Javier Praena1,2, Ignacio Porras3, Marta Sabate-Gilarte1,4, Proposal to the ISOLDE and Neutron Time-of-Flight Committee 33S(n,α)30Si cross section measurement at n_TOF EAR2: data below 10 keV. Javier Praena1,2, Ignacio Porras3, Marta Sabate-Gilarte1,4, José M. Quesada1, Hanna Koivunoro5,6 F. Arias de Saavedra3 and M. Pedrosa3 for the n_TOF collaboration   Universidad de Sevilla, Spain Centro Nacional de Aceleradores, Sevilla, Spain Universidad de Granada, Spain CERN, Switzerland Department of Physics, University of Helsinki, Finland Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland

Plan of the talk. General motivations for 33S(n,). Status of the 33S(n,) cross-section data including our previous measurement at n_TOF EAR-1. Motivations for 33S(n,) at EAR-2. Count rate and beam time request. 2 Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Motivations for 33S(n,α)30Si measurement Astrophysics: Data for alpha-nucleus potential used in HFSM calculation of the p-isotopes nucleosynthesis. (>A). Origin and abundance of 36S is an open question. Medical physics: 33S as cooperative target for BNCT. 3 Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Motivations: 36S nucleosynthesis MACS, kT=30 keV Auchampaugh et al PRC 12 1126 (1975) (690170) mb TOF Wagemans et al NPA 469 497 (1987) (22720) mb Schatz et al PRC 51 379 (1995) (1759) mb Activation Woosley et al At. D. Nucl. D. Tab. 22 371 (1978) 224 mb Model 36S is formed by s-process or spallation processes. The time integrated s-process flow in the region 28Si-42Ca. The process is mostly determined by (n,) on the abundant seed nuclei, 28Si and 32S. Concerning the production of 36S is sensitive to the interplay of the branchings 33S, 36Cl and 39Ar. Reifarth et al [Astro. J. 528:573-581 (2000)] obtained the MACS of 34S(n,) by the activation technique showing that 34S could act as bottle-neck in this path. 34S seed is highly sensitivity to the 33S(n,). The origin of 36S remains an open question. S-36 is an indication of the s-process for light nuclei. Here I show the time integrated s-process flow in the region Si-Ca as shown by Schatz et al. The process is mostly determined by Si-28 and S-32. But also is sensitive to the interplay of S-33, Cl-36 and Ar-39 which are the main branching points in this region. In the table, I point out the important difference between the available MACS. Reifarth et al by activation obtained the MACS of S34 that induce to thick that S34 acts as bottle-neck in this possible path for the nucleosynthesis of S36. In any case the origin of the S36 remains an open question. Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Motivations: 33S as cooperative target in NCT 10-30 keV Past: thermal neutron beams from nuclear reactor. Future: epithermal neutron beams (keV) from accelerator-based neutron source. The energy of the neutron beam is very adequate for 33S. Experimental treatments. Finland. http://clinicaltrials.gov/show/NCT00114790 Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Motivations: 33S as cooperative target in NCT* Eα=3 MeV 10-30 keV 33S Depth (cm) 33S(n,α) (Q=3.1 MeV). Data are discrepant in the RRR (13-100 keV). Motivation for measuring at EAR1. The presence 33S enhances the dose in the first centimeters in tissue. For predicting its effect at greater depths it is mandatory data at low neutron energies. There is no experimental data from thermal to 10 keV. EAR2!!!! S-33 concentration of the order of mg/g based on the addition of cystine to the culture medium, as PW Gout et al., , Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells, Leukemia 11, 1329–1337 (1997). Selectivily Coderre et al., J. Nucl. Med. 27, 1157 (1986). * I. Porras Phys. Med. Biol. 53 (2008), J. Praena et al, ARI, 88 (2014) 203.

Status of 33S(n,α)30Si experimental data. Auchampaugh et al PRC 12 1126–33 1975: (n,) and (n,) from 10 to 700 keV. TOF. Wagemans et al NPA 469 497–506 , 1987: (n,) from 10 keV to 1 MeV. TOF. Coddens et al NPA 469 480–96 , 1987: (n,tot) from 10 keV to 2 MeV. TOF. Wagemans et al Auchampaugh et al NO DATA BELOW 10 keV The experimental data available for S33(n,a) reaction are the indicated in this slide. We think we can improve the energy resolution of previous measurements; we could fix the value of the resonance parameters of the low lying resonances. Coddens et al Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Status 33S(n,α) data at n_TOF EAR 1 (Dec 2012) NO DATA BELOW 10 keV The experimental data available for S33(n,a) reaction are the indicated in this slide. We think we can improve the energy resolution of previous measurements; we could fix the value of the resonance parameters of the low lying resonances. Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Status 33S(n,α) data at n_TOF EAR 1: results Preliminary result of our analysis. Comparison between sample 1 and Wagemans data for the first resonance (13 keV) The final result depends on the characterization of the mass of the samples. The experimental data available for S33(n,a) reaction are the indicated in this slide. We think we can improve the energy resolution of previous measurements; we could fix the value of the resonance parameters of the low lying resonances. Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

33S(n,α)30Si experimental data at thermal The experimental data available for S33(n,a) reaction are the indicated in this slide. We think we can improve the energy resolution of previous measurements; we could fix the value of the resonance parameters of the low lying resonances. 1/v extrapolation from thermal to 10 keV may provide wrong cross-section data Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

33S(n,α)30Si evaluations Only EAF-2010 shows a resonance structure in the keV region but XS 20 times lower than experimental data. Orders of magnitude difference between the available evaluations below 10 keV Regarding the evaluations the situation is confusing. In the figure it is shown ENDF/B-VII.1, EAF-2010 and TEDNL-2010. Other data base match ENDF (in blue) or TENDL (in red). It could be noticed that only EAF-2010 shows a resonance structure in the keV region. It is impressive that there are 4 orders of magnitude between the evaluations. Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Why 33S(n,α) EAR-2? EAR-2 tof 20 m tof EAR-1 Pb 200 m Protons Neutrons Regarding the evaluations the situation is confusing. In the figure it is shown ENDF/B-VII.1, EAF-2010 and TEDNL-2010. Other data base match ENDF (in blue) or TENDL (in red). It could be noticed that only EAF-2010 shows a resonance structure in the keV region. It is impressive that there are 4 orders of magnitude between the evaluations. Neutrons (meV to GeV) tof EAR-1 Pb 200 m Protons 1 cm cooling (water) 4 cm moderator (water/borated water)

33S(n,α)30Si count rate at EAR-2 for 2e18 The counting rate has been estimated by using the experimentally measured neutron flux at EAR-2. Regarding the evaluations the situation is confusing. In the figure it is shown ENDF/B-VII.1, EAF-2010 and TEDNL-2010. Other data base match ENDF (in blue) or TENDL (in red). It could be noticed that only EAF-2010 shows a resonance structure in the keV region. It is impressive that there are 4 orders of magnitude between the evaluations. The International Commission on Radiation Units and Measurements (ICRU) recommends that the radiation dose delivered should be within 5% of the prescribed dose. ICRU 1978 Dose Specification for Reporting External Beam Therapy with Photons and Electrons ICRU Report 29 (Bethesda, MD: ICRU). This means that uncertainty at each step within the treatment process, including cross-section data should be significantly smaller than 5%. Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2

Summary of 33S(n,α) proposal at n_TOF-EAR2 The objective is to measure the 33S(n,) cross section relative to 10B(n,) at EAR-2 to provide data below 10 keV for the first time. We already performed an experiment (Dec 2012) at EAR-1 to resolve the resonances (CERN-INTC-2012-006/INTC-P-322) . We have resolved the resonances and the data will be provided soon. We have no data below 10 keV. We have ready the samples and the detectors. Data below 10 keV are very important for our study of S-33 as NCT target. Simulations. Also may provide better MACS for astrophysics. We have estimated 2e18 protons in order to have less that 5% uncertainty in the most significant neutron energy region. (ICRU-78) And finally the proposal objectives and beam request: The main objective is to measure the 33S(n,) cross section relative to the 10B(n,) cross section by using the yet running Micromegas detector. The idea is to cover at least the astrophysics energy range of interest and to resolve the low lying resonances. We have estimated 1018 protons to have a statistical uncertainty at the peak of the lowest lying resonances better than 3%. Javier Praena, INTC Nov 2014, 33S(n,) at n_TOF EAR-2 Nicola Colonna 14

THANK YOU FOR YOUR ATTENTION Javier Praena1,2, Ignacio Porras3, Marta Sabate-Gilarte1,4, José M. Quesada1, Hanna Koivunoro5,6 F. Arias de Saavedra3 and M. Pedrosa3 On behalf of the n_TOF collaboration   Universidad de Sevilla, Spain Centro Nacional de Aceleradores, Sevilla, Spain Universidad de Granada, Spain CERN, Switzerland Department of Physics, University of Helsinki, Finland Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland

MC Simulation of absorbed and equivalent dose in water, Porras [3]. Neutron point-like source with energy 13.5 keV (first resonance) Homogeneous medium (water) except a shell with 33S. Interactions: elastic scattering by 1H, 16O, 33S and 33S(n,). 1H, 16O data from EXFOR. 33S(n,) from conservative value [5]; ([5])= (415) eV, ([8])= (833) eV 33S(n,elas)= 33S(n,tot)[8]-33S(n,)[5]; 33S(n,elas) is the highest possible with the data available, so the probability of losing energy for the neutron is also maximum being the probability of alpha emission minimum (conservative). In this context Ignacio Porras performed a series of simulations of the absorbed dose and equivalent dose absorbed in the shell with S33. He considered isotropic point-like sources of 13.5 and 24 keV in the center of sphere fulfill of a homogeneous medium (water because similar to human tissue) with a shell with a concentration of S33. The interactions that he took into account were (…). For the elastic cross section of H and O he took the data from EXFOR. Also for S33, in EXFOR the S33(n,a) cross section is the one measured by Wagemans [5] with is conservative respect Coddens [8]. In case of Wagemans the G_a is 41 and in case of Coddens 83. For the S33(n,n) Porras used the difference between the (n,tot) (Coddens is the only data) and (n,a) of Wagemans so S33 is the maximum. This is also conservative in terms of DOSE because the probability of losing energy for a neutron is maximum, and in his simulation an alpha particle is only emitted by the S33 when it has exactly 13.5 or 24 keV for the second simulation. Summarizing the simulation of Porras is conservative respect the production of alpha by neutron capture of S33.

Monte Carlo Simulations: Porras Phys. Med. Biol. 53 (2008) Motivations:33S as cooperative target in NCT Multidisciplinary research: nuclear physics, boron chemistry and nano technology. At En=13.5 keV  E3.1 MeV, LET250 keV/m and x15m. Monte Carlo Simulations: Porras Phys. Med. Biol. 53 (2008) Neutron point-like source with energy 13.5 keV & 24 keV (resonances). Homogeneous medium (water) except a shell with 33S. 33S(n,), conservative value: = (415) eV (Wagemans et al). = (833) eV (Coddens et al) With the conservative values of the  it should be possible to deliver enough dose. The concentration of 33S and/or the neutron fluence could be decrease with the n_TOF experiment. On the other hand, there is a multidisciplinary research to study the possibility of S33 as a cooperative target for BNCT since the LET and range of the alpha particle should be appropriate for this experimental therapy. The idea and first simulations are due to Porras and were published in Physics in Medice and Biology. Here I show briefly the idea. It is considerer neutron point-like source with energies that of the two first resonances. And it is simulated the Equivalent dose in a water shell with a concentration of S33. The results show that the dose could be closed to that of a radiotherapy treatment. Even in the simulation it was used the conservative value of the resonance parameter of Wagemans et al. With the experiment at n_TOF we could fix these values and probably it should be possible to decrease the neutron fluence and/or the sulfur concentration. Javier Praena, CNA-Universidad de Sevilla, España

Test 2011: natS and 33S samples FINAL METHOD: external heating of the chamber, Kapton (60 C), I=70 A. Person in charge: Wil Vollenberg – Vacuum Surface Coatings (CERN) In case of 33S it was evaporated 15 mg (75 m/cm2, thick) and 5 mg (25 m/cm2, thin) Conditions: 1 h vacuum pump, 2 h heating of Kapton and chamber, 5 min 70 A for S 1 h keeping on the temperature after coating. Heated Kapton sample With thin Cu film With thin CuS Heating tape Heating tape Now I pass to the test performance last November 2011. One of the main challenges was the sample coating. The person in charge has been Wil Vollenberg of the Vacuum Surface Coatings. The final solution was to evaporate sulfur on to a heated kapton sample with a thin film of Chrome, titanium and Copper. In this picture it is shown the chamber (also heated), this is a picture of the sample before the Sulfur evaporation (the square is the copper) and then after the evaporation it is formed the sample, which is the circle with dimension of 8 cm diameter. Javier Praena, CNA-Universidad de Sevilla, España Nicola Colonna 19

Sample characterization at Centro Nacional de Aceleradores Rutherford Backscattering conditions: - Alpha beam. 3.5 MeV. ++He. - Backscattered alphas detected at 165 degrees. Cu not reacting with 33S I showed this slide in the last meeting in Lisbon. I would like to remember that the sample coating ans their characterization are big challenges in this experiment. Wil Vollenberg of the Vacuum Surface Coatings unit at CERN found an original solution that consists: starting from a Kapton foil with thin layers of Ti and Cr, Cu is evaporated. Then sulfur 33 is evaporated in the conditions indicated in the slide. A Cooper-Sulfur compound is formed. It is very important to notice that in previous experiments the sublimation of sulfur in vacuum was a big problem. We are running in Ar at atmospheric pressure but RBS characterization requires high vacuum. 33S (“thin”) Cu of the 33SCu compound n_TOF Meeting June 2014 - Javier Praena – 33S(n,α) Nicola Colonna 20

As boron is not a naturally present element in biomolecules, it has to be attached to certain compounds that tumor cells can absorbe in a larger quantity than normal ones. This is the case of the compound Boron-phenyl-alanine (BPA), which is the only compound used in the most recent clinical trials. This compound have been observed to accumulate in tumors with ratios tumor/normal tissue of 3.5, on average. The concentrations reached inside the cells are small, of the order of 10-20 microg/g of tissue (ppm). In spite of this fact, recent clinical trials, specially those performed in Finland and Japan, have produced very encouraging results for tumors of very bas prognosis (and for which other there are no other adequate treatments) as Glioblastoma Multiforme, the deadliest brain cancer, and recurrent Head and Neck cancers. The fact that the cross section of 33S(n,alpha) is expected to be much smaller than for Boron could be compensated by means of a larger cell uptake and tumor selectivity. Sulfur is an essential element in the cell methabolism, and due to the enhanced reproductive ability of tumor cells, it is a good candidate by targeting them by means of sulfur aminoacids as cystine, which is a key compound in the synthesis of Glutathione, a biological process that is required for the growth of tissues. There are in vitro studies of cystine uptake by T-cell tumor lines which show sulfur concentrations of the order of mg/g (ppt), even when the cystine is added to the culture medium at a level in the physiological range [1]. Another example is Thiouracil that has observed to be uptaken by melanoma cells because it binds to the precursors of melamine and not to the preformed melamine. There have been found in malignant cells concentrations of Thiouracil 50 times greater than those in normal cells [2]. In addition to this, sulfur is present in different peptides and proteins of important biological roles and in nanoparticles [3] with adequate features for passive tumor targeting via the enhanced permeation and retention effect (EPR) on tumors. [1] PW Gout, YJ Kang, DJ Buckley, N Bruchovsky and AR Buckley, Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells, Leukemia 11, 1329–1337 (1997). [2] JA Coderre, S Packer, RG Fairchild, D Greenberg, B Laster, P Micca and I Fand, Iodothiouracil as a melanoma localizing agent. J Nucl Med. 27, 157-64 (1986). [3] R Tenne, Inorganic Nanotubes and Fullerene-Like Materials, Nature Nanotechnology 1, 103-111 (2006).

Motivations: (n,) data for HFSM The p-process: 32 proton-rich stable isotopes cannot be formed in neutron capture scenarios. Candidate: SN-II, sequences of (,x) and -decay. For the p-isotopes nucleosynthesis the calculations with Hauser Feshbach Statistical Models to reproduce the solar abundances disagree in more than a factor of 2 in case of neutron- and proton-induced cross sections. For alpha-induced cross sections the discrepancies between solar abundances experimental data and calculations are much larger that 2 (-nucleus potential). Experimental efforts: measured data for testing and improving HFSM calculations. [At. Dat. Nucl. Dat. Tab. 75, 1 (2000)], [At. Dat. Nucl. Dat. Tab. 79, 47 (2001)] Concerning to astrophysics, in general there is a request of (n,a) cross section data for p-process. There are around 32 proton-rich stable isotopes that cannot be formed in neutron capture scenarios so they are shielded by stable isotopes from the r-process decay chain and lie out the s-process reaction sequence. In the picture it is shown 3 of these isotopes. These isotopes are attributed to p-process that consists in sequences of photodissociations and beta decays. The astrophysical site of p-process is still under discussion and the most probably site is the Supernova tipe II. For the p-isotopes nucleosynthesis the calculations with Hauser Feshbach Statistical Models to reproduce the solar abundances disagree in more than a factor of 2 in case of neutron- and proton-induced cross sections. For alpha-induced cross sections the discrepancies between solar abundances experimental data and calculations are much larger that 2. So experimental efforts are request to measure data for testing and improving HFSM calculations. Javier Praena, CNA-Universidad de Sevilla, España