First results on DNA clustered damage combining direct and

coverage: 1 keV –108 keV ... Relaxation step allowing a modelling of the genome domains in G0/G1 phase of the cell cycle. 5. ... calculations for comp...

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First results on DNA clustered damage combining direct and indirect effects with Geant4-DNA

MCMA-2017 October 15-18,2017 Naples, Italy

Carmen Villagrasa IRSN

representing the efforts of the Geant4-DNA Collaboration

http://geant4-dna.org

http://geant4-dna.org

Outlook

1. Main recent developments of the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit 2. First results on DNA clustered damage combining direct and indirect effects with Geant4-DNA

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Outlook

1. Main recent developments of the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit 2. First results on DNA clustered damage combining direct and indirect effects with Geant4-DNA

MCMA-2017 15-18 October 2017 Naples, Italy

3

http://geant4-dna.org

Geant4-DNA : Modelling biological effects Geant4 for radiobiology? LIMITATIONS prevent its usage for the modelling of biological effects of ionising radiation at the sub-cellular & DNA scale  Condensed-history approach - No step-by-step transport on small distances, a key requirement for micro/nanodosimetry

 Low-energy limit applicability of EM physics models is limited - « Livermore » Low Energy EM models can technically go down to 10 eV but accuracy limited < 250 eV - 100 eV for « Penelope 2008 » Low Energy EM models, accurate down to 1 keV

 No description of target molecular properties - Liquid water, DNA nucleotides, other ?

 Only physical particle-matter interactions - At the cellular level, physical interactions are NOT the dominant processes for DNA damage at low LET...

Geant4-DNA: Main objective Extend the general purpose Geant4 Monte Carlo toolkit for the simulation of interactions of radiation with biological systems at the cellular and DNA level in order to predict early and late DNA damage in the context of manned space exploration missions (« bottom-up » approach). Designed to be developed and delivered in a FREE software spirit under Geant4 license, easy to upgrade and improve. MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

The Geant4-DNA project Physical stage Step-by-step modelling of physical interactions of incoming and secondary ionizing radiation with biological medium ( mainly liquid water mainly).

• ionized target molecules • excited target molecules • solvated electrons

Physico-Chemical /Chemical stage • Radical production • Diffusion • Chemical interactions Geometry DNA molecule structure, chromatin fiber, chromosomes, cell nucleus, voxel cells…

Biological stage DIRECT DNA damages

t=0 MCMA-2017 15-18 October 2017 Naples, Italy

Biological stage INDIRECT DNA damages

t=10-15s

REPAIR

t=10-6s 5

http://geant4-dna.org

Simulation of the Physical stage

MCMA-2017 15-18 October 2017 Naples, Italy

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Overview of physics models for liquid water •



Electrons –

Protons & H –

Excitation (*)

Elastic scattering





Screened Rutherford and Brenner-Zaider below 200 eV



Updated alternative version by Uehara



Independent Atom Method (IAM) by Mott et al. & VLE data in ice from CPA100 TS code



Partial wave framework model by Champion et al.,

Born and Bethe theories above 500 keV, from Dingfelder et al.



Ionisation •

500 keV (relativistic + Fermi density)

Ionisation





5 levels for H2O



Dielectric formalism & FBA using Heller optical data up to 1 MeV, and low energy



corrections, by Emfietzoglou et al.



Charge change (*) •



Improved alternative version by Emfietzoglou and Kyriakou



Relativistic Binary Encounter Bethe (RBEB) by Terrissol from CPA100 TS code

Excitation (*)





Dielectric formalism & FBA using Heller optical data and semi-empirical low energy

Excitation (*) and ionisation •







Dielectric formalism by Dingfelder from CP100 TS code





Michaud et al. xs measurements in amorphous ice



Factor 2 to account for phase effect



Melton xs measurements

Med. Phys. 37 (2010) 4692 (link) Appl. Radiat. Isot. 69 (2011) 220 (link) Med. Phys. 42 (2015) 3870 (link) Phys. Med. 31 (2015) 861 (link) Nucl. Instrum. and Meth. B 343 (2015) 132 (link) Phys. Med. 32 (2016) 1833 (link)

Ionisation •

Speed scaling and global effective charge by Booth and Grant

Photons –

PhD theses of H. N. Tran (2012), Q. T. Pham (2014), J. Bordes (2017) (*) only available in Geant4-DNA

Classical approach by Everhart et al.

Li, Be, B, C, N, O, Si, Fe –



Semi-empirical models from Dingfelder et al.

Nuclear scattering •



Dissociative attachment (*)

Charge change (*) •

Vibrational excitation (*) •

Speed and effective charge scaling from protons by Dingfelder et al.

corrections, , derived from the work of Emfietzoglou et al. Improved alternative version by Emfietzoglou and Kyriakou

Classical approach by Everhart et al.

He0, He+, He2+ –

5 levels for H2O

Analytical parametrizations by Dingfelder et al.

Nuclear scattering •





Rudd semi-empirical approach by Dingfelder et al. and Born and Bethe theories & dielectric formalism above

3 contributions to the interaction potential



Miller & Green speed scaling of e- excitation at low energies and

from EM « standard » and « low energy » •

Default: « Livermore » (EPDL97)

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Other bio-materials (1) •

Part of the effort to extend Geant4-DNA models to other materials than liquid water



Cross sections for biological materials are proposed since Geant4 10.4 Beta by IRSN team (C. Villagrasa, S. Meylan), applicable to DNA constituents –

tetrahydrofuran (THF), trimethylphosphate (TMP), pyrimidine (PY) and purine (PU)



serving as precursors for the deoxyribose and phosphate groups in the DNA backbone as well as for bases



For the following incident particles –

electrons (12 eV-1keV, elastic + excitation + ionisation) : from measurements @ PTB, Germany



protons (70 keV-10 MeV, ionisation) from the HKS approach

Eg. total electron ionisation cross sections in THF

See ICSD extended example More details in Rad. Phys. Chem. 130 (2017) 459–479

http://geant4-dna.org

Other ongoing developments for the physical stage •

New models describing ionisation of the four bases of DNA (adenine, thymine, cytosine and guanine) by incident protons, by Z. Francis (St Joseph U., Lebanon) large energy coverage: 1 keV – 108 keV; based on the relativistic analytical Rudd approach, fitted to experimental data will be publicly released in the near future. J. Appl. Phys. 122 (2017) 014701



Extension of Geant4-DNA for the modelling of radiosensitization from gold nanoparticles. Activity initiated in 2016 by D. Sakata (Bordeaux U., France). Discrete processes for electrons: elastic (ELSEPA), ionization (modified RBEBV), electronic (4 channels) and bulk plasmon (Quinn's) excitation. Nucl. Instrum. Meth. B 373 (2016) 126 & J. Appl. Phys. 120 (2016) 244901



Accelerating simulations: variance reduction. An new extended example, "splitting", provided by J. Ramos-Mendes (UCSF) is provided to illustrate variance reduction technique in the Geant4-DNA ionisation process Phys. Med. Biol. 62 (2017) 5908-5925

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Simulation of the Physico-chemical stage & Chemical stage

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Simulation of the Physico-chemical stage • During this stage, water molecules • Dissociate if ionized • Relax or dissociate if excited

J. Comput. Phys. 274 (2014) 841

Electronic state

Dissociation channels

Fraction (%)

All single ionization states

H3O + + •OH

100

Excitation state A1B1: (1b1) → (4a1/3s)

•OH + H•

H2O + ΔE H3O + + •OH + e-aq (AI) •OH + •OH + H 2 H2O + ΔE

65 35 55 15 30

H3O + + •OH + e-aq (AI) H2O + ΔE

50 50

Excitation state B1A1: (3a1) → (4a1/3s) Excitation state: Rydberg, diffusion bands Dissociative attachment

•OH

+ OH- + H2

100

• Products thermalize down to their energy of diffusion at equilibrium MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Simulation of the Chemical stage J. Comput. Phys. 274 (2014) 841

Species

Diffusion coefficient D (10-9 m2 s-1)

H3O +

9.0

H•

Reaction

Reaction rate (107 m3 mol-1 s-1)

7.0

H3O+ + OH- → 2 H2O

14.3

OH-

5.0

•OH + e-aq → OH-

2.95

e-aq

4.9

H• + e-aq + H2O→ OH- + H2

2.65

H2

5.0

H3O+ + e-aq → H• + H2O

2.11

•OH

2.8

H• + •OH → H2O

1.44

H2O2

1.4

H2O2 + e-aq → OH- + •OH

1.41

H• + H • → H2

1.20

e-aq + e-aq + 2 H2O→ 2 OH- + H2

0.50

•OH + •OH → H2O2

0.44

We propose by default the set of parameters published by the authors of the PARTRAC software (Kreipl et al., REB 2009). However, these parameters can be modified by the user.

MCMA-2017 15-18 October 2017 Naples, Italy

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Simulation of the Chemical stage with Geant4-DNA ▌ Four

examples are available in Geant4 in the « extended examples/medical/dna » category of Geant4 examples  CHEM1: activating chemistry  CHEM2: how to set minimum time step limits  CHEM3: user interactivity and visualization  CHEM4: extraction of time dependent radiochemical yields (G) in a range of

deposited energy. Number of molecules of a given species for 100 eV of deposited

energy G(t)=

𝑁(𝑡) 𝐸𝑑𝑒𝑝

with

N(t) number of molecules at time t Edep Deposited energy scaling to 100 eV

▌ Note  Examples can be run in MultiThreading mode  Chemistry works in with G4_WATER material

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http://geant4-dna.org

Geometrical models

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Geometrical models examples •

PDB Protein data bank interface. http://pdb4dna.in2p3.fr. pdb4dna extended example: Comput. Phys. Comm. 192 (2015) 282. Reading of PDB files Build bounding boxes from atom coordinates, Search for closest atom from a given point, Geometry and visualization : 3 granularities (1) Barycenter of nucleotides (2) Atomistic (3) Barycenter of nucleotide components (1) (1)

(2)



(3)

Modeling E coli bacteria. PhD thesis of N. Lampe (2017) (in press). "integral" simulation & scoring of early damage fully driven by UI commands

MCMA-2017 15-18 October 2017 Naples, Italy

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...and the first relaxed human fibroblast cell

Comput. Phys. Comm. 204 (2016) 159 MCMA-2017 15-18 October 2017 Naples, Italy

http://geant4-dna.org

Outlook

1. Main recent developments of the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit 2. First results on DNA clustered damage combining direct and indirect effects with Geant4-DNA

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

DnaFabric – Generation of a cell nucleus model DNAFabric: C++ software : generation, modification and 3D geometries that can be exported to Geant4. Comput. Phys. Comm. 204 (2016) 159 1.

Choice of shape (ellipsoid, sphere, elliptical cylinder…) and nucleus size.

2.

Generation of an empty nucleus phantom.

3.

Choice and placement of the genome inside the nucleus in a condensed form.

4.

Relaxation step allowing a modelling of the genome domains in G0/G1 phase of the cell cycle.

5.

Filling step of the genome domains with different voxels containing chromatin fibers with a molecular definition of DNA volumes.

6.

Export of the nucleus geometry towards the simulation chain based on Geant4-DNA

Different types of voxels

MCMA-2017 15-18 October 2017 Naples, Italy

Example of a generation of a fibroblast cell nucleus 18

http://geant4-dna.org

DnaFabric – Generation of a cell nucleus model

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Simulation chain for clustered DNA damage calculation Control Room 1 Start

1

End

Build simulation for 1000 initial particles

10

2

Correct uncertainty

Control Room 2

Generation and Export of DNA geometry

Statistical analysis

File generation

DnaFabric

9

3

Geometry

4

Physical Stage simulation Geant4-DNA (modified)

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Simulation of experimental conditions for comparaison with litterature data (ex. fragment calculations for comparison with PFGE data)

Unstable water molecules are extracted. « input » files are created for initating physicochemical stage

5

Physico-Chemical and Chemical stage simulation

Geant4-DNA (modified)

MCMA-2017 15-18 October 2017 Naples, Italy

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Determination of the strand breaks (SB)

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8 Calculation of clustered DNA damage (DSB, DSB+,..)

DBSCAN

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http://geant4-dna.org

Simulation using Geant4-DNA and SB criteria: Direct effects Physical stage using the Geant4-DNA (V10.01) models Use of G4EmDNAPhysics (V10,01, defaults)  Complete cell nucleus: ~36.109 molecular volumes

 Specificities of the simulation chain : - Modified Parameterization used for the ~2 million voxels of the DNA geometry (5 different types of voxels: straight, left, right, up and down) - Modifications of Geant4 allowing the multithreaded calculation in such parameterization  Direct SB: Use a threshold value on the cumulated energy deposited in the backbone region: 17.5 eV

Ionization or excitation

Cumulated energy deposited > 17,5 eV

Direct Strand Break MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Simulation of the physico-chemical and chemical stages The DNA target geometry volume are treated as ‘static’ chemical species (no diffusion) and their chemical product is recorded: -histone proteins make “disappear” any radical diffusing at a distance< the histone radius (sphere) - OH· radicals interacting with DNA bases give rise to a base damaged - 40% OH· radicals interacting with deoxyribose are registered as an indirect SB .

1 1 1 1 1

1B.

MCMA-2017 15-18 October 2017 Naples, Italy

Aydogan et al. Rad. Res. 169 (2008) 223-231 22

http://geant4-dna.org

Simulation of the physico-chemical and chemical stages The DNA target geometry volume are treated as ‘static’ chemical species (no diffusion) and their chemical product is recorded: -histone proteins make “disappear” any radical diffusing at a distance< the histone radius (sphere) - OH· radicals interacting with DNA bases give rise to a base damaged - 40% OH· radicals interacting with deoxyribose are registered as an indirect SB .

The clustering algorithm DBSCAN is then used on the results combining SB produced by direct effects and indirect effects to reveal DSB

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Scoring of DNA clustered damage Physical stage

Chemical stage OH / 2deoxyribose

Ionization ou excitation Radical OH

Energy deposited in the backbone > 17,5 eV

40% reactions kept [BALASUBRAMANIAN et al., 1998]

Indirect Break

Direct Break

Clustering algorithm (at least 2 SB located in opposite strands and separated by less than 10 bp)

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http://geant4-dna.org

Results on the number of DSB/Gy/Gbp for protons for Protons a fibroblast cell nucleus DSB/pp → fragments /pp → NDSB/event (Sbp) Cell nucleus

This work

*Meylan S., Incerti S., Karamitros M., Tang N., Bueno M., Clairand I., Villagrasa C., accepted in Scientific Reports (2017)

MCMA-2017 15-18 October 2017 Naples, Italy

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http://geant4-dna.org

Conclusions-> Simulation Chain  First results of DSB simulations using Geant4-DNA (Physical +Chemical stages). Others are ongoing  Importance of a realistic DNA geometrical model  Great influence of the criteria chosen for the quantification of the direct SB and indirect SB

Update of the simulation chain to the late version of Geant4-DNA-> Public release Including a library of geometries built using DNAFabric

MCMA-2017 15-18 October 2017 Naples, Italy

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Thank you for your attention… and a special thank you to Our main developers Theory & MC experts Marie-Claude Bordage (INSERM, France) Julien Bordes (INSERM, France) – PhD on-going Michael Dingfelder (ECU, USA) Ziad Francis (St Joseph U., Lebanon) Dimitris Emfietzoglou (Ioannina U., Greece) Vladimir Ivantchenko (G4AI Ltd, UK) Werner Friedland (Helmholtz Z., Germany) Mathieu Karamitros (Bordeaux, France) Francesc Salvat (Barcelona U., Spain) Ioanna Kyriakou (Ioannina U., Greece) Nathanael Lampe (Melbourne, Australia) Sylvain Meylan (Paris, France) Shogo Okada (Kobe U., Japan) Dosatsu Sakata (Bordeaux U., France) Wook-Geun Shin (Bordeaux U., France) – PhD starting Nicolas Tang (IRSN, France) – PhD on-going Hoang N. Tran (CEA, Saclay & Ton Duc Thang U., Vietnam) Carmen Villagrasa (IRSN, France) Marion Bug (PTB, Germany) (alumni) Morgane Dos Santos (IRSN, France) (alumni) Yann Perrot (Paris, France) (alumni) Trung Q. Pham (HMH, Vietnam) (alumni) Vaclav Stepan (NPI Prague, Czech Rep.) (alumni)

http://geant4-dna.org

If you use Geant4-DNA, please be kind to cite in your work our two collaboration papers Phys. Med. 31 (2015) 861-874 (link) Med. Phys. 37 (2010) 4692-4708 (link)

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Cross section models for electrons

Phys. Med. 31 (2015) 861 (link)

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Med. Phys. 42 (2015) 3870 (link)

Ioannina models (1) •

A new set of alternative models improving the accuracy of electrons interactions, developped by I. Kyriakou and D. Emfietzoglou, Ioannina U., Greece



Main improvements –

truncation algorithm modifies imaginary part of the dielectric function model : •

enhance the contribution of the excitation states [see (a)] while eliminating the contribution of each ionization state below the corresponding binding energy with a concomitant smoothing at the near-threshold region [see (b)]



low energy corrections for exchange and correlation in electron–electron interactions and corrections for the departure from the plane-wave 1rst-order perturbation theory



elastic sc.: screening factor proposed by Uehara from vapor experimental data, instead of Grosswendt-Waibel

Imaginary part of the dielectric function model

Contribution of ionizations and excitations to the total inelastic cross section

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Ioannina models (2) Exzample of verification & validation in liquid water Dose Point Kernels



W-value (mean energy to create an ion pair)

DPK (MeV/nm)



The larger the excitation-to-ionization cross section ratio is, the higher the W-value since a smaller number of ion pairs will be formed (for the same electron energy dissipated) Some difference with the experimental data for gaseous water is expected and confirms the well-established higher ionization yield of the liquid phase compared to the gas phase. Med. Phys. 42 (2015) 3870 (link) J. Appl. Phys. 32 (2016) 119, 194902 (link)

Much less diffusive DPKs with the new inelastic model. With the default model, small excitation cross sections (dominant at large distance and low energy) allow these very low energy electrons to diffuse much longer distances in the medium before their energy falls below the cut-off

Phys. Med. 32 (2016) 1833 (link)

CPA100 models (1) An alternative set of models for electrons (10 eV – 255 keV) from the CPA10 Track Structure code (M. Terrissol, M. C. Bordage, Toulouse U. , France)

Integral cross sections for electrons





CPA100 excitation model is in better agreement with the only experimental data in the gaseous water by Munoz et al. one order of magnitude, between the CPA100 model and the Geant4-DNA default model for each excitation state

Software preservation

Differential ionisation cross section

• good agreement between data and CPA100 cross sections, especially at low ejected kinetic energies (where the differential cross section is the largest). • main differences between Geant4-DNA default model and the experimental data are observed at ejected electron energy W lower than 10 eV. 31

Phys. Med. 32 (2016) 1833 (link)

CPA100 models (2) Numbers of interactions

Track length, penetration & projection range



The main differences appear in the number of excitations from 20 keV down to 20 eV, originating from the difference of magnitude between CPA100 and Geant4-DNA default excitation cross sections



differences between the models are larger when considering track length, rather than the number of collisions, especially at low energies (<1 keV) (eg. 50% at 50 eV) electrons lose less energy and consequently travel larger distances in liquid water when simulated using Geant4DNA default models compared to CPA100 (CPA100 inelastic cross sections are larger)

CPA100 models (3) Example of Dose Point Kernel comparison in liquid water between - Geant4-DNA option 2 (default) - Geant4-DNA option 4 (Ioannina) - Geant4-DNA CPA100 models - PENELOPE 2011 The comparison with the reference Monte Carlo code PENELOPE, set to perform step-by-step simulation, showed very good agreement. For all tested energies, the maximum relative difference between simulated DPK, which occurs for 1 keV electrons, is less than 10 %.

Nucl. Instrum. and Meth. B 398 (2017) 13 (link)

J. Appl. Phys. 122 (2017) 014701 (link)

Other bio-materials (2) •

New model describing ionisation of the four bases of DNA (adenine, thymine, cytosine and guanine) by incident protons, by Z. Francis (St Joseph U., Lebanon)



large energy coverage: 1 keV – 108 keV



based on the relativistic analytical Rudd approach, fitted to experimental data



will be publicly released in the near future

Single differential cross section

Total cross section

Stopping power

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Investigation of radiotherapy sensitization using high-Z nanoparticles Graphic: Sébastien Tribot



"Hot" topic: high-Z NP internalized in cells could boost

energy deposition and increase the efficacy of radiotherapy



Well established for photon beams (photoelectric effect),

not so clear for proton beams…



Still a challenge to perform mechanistic simulations –

We initiated a specific Geant4-DNA activity on the subject in 2015



Simulation of physics + physico-chemistry + chemistry around NP (using Livermore for Gold)



Eg. Radiolysis Enhancement Factor as a function of distance from GNP compared to WNP



Underlined the necessity to extend Geant4-DNA models to high-Z metals Nucl. Instrum. Meth. B 373 (2016) 126 (link)

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J. Appl. Phys. 120 (2016) 244901 (link)

High-Z materials : gold •

Extension of Geant4-DNA for the modelling of radiosensitization from gold nanoparticles



Activity initiated in 2016 by D. Sakata (Bordeaux U., France)



Discrete processes for electrons: elastic (ELSEPA), ionization (modified RBEBV), electronic (4 channels) and bulk plasmon (Quinn's) excitation



Models will be delivered in the near future (probably 2018) - See D. Sakata's talk (Friday)

Integral cross sections for electrons

Eg. of validation (5 cm gold plate)

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Simulation of G-values •

A new extended example is provided: "chem4", my P. Piersimoni and M. Karamitros



Hypotheses –

infinite volume: the energy lost by the primary equals the deposited energy since all secondary particles slow down to thermal energy



two thresholds •

The primary is killed once it has deposited more energy than a selectable minimum threshold, T1



When the primary particle looses more energy in few interaction steps than a maximum allowed threshold, T2, the event is aborted



this allows to calculate G-values on the deposited energy range [T1,T2]



can be set using UI commands : /primaryKiller/eLossMin 1 keV # primary is killed if deposited E is greater than this value /primaryKiller/eLossMax 2 keV # event is aborted if deposited E is greated than this value



Can run in MT mode



Results are stored in ROOT format and can me vizualised using a dedicated ROOT interface (plotG)

Eg. : species by 10 incident electrons of 100 keV (beam.in)

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Perspectives •

PHYSICS –

Inclusion of alternative or improved cross section models for electrons and ions •



PHYSICO-CHEMISTRY/CHEMISTRY –

Alternative approach for the simulation of radiolysis



Combination of geometry & chemistry : two approaches





Liquid water + DNA-like materials + gas materials for nanodosimeters + metals



Granular approach



Composite material & voxellized approach

Addition of scavenger species and reactions

BIOLOGY –

Multi-scale geometrical models of biological targets, including « deformable » geometries



Prediction of direct and non-direct DNA simple & complex damages in plasmids and realistic cells



Time evolution of damage: repair processes for the simulation of late damage



COMPUTING ACCELERATION: GPU FOR CHEMISTRY



VERIFICATION (WITH OTHER CODES) AND VALIDATION (WITH EXPERIMENTAL DATA)

All these developments take time – once published, they are delivered publicly in Geant4

http://geant4-dna.org

DNA geometrical model used in the simulation DNA target geometry : Molecular description of the DNA target to simulate the physical and chemical interaction between the radical species and the DNA. S. Meylan PhD work, IRSN

Desoxyribose radius: 0,29nm Phosphate radius : 0,27nm Base radius: 0,30nm Desoxyribose volume: ~0,09nm3 Phosphate volume: ~0,06 Base volume: ~0,09nm3 We take into account the hydration shell (Γ = 12) by using a water envelop. MCMA-2017 15-18 October 2017 Naples, Italy

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Comparison between experimental results and simulation α 8 MeV (160 keV/µm)

p 3 MeV

α 20 MeV (37 keV/µm)

α 10 MeV ( 90 keV/µm)

Pattern of irradiation

(23 keV/µm)

Simulation: At least 1 DSB compared to Foci probability

Probability of RIF formation per particle track

1.1

foci observed: 5/5?-> probability foci/track

Cell nucleus

Bio

threshold

linear

all ion

1.0 0.9

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0

20

40

60

80

LET (keV

ICRS-13 RPSD-2016

3-6 October 2016 Paris, France

100

120

140

160

µm-1)

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Résultats et discussion

IV.2) Variation du critère de sélections

▌ Bon

accord avec KURBUC lorsque le seuil de 12,5 eV est utilisé

▌ Critère

de sélection ++

▌ Cassures

directes ++

Soutenance de thèse S. Meylan

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