, Lapaillerie, Delphine, Munir, Soundasse, Subra, Frédéric, Leh, Hervé, Deprez, Eric, Parissi, Vincent, Delelis, Olivier, Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre génomique fonctionnelle, Université Bordeaux Segalen - Bordeaux 2, Department of Microbiology, Kohat University of Science and Technology (KUST), Laboratoire de Biotechnologie et Pharmacogénétique Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Bioalliancepharma, and Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA)

Subjects
0301 basic medicine, Virus Integration, [SDV]Life Sciences [q-bio], HIV Integrase, Microbiology, Biochemistry, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Retrovirus, law, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, HIV Long Terminal Repeat, 030102 biochemistry & molecular biology, biology, Chemistry, Cell Biology, Integrases, biology.organism_classification, Reverse transcriptase, Long terminal repeat, 3. Good health, Integrase, Cell biology, 030104 developmental biology, Viral replication, DNA, Viral, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, biology.protein, Recombinant DNA, DNA, Circular, DNA
Abstract

Integration of the HIV-1 DNA into the host genome is essential for viral replication and is catalyzed by the retroviral integrase. To date, the only substrate described to be involved in this critical reaction is the linear viral DNA produced in reverse transcription. However, during HIV-1 infection, two-long terminal repeat DNA circles (2-LTRcs) are also generated through the ligation of the viral DNA ends by the host cell's nonhomologous DNA end-joining pathway. These DNAs contain all the genetic information required for viral replication, but their role in HIV-1's life cycle remains unknown. We previously showed that both linear and circular DNA fragments containing the 2-LTR palindrome junction can be efficiently cleaved in vitro by recombinant integrases, leading to the formation of linear 3′-processed–like DNA. In this report, using in vitro experiments with purified proteins and DNAs along with DNA endonuclease and in vivo integration assays, we show that this circularized genome can also be efficiently used as a substrate in HIV-1 integrase-mediated integration both in vitro and in eukaryotic cells. Notably, we demonstrate that the palindrome cleavage occurs via a two-step mechanism leading to a blunt-ended DNA product, followed by a classical 3′-processing reaction; this cleavage leads to integrase-dependent integration, highlighted by a 5-bp duplication of the host genome. Our results suggest that 2-LTRc may constitute a reserve supply of HIV-1 genomes for proviral integration.

Published
2019
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22. Using stable distributions to characterize proton pencil beams

Author

Heuvel, Frank Van den, Fiorini, Francesca, Schreuder, Niek, and George, Ben

Subjects
dosimetry, protons, Physics::Medical Physics, FOS: Physical sciences, modeling, Physics - Medical Physics, Physical Phenomena, lateral scatter, COMPUTATIONAL AND EXPERIMENTAL DOSIMETRY, Physics::Accelerator Physics, Medical Physics (physics.med-ph), Monte Carlo Method, Research Articles, Research Article, proton
Abstract

Purpose To introduce and evaluate the use of stable distributions as a methodology to quantify the behavior of proton pencil beams in a medium. Methods The proton pencil beams of a clinically commissioned proton treatment facility are replicated in a Monte Carlo simulation system (FLUKA). For each available energy, the beam deposition in water medium is characterized by the dose deposition. Using a stable distribution methodology, each beam with a nominal energy E is characterized by the lateral spread at depth z: S(z; α, γ, E) and a total energy deposition ID(z, E). The parameter α describes the tailedness of the distributions, while γ is used to scale the size of the function. The beams can then be described completely by a function of the variation of the parameters with depth. Results Quantitatively, the fit of the stable distributions, compared to those implemented in some standard treatment planning systems, are equivalent for all but the highest energies (i.e., 230 MeV/u). The decrease in goodness of fit makes this methodology comparable to a double Gaussian approach. The introduction of restricted linear combinations of stable distributions also resolves that particular case. More importantly, the meta‐parameterization (i.e., the description of the dose deposition by only providing the fitted parameters) allows for interpolation of nonmeasured data. In the case of the clinical commissioning data used in this paper, it was possible to only commission one out of five nominal energies to obtain a viable dataset, valid for all energies. An additional parameter β allows to describe asymmetric beam profiles as well. Conclusions Stable distributions are intrinsically suited to describe proton pencil beams in a medium and provide a tool to quantify the propagation of proton beams in a medium.

Published
2018

23. HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition

Author

Fiorini, Francesca, Robin, Jean-Philippe, Kanaan, Joanne, Borowiak, Malgorzata, Croquette, Vincent, Le Hir, Hervé, Jalinot, Pierre, Mocquet, Vincent, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Statistique de l'ENS (LPS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I

Subjects
Human T-lymphotropic virus 1, Science, [SDV]Life Sciences [q-bio], Gene Products, tax, Article, Nonsense Mediated mRNA Decay, Protein Transport, Adenosine Triphosphate, Protein Domains, Host-Pathogen Interactions, Mutation, Trans-Activators, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Q, lcsh:Science, RNA Helicases, ComputingMilieux_MISCELLANEOUS, HeLa Cells
Abstract

Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD. These mechanistic insights reveal how HTLV-1 hijacks the central component of NMD to ensure expression of its own genome., UPF1 is a central protein in nonsense-mediated mRNA decay (NMD), but contribution of its RNA processivity to NMD is unclear. Here, the authors show how the retroviral Tax protein interacts with and inhibits UPF1, and demonstrate that UPF1’s translocase activity contributes to NMD.

Published
2018
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29. In vitro, in cellulo and structural characterizations of the interaction between the integrase of Porcine Endogenous Retrovirus A/C and proteins of the BET family

Author

Gallay, Kathy, primary, Blot, Guillaume, additional, Chahpazoff, Margaux, additional, Yajjou-Hamalian, Halima, additional, Confort, Marie-Pierre, additional, De Boisséson, Claire, additional, Leroux, Aurélie, additional, Luengo, Catherine, additional, Fiorini, Francesca, additional, Lavigne, Marc, additional, Chebloune, Yahia, additional, Gouet, Patrice, additional, Moreau, Karen, additional, Blanchard, Yannick, additional, and Ronfort, Corinne, additional

Published
2019
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30. Human H4 tail stimulates HIV-1 integration through binding to the carboxy-terminal domain of integrase

Author

Mauro, Eric, primary, Lesbats, Paul, additional, Lapaillerie, Delphine, additional, Chaignepain, Stephane, additional, Maillot, Benoit, additional, Oladosu, Oyindamola, additional, Robert, Xavier, additional, Fiorini, Francesca, additional, Kieffer, Bruno, additional, Bouaziz, Serge, additional, Gouet, Patrice, additional, Ruff, Marc, additional, and Parissi, Vincent, additional

Published
2019
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31. A mechanistic study of helicases with magnetic traps

Author

Hodeib, Samar, Raj, Saurabh, Manosas, Maria, Zhang, Weiting, Bagchi, Debjani, Ducos, Bertrand, Fiorini, Francesca, Kanaan, Joanne, Le Hir, Hervé, Allemand, Jean-François, Bensimon, David, Croquette, Vincent, Laboratoire de Physique Statistique de l'ENS (LPS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Departament de Física de la Matèria Condensada, Universitat de Barcelona (UB), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), UFR des Sciences Pharmaceutiques et Biologiques, Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)

Subjects
DNA Replication, [SDV]Life Sciences [q-bio], DNA Helicases, Nucleic Acid Heteroduplexes, Reviews, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA, RNA Helicases, ComputingMilieux_MISCELLANEOUS, RNA, Double-Stranded
Abstract

Helicases are a broad family of enzymes that separate nucleic acid double strand structures (DNA/DNA, DNA/RNA, or RNA/RNA) and thus are essential to DNA replication and the maintenance of nucleic acid integrity. We review the picture that has emerged from single molecule studies of the mechanisms of DNA and RNA helicases and their interactions with other proteins. Many features have been uncovered by these studies that were obscured by bulk studies, such as DNA strands switching, mechanical (rather than biochemical) coupling between helicases and polymerases, helicase-induced re-hybridization and stalled fork rescue.

Published
2017
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38. Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities

Author

Fiorini, Francesca, Bagchi, Debjani, Le Hir, Hervé, Croquette, Vincent, Laboratoire de Physique Statistique de l'ENS (LPS), Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2015
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42. Prognostic role of internal jugular vein preservation in neck dissection for head and neck cancer

Author

Gallo, O., Santoro, R., Fiorini, FRANCESCA ROMANA, Meccariello, G., Laganà, R. M., Paiar, Fabiola, and Maio, V.

Subjects
Male, head and neck squamous cell carcinoma, neck recurrence, Predictive Value of Tests, Humans, Adjuvant, Aged, Neoplasm Staging, Radiotherapy, Carcinoma, extracapsular spread, internal jugular vein, neck dissection, Carcinoma, Squamous Cell, Female, Head and Neck Neoplasms, Jugular Veins, Lymph Nodes, Lymphatic Metastasis, Middle Aged, Neck Dissection, Neoplasm Recurrence, Local, Organ Sparing Treatments, Prognosis, Radiotherapy, Adjuvant, Treatment Outcome, Surgery, Oncology, Neoplasm Recurrence, Squamous Cell, Local
Abstract

Sparing internal jugular vein (IJV) in neck dissection for head and neck cancer is controversial. We aimed at evaluating the prognostic impact of IJV preservation.We examined 206 files of head and neck cancer patients who underwent radical or modified radical neck dissection at the Otolaryngology University of Florence. The site of primary tumor was larynx and hypopharynx in 44.66%, oropharynx in 25.24%, oral cavity in 23.3%, unknown in 4.85%, salivary glands and rhinopharynx in 0.97%. In 60.19% the IJV was resected, in 39.81% preserved. Prognostic impact of IJV preservation was assessed by Kaplan-Meier and multivariate analysis.Neck recurrence occurred in 25.2%: the IJV was resected in 42.31%, in 57.69% preserved (P = 0.02). At multivariate analysis, neck recurrence resulted significantly associated to extracapsular spread (ECS) (P = 0.009), IJV preservation (P = 0.01), positive margins (P = 0.02). In ECS positive patients, a higher risk of neck recurrence was documented for IJV preservation (P = 0.012). A worse prognosis was observed for patients with IJV spared (P = 0.06).IJV preservation is associated with an increased risk of neck failure and a worse outcome, mainly in patients with ECS of nodes.

Published
2013

43. HTLV Tax repress nonsense mediated mRNA decay by inhibiting the ATPase activity of UPF1

Author

LeHir Hervé, Fiorini Francesca, Mocquet Vincent, Jalinot Pierre, and Robin Jean-Philippe

Subjects
Genetics, Messenger RNA, biology, Nonsense-mediated decay, Helicase, RNA, biology.organism_classification, RNA Helicase A, Cell biology, Infectious Diseases, Retrovirus, Virology, Poster Presentation, biology.protein, HD domain, Ribonucleoprotein
Abstract

The Nonsense Mediated mRNA Decay (NMD) is a mRNA quality surveillance pathway that regulates the stability of mRNAs harboring a premature termination codon, avoiding the production of truncated proteins with potential oncogenic properties. NMD regulates also the expression levels of 10 to 15% of human genes such as those regulating the hematopoietic cell differentiation, the maintenance of chromosome structure and function and retroviral RNA. Due to its role in the control of expression of gene involved in the immune response, and the targeting of viral RNA, NMD is now also considered as a viral restriction mechanism. Describing the details of the interplay between HTLV and the NMD is then important to better understand how the virus evades this surveillance and to determine a role of the NMD in the associated pathologies. At the center of the NMD pathway, UPF1 orchestrates a dynamic network of interactions leading to its own structural rearrangement as well as the ribonucleoprotein (RNP) remodeling. In particular, its N-terminal domain (CH domain) repress its ATPase and helicase acitvities held by the central domain (HD domain) until it interacts with the other core factor UPF2 in the early steps of NMD. We showed for the first time that the retrovirus HTLV-1 was able to protect its RNA and modulate some of its transcriptional activators by inhibiting NMD. Now we focuse our attention in deciphering the mechanistics of this inhibition. Thus we demonstrate that HTLV-1 Tax protein targets the RNA helicase UPF1. We found that in cells transfected with a complete provirus, Tax is associated to the NMD sensitive mRNA in an UPF1 dependent manner. This interaction between Tax and the HD domain of UPF1 inhibits the ATPase acivity of UPF1. The homology in amine acid sequence as well as competition assays lead us to the conclusion that Tax could mimics the CH domain in order to maintain a repressive effect even in the latter steps of the pathway. This conclusion is supported in vivo by the accumulation of intermediary complexes stalled on an NMD target. Finally we identified the Tax binding site necessary for this inhibition. Then those data provide structural insights on the regulation of the RNA helicase UPF1 functionning as well as a precise mechanistic of Tax inhibitory effect during NMD.

Published
2015

46. RNA Helicases on the Move

Author

Saurabh, Raj, primary, Bagchi, Debjiani, additional, Fiorini, Francesca, additional, Le Hir, Hervé, additional, Tanner, Kyle, additional, Banroques, Josette, additional, and Croquette, Vincent, additional

Published
2014
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