Cyanines as efficient photosensitizers in photodynamic reaction: photophysical properties and in vitro photodynamic activity.

The purpose of the present study was to explore the potential application of cyanines in photodynamic treatment. The photophysical features of four cyanines (KF570, HM118, FBF-749, and ER-139) were investigated by elemental and spectral analyses. Two malignant cell lines (MCF-7/WT and MCF-7/DOX) were used to test the potential for use in the photodynamic therapy. The cytotoxic effects of these dyes were determined by the MTT assay after 4 and 24 h of incubation with the cyanine. KF570 and HM118 were irradiated with red light (630-nm filter) and FBF-749 and ER-139 with green light (435-nm filter). The results showed that the cyanine HM118 demonstrated a major phototoxic effect. It was also noted that the efficiency of photodynamic therapy was higher in the doxorubicin-resistant cell line (MCF-7/DOX).

The influence of phenothiazine derivatives on doxorubicin treatment in sensitive and resistant human breast adenocarcinoma cells.

Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy and hormone therapy. Most cancers either are increasingly resistant to any initial treatment or acquire resistance to a broad spectrum of anticancer drugs over time. Combination of more than one drug or combination with multidrug resistance (MDR) modifiers will possibly support the efficiency of the applied therapy. Understanding the MDR mechanisms in malignancies is crucial for developing novel strategies for treatment. The main goal of our study was to determine the cytostatic effect of doxorubicin in combination with phenothiazine derivatives (PD; promazine and triflupromazine) in doxorubicin-sensitive (MCF-7/WT) and -resistant (MCF-7/DOX) human breast adenocarcinoma cell lines. We determined cytotoxicity of the investigated compounds (MTT assay) after 24 and 48 h. The effect of phenothiazine derivatives was evaluated and doxorubicin localization was performed using confocal microscopy. The mode of the cell death was examined by the comet assay. We also determined the expression of P-glycoprotein (P-gp), which is a membrane-associated protein responsible for the multidrug resistance.

Experimental investigation at CATANA facility of n-10B and p-11B reactions for the enhancement of proton therapy.

The aim of the NEPTUNE (Nuclear process-driven Enhancement of Proton Therapy UNravEled) project is to investigate in detail both the physical and radiobiological phenomena that could justify an increase of the proton-induced cytogenetic effects in cells irradiated in presence of an agent containing natural boron. In this work, a double-stage silicon telescope coupled to different boron converters was irradiated at the CATANA proton therapy facility (INFN-LNS) for studying the proton boron fusion and the neutron boron capture reactions by discriminating secondary particles from primary protons. Different boron targets were developed by depositing boric acid, enriched with a higher than 99% content of 10B or 11B, on a 50 µm thick PolyMethilMetacrylate (PMMA) substrate. The 10B target allows to evaluate the contribution of lithium and alpha particles produced by the boron neutron capture reaction triggered by secondary thermal neutrons, while the 11B target is exploited for studying the effect of the p + 11B → 3α nuclear reaction directly triggered by primary protons. Experimental results clearly show the presence of alpha particles from both the reactions. The silicon telescope is capable of discriminating, by means of the so-called "scatter plots", the contribution of alpha particles originated by thermal neutrons on 10B with respect to the ones produced by protons impinging on 11B. Although a reliable quantitative study of the alpha production rate has not been achieved yet, this work demonstrates that low energy and, therefore, high-LET particles from both the reactions can be measured.

Integrated quantitative PIXE analysis and EDX spectroscopy using a laser-driven particle source.

Among the existing elemental characterization techniques, particle-induced x-ray emission (PIXE) and energy-dispersive x-ray (EDX) spectroscopy are two of the most widely used in different scientific and technological fields. Here, we present the first quantitative laser-driven PIXE and laser-driven EDX experimental investigation performed at the Centro de Láseres Pulsados in Salamanca. Thanks to their potential for compactness and portability, laser-driven particle sources are very appealing for materials science applications, especially for materials analysis techniques. We demonstrate the possibility to exploit the x-ray signal produced by the co-irradiation with both electrons and protons to identify the elements in the sample. We show that, using the proton beam only, we can successfully obtain quantitative information about the sample structure through laser-driven PIXE analysis. These results pave the way toward the development of a compact and multifunctional apparatus for the elemental analysis of materials based on a laser-driven particle source.

Cyclization of flavokawain B reduces its activity against human colon cancer cells.

Chalcones are naturally occurring compounds exhibiting biological activity through multiple mechanisms. Flavokawain B is one of chalcones found in kava plant. In our studies, we focused on the anticancer activity of flavokawain B in colorectal cancer cells LoVo and its resistant to doxorubicin subline-LoVo/Dx. Strong cytotoxic activity of flavokawain B and its ability to inhibit the proliferation in both cell lines was detected. These effects accompanied with induction cell cycle arrest in G2/M phase and the presence of SubG1 fraction. Flavokawain B at low concentration led to increase of caspase-3 activity. The chalcone-induced apoptosis was also confirmed by DNA fragmentation. In our work, the conversion of flavokawain B to corresponding flavanone-5,7-dimetoxyflavanone-was shown to be more extensive in cancer than in non-cancer cells. We found that the cyclization of the chalcone was related to the significant decrease in the cytotoxicity. Cell proliferation and cell cycle progression were not impaired significantly in the studied cancer cells incubated with 5,7-dimethoxyflavanone. We did not observe apoptosis in the cells incubated with flavanone. The results from biological studies agreed with the theoretical activity that emerges from structural parameters.

MICRODOSIMETRY AT NANOMETRIC SCALE WITH AN AVALANCHE-CONFINEMENT TEPC: RESPONSE AGAINST A HELIUM ION BEAM.

The tissue-equivalent proportional counter (TEPC) is the most accurate device for measuring the microdosimetric properties of a particle beam but, since the lower operation limit of common TEPCs is ~0.3 µm, no detailed information on the track structure of the impinging particles can be obtained. The pattern of particle interactions at the nanometric level is measured directly by only three different nanodosimeters worldwide: practical instruments are not yet available. In order to partially fill the gap between microdosimetry and track-nanodosimetry, a low-pressure avalanche-confinement TEPC was designed and constructed for simulating tissue-equivalent sites down to the nanometric region. The present paper aims at describing the response of this TEPC in the range 0.3 µm-25 nm to a 62 MeV/n 4He ion beam. The experimental results, for depths near the Bragg peak, show good agreement with FLUKA simulations and suggest that, for smaller depths, the distribution is highly influenced by secondary electrons.

Analysis of the CONRAD computational problems expressing only stochastic uncertainties: neutrons and protons.

Within the scope of CONRAD (A Coordinated Action for Radiation Dosimetry) Work Package 4 on Computational Dosimetry jointly collaborated with the other research actions on internal dosimetry, complex mixed radiation fields at workplaces and medical staff dosimetry. Besides these collaborative actions, WP4 promoted an international comparison on eight problems with their associated experimental data. A first set of three problems, the results of which are herewith summarised, dealt only with the expression of the stochastic uncertainties of the results: the analysis of the response function of a proton recoil telescope detector, the study of a Bonner sphere neutron spectrometer and the analysis of the neutron spectrum and dosimetric quantity H(p)(10) in a thermal neutron facility operated by IRSN Cadarache (the SIGMA facility). A second paper will summarise the results of the other five problems which dealt with the full uncertainty budget estimate. A third paper will present the results of a comparison on in vivo measurements of the (241)Am bone-seeker nuclide distributed in the knee. All the detailed papers will be presented in the WP4 Final Workshop Proceedings.

CYSP-HS: A new version of the CYSP directional neutron spectrometer with increased sensitivity.

CSYP (CYlindrical SPectrometer) is a directional neutron spectrometer based on a single moderator embedding multiple thermal neutron detectors. Similarly to Bonner Spheres, CYSP responds from thermal up to GeV neutrons and the spectrum is obtained via few-channel unfolding methods. CYSP has the shape of a polyethylene cylinder with diameter 50 cm and height 65 cm. Owing on a thick collimator and on a specifically designed shielding structure, the internal detectors only respond to neutrons coming from a known direction. Internal thermal neutron detectors are one-cm2 6LiF-covered silicon diodes. Un upgraded version of CYPS was developed to work in low intensity applications, such as cosmic field measurements. It is called CYSP-HS (High-Sensitivity) and is equipped with large area 6LiF-covered silicon diodes (LATND, Large Area Thermal Neutron Detectors). Compared with the former CYSP, the sensitivity increased approximately by an order of magnitude. This paper presents CYSP-HS focusing on the new internal detectors, the response matrix and its verification in a reference field of Am-Be available at the Politecnico di Milano.

MICRODOSIMETRIC STUDY AT THE CNAO ACTIVE-SCANNING CARBON-ION BEAM.

The Italian National Centre for Oncological Hadrontherapy (CNAO) has been treating patients since 2011 with carbon-ion beams using the active-scanning modality. In such irradiation modality, the beam spot, which scans the treatment area, is characterised by very high particle-fluence rates (more than 105 s-1 mm-2). Moreover, the Bragg-peak is only ~1 mm-FWHM. Commercial tissue-equivalent proportional counters (TEPC), like the Far West Technologies LET-½, are large, hence they have limited capability to measure at high counting fluence rates. In this study we have used two home-made detectors, a mini-TEPC 0.81 mm2 in sensitive area and a silicon telescope 0.125 mm2 in sensitive area, to perform microdosimetric measurements in the therapeutic carbon-ion beam of CNAO. A monoenergetic carbon-ion beam of 189.5 ± 0.3 MeV/u scanning a 3 × 3 cm2 area has been used. Spectral differences are visible in the low y-value region, but the mean microdosimetric values, measured with the two detectors, result to be pretty consistent, as well as the microdosimetric spectra in the high y-value region.

A NOVEL TEPC FOR MICRODOSIMETRY AT NANOMETRIC LEVEL: RESPONSE AGAINST DIFFERENT NEUTRON FIELDS.

Tissue equivalent proportional counter (TEPC) is the most accurate device for measuring the microdosimetric properties of a particle beam, nevertheless no detailed information on the track structure of the impinging particles can be obtained, since the lower operation limit of common TEPCs is ~0.3 µm. On the other hand, the pattern of particle interactions at the nanometer level is measured by only three different nanodosimeters worldwide: practical instruments are not yet available. In order to partially fill the gap between microdosimetry and track-nanodosimetry, a low-pressure avalanche-confinement TEPC was recently designed and constructed for simulating tissue-equivalent sites down to the nanometric region. The present article aims at describing the response of this newly developed TEPC in the range 0.3 µm-25 nm against a fast neutron field from a 241Am-Be source and a quasi-monoenergetic neutron beam. The experimental results are in good agreement with Monte Carlo simulations carried out with the FLUKA code.

Miniaturized microdosimeters as LET monitors: First comparison of calculated and experimental data performed at the 62 MeV/u 12C beam of INFN-LNS with four different detectors.

PURPOSE: The aim of this paper is to investigate the limits of LET monitoring of therapeutic carbon ion beams with miniaturized microdosimetric detectors. METHODS: Four different miniaturized microdosimeters have been used at the 62 MeV/u 12C beam of INFN Southern National Laboratory (LNS) of Catania for this purpose, i.e. a mini-TEPC and a GEM-microdosimeter, both filled with propane gas, and a silicon and a diamond microdosimeter. The y-D (dose-mean lineal energy) values, measured at different depths in a PMMA phantom, have been compared withLET¯D (dose-mean LET) values in water, calculated at the same water-equivalent depth with a Monte Carlo simulation setup based on the GEANT4 toolkit. RESULTS: In these first measurements, no detector was found to be significantly better than the others as a LET monitor. The y-D relative standard deviation has been assessed to be 13% for all the detectors. On average, the ratio between y-D and LET¯D values is 0.9 ±â€¯0.3, spanning from 0.73 ±â€¯0.08 (in the proximal edge and Bragg peak region) to 1.1 ±â€¯0.3 at the distal edge. CONCLUSIONS: All the four microdosimeters are able to monitor the dose-mean LET with the 11% precision up to the distal edge. In the distal edge region, the ratio of y-D to LET¯D changes. Such variability is possibly due to a dependence of the detector response on depth, since the particle mean-path length inside the detectors can vary, especially in the distal edge region.

DEVELOPING RADIATION RESISTANT THERMAL NEUTRON DETECTORS FOR THE E_LIBANS PROJECT: PRELIMINARY RESULTS.

Radiation-resistant, gamma-insensitive, active thermal neutron detectors were developed to monitor the thermal neutron cavity of the E_LIBANS project. Silicon and silicon carbide semiconductors, plus vented air ion chambers, were chosen for this purpose. This communication describes the performance of these detectors, owing on the results of dedicated measurement campaigns.

INTENSE THERMAL NEUTRON FIELDS FROM A MEDICAL-TYPE LINAC: THE E_LIBANS PROJECT.

The e_LiBANS project aims at producing intense thermal neutron fields for diverse interdisciplinary irradiation purposes. It makes use of a reconditioned medical electron LINAC, recently installed at the Physics Department and INFN in Torino, coupled to a dedicated photo-converter, developed within this collaboration, that uses (γ,n) reaction within high Z targets. Produced neutrons are then moderated to thermal energies and concentrated in an irradiation volume. To measure and to characterize in real time the intense field inside the cavity new thermal neutron detectors were designed with high radiation resistance, low noise and very high neutron-to-photon discrimination capability. This article offers an overview of the e_LiBANS project and describes the results of the benchmark experiment.

Neutron spectrometry with a monolithic silicon telescope.

A neutron spectrometer was set-up by coupling a polyethylene converter with a monolithic silicon telescope, consisting of a DeltaE and an E stage-detector (about 2 and 500 microm thick, respectively). The detection system was irradiated with monoenergetic neutrons at INFN-Laboratori Nazionali di Legnaro (Legnaro, Italy). The maximum detectable energy, imposed by the thickness of the E stage, is about 8 MeV for the present detector. The scatter plots of the energy deposited in the two stages were acquired using two independent electronic chains. The distributions of the recoil-protons are well-discriminated from those due to secondary electrons for energies above 0.350 MeV. The experimental spectra of the recoil-protons were compared with the results of Monte Carlo simulations using the FLUKA code. An analytical model that takes into account the geometrical structure of the silicon telescope was developed, validated and implemented in an unfolding code. The capability of reproducing continuous neutron spectra was investigated by irradiating the detector with neutrons from a thick beryllium target bombarded with protons. The measured spectra were compared with data taken from the literature. Satisfactory agreement was found.

Neutron measurements in radiotherapy: A method to correct neutron sensitive devices for parasitic photon response.

One of the major causes of secondary malignancies after radiotherapy treatments are peripheral doses, known to increase for some newer techniques (such as IMRT or VMAT). For accelerators operating above 10MV, neutrons can represent important contribution to peripheral doses. This neutron contamination can be measured using different passive or active techniques, available in the literature. As far as active (or direct-reading) procedures are concerned, a major issue is represented by their parasitic photon sensitivity, which can significantly affect the measurement when the point of test is located near to the field-edge. This work proposes a simple method to estimate the unwanted photon contribution to these neutrons. As a relevant case study, the use of a recently neutron sensor for "in-phantom" measurements in high-energy machines was considered. The method, called "Dual Energy Photon Subtraction" (DEPS), requires pairs of measurements performed for the same treatment, in low-energy (6MV) and high energy (e.g. 15MV) fields. It assumes that the peripheral photon dose (PPD) at a fixed point in a phantom, normalized to the unit photon dose at the isocenter, does not depend on the treatment energy. Measurements with ionization chamber and Monte Carlo simulations were used to evaluate the validity of this hypothesis. DEPS method was compared to already published correction methods, such as the use of neutron absorber materials. In addition to its simplicity, an advantage of DEPs procedure is that it can be applied to any radiotherapy machine.

TWO NEW SINGLE-EXPOSURE, MULTI-DETECTOR NEUTRON SPECTROMETERS FOR RADIATION PROTECTION APPLICATIONS IN WORKPLACE MONITORING.

This communication describes two new instruments, based on multiple active thermal neutron detectors arranged within a single moderator, that permit to unfold the neutron spectrum (from thermal to hundreds of MeV) and to determine the corresponding integral quantities with only one exposure. This makes them especially advantageous for neutron field characterisation and workplace monitoring in neutron-producing facilities. One of the devices has spherical geometry and nearly isotropic response, the other one has cylindrical symmetry and it is only sensitive to neutrons incident along the cylinder axis. In both cases, active detectors have been specifically developed looking for the criteria of miniaturisation, high sensitivity, linear response and good photon rejection. The calculated response matrix has been validated by experimental irradiations in neutron reference fields with a global uncertainty of 3%. The measurements performed in realistic neutron fields permitted to determine the neutron spectra and the integral quantities, in particular H*(10).

A solid state microdosimeter based on a monolithic silicon telescope.

A monolithic silicon telescope, consisting of a DeltaE and an E stage-detector ( approximately 1.9 microm and 500 microm thick, respectively), was coupled to a polyethylene converter in order to investigate the feasibility of a solid state microdosimeter with respect to the field-funnelling effect. This work discusses the preliminary results of an analytical approach for the correction of a spectrum measured with this silicon-based microdosimeter for tissue-equivalence and geometrical effects. The device was irradiated with 2.7 MeV monoenergetic neutrons at the INFN-Laboratori Nazionali di Legnaro (Legnaro, Italy). The non tissue-equivalence of silicon was corrected by exploiting the signals generated in the E-stage. The correction for the sensitive volume geometry was optimised by taking into account the track length distribution of the recoil-protons generated in the converter. The derived dose distribution of the energy imparted per event was compared to the one measured with a cylindrical tissue-equivalent proportional counter (TEPC). The agreement is satisfactory.

Charge collection imaging of a monolithic DeltaE-E telescope for radiation protection applications.

The development of microdosimeters and particle telescopes is important for risk assessment in space and aviation applications. The charge collection properties of a monolithic particle telescope, suitable for both microdosimetry and fluence based approaches, were studied using an ion microprobe.

ETHERNES: A new design of radionuclide source-based thermal neutron facility with large homogeneity area.

A new thermal neutron irradiation facility based on an (241)Am-Be source embedded in a polyethylene moderator has been designed, and is called ETHERNES (Extended THERmal NEutron Source). The facility shows a large irradiation cavity (45 cm × 45 cm square section, 63 cm in height), which is separated from the source by means of a polyethylene sphere acting as shadowing object. Taking advantage of multiple scattering of neutrons with the walls of this cavity, the moderation process is especially effective and allows obtaining useful thermal fluence rates from 550 to 800 cm(-2) s(-1) with a source having nominal emission rate 5.7×10(6) s(-1). Irradiation planes parallel to the cavity bottom have been identified. The fluence rate across a given plane is as uniform as 3% (or better) in a disk with 30 cm (or higher) diameter. In practice, the value of thermal fluence rate simply depends on the height from the cavity bottom. The thermal neutron spectral fraction ranges from 77% up to 89%, depending on the irradiation plane. The angular distribution of thermal neutrons is roughly isotropic, with a slight prevalence of directions from bottom to top of the cavity. The mentioned characteristics are expected to be attractive for the scientific community involved in neutron metrology, neutron dosimetry and neutron detector testing.