Hedgehog Pathway Inhibition Hampers Sphere and Holoclone Formation in Rhabdomyosarcoma

Altres ajuts: This work was supported by grants from Institut Català d'Oncologia (ICO), Instituto de Salud Carlos III (RTICC-RD12/0036/0016 and RD12/0036/0027; PI11/00740 and PI14/00647), Fundació A. BOSCH, and ajuts predoctorals VHIR.Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and can be divided into two main subtypes: embryonal (eRMS) and alveolar (aRMS). Among the cellular heterogeneity of tumors, the existence of a small fraction of cells called cancer stem cells (CSC), thought to be responsible for the onset and propagation of cancer, has been demonstrated in some neoplasia. Although the existence of CSC has been reported for eRMS, their existence in aRMS, the most malignant subtype, has not been demonstrated to date. Given the lack of suitable markers to identify this subpopulation in aRMS, we used cancer stem cell-enriched supracellular structures (spheres and holoclones) to study this subpopulation. This strategy allowed us to demonstrate the capacity of both aRMS and eRMS cells to form these structures and retain self-renewal capacity. Furthermore, cells contained in spheres and holoclones showed significant Hedgehog pathway induction, the inhibition of which (pharmacologic or genetic) impairs the formation of both holoclones and spheres. Our findings point to a crucial role of this pathway in the maintenance of these structures and suggest that Hedgehog pathway targeting in CSC may have great potential in preventing local relapses and metastases

Results of a combined monolithic crystal and an array of ASICs controlled SiPMs

[EN] In this work we present the energy and spatial resolutions we have obtained for a γ ray detector based on a monolithic LYSO crystal coupled to an array of 256 SiPMs. Two crystal configurations of the same trapezoidal shape have been tried. In one approach all surfaces were black painted but the exit one facing the photosensor array which was polished. The other approach included a retroreflector (RR) layer coupled to the entrance face of the crystal powering the amount of transmitted light to the photosensors. Two coupling media between the scintillator and the SiPM array were used, namely direct coupling by means of optical grease and coupling through an array of light guides. Since the same operational voltage was supplied to the entire array, it was needed to equalize their gains before feeding their signals to the Data Acquisition system. Such a job was performed by means of 4 scalable Application Specific Circuits (ASICs). An energy resolution of about 24.4% has been achieved for the direct coupling with the RR layer together with a spatial resolution of approximately 2.9 mm at the detector center. With the light guides coupling the effects of image compression at the edges are significantly minimized, but worsening the energy resolution to about 33.1% with a spatial resolution nearing 4 mm at the detector center. & 2013 Elsevier B.V. All rights reserved.cknowledgments This work was supported by the Centre for Industrial Technological Development co-funded by FEDER through the Technology Fund (DREAM Project, IDI-20110718), the Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (IþDþI) under Grant no. FIS2010-21216-CO2-01 and the Valencian Local Government under Grant PROMETEO 2008/114Conde Castellanos, PE.; González Martínez, AJ.; Hernández Hernández, L.; Bellido, P.; Iborra Carreres, A.; Crespo Navarro, E.; Moliner Martínez, L.... (2014). Results of a combined monolithic crystal and an array of ASICs controlled SiPMs. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 734:132-136. https://doi.org/10.1016/j.nima.2013.08.079S13213673

Calibration and performance tests of detectors for laser-accelerated protons

We present the calibration and performance tests carried out with two detectors for intense proton pulses accelerated by lasers. Most of the procedures were realized with proton beams of 0.46-5.60 MeV from a tandem accelerator. One approach made use of radiochromic films, for which we calibrated the relation between optical density and energy deposition over more than three orders of magnitude. The validity of these results and of our analysis algorithms has been confirmed by controlled irradiation of film stacks and reconstruction of the total beam charge for strongly non-uniform beam profiles. For the spectral analysis of protons from repeated laser shots, we have designed an online monitor based on a plastic scintillator. The resulting signal from a photomultiplier directly measured on a fast oscilloscope is especially useful for time-of-flight applications. Variable optical filters allow for suppression of saturation and an extension of the dynamic range. With pulsed proton beams we have tested the detector response to a wide range of beam intensities from single particles to 3 ×105 protons per 100 ns time interval.Project funded by the Spanish Ministry of Economy and Competitiveness and co-funded with FEDER's funds within the INNPACTO 2011 program under Grant No. IPT-2011-0862-900000. This work was supported by the Spanish Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I+D+i) under Grant No. TEC 2013-48036-C3-1-R and the Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013. The work of A. J. Gonzalez is financed by CSIC with a JAE-Doc contract under Junta de Ampliacion de Estudios program, cofinanced by the European Social Fund.Peer Reviewe

Effect of noise in CT image reconstruction using QR- Decomposition algorithm

[EN] The QR-Decomposition algorithm for CT 3D image reconstruction uses a linear system of equations to model the CT system response. Linear systems have a condition number that can be used to estimate the image noise. In this work the number of projections and the number of pixels in the detector have been studied to characterize the CT and the linear system of equations. The condition number of the system is estimated for the previous parameters used to generate the CT model with the aim of characterizing how these parameters affect the condition number and therefore bound the image noise level. It is shown that the condition number mainly depends on the size of pixels of the detector rather than the number of projections and this algorithm can be applied to low dose CT 3D image reconstruction without compromising image qualityThis work was supported by the Spanish Plan Nacional de Investigacion Científica, Desarrollo e Innovación Tecnológica (I+D+I) under Grant No. FIS2010-21216-CO2-01 and Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013Iborra, A.; Rodríguez-Álvarez, MJ.; Soriano, A.; Sánchez, F.; Bellido, P.; Conde, P.; Crespo, E.... (2013). Effect of noise in CT image reconstruction using QR- Decomposition algorithm. IEEE. 5-9. http://hdl.handle.net/10251/167122S5

Statistical moments of scintillation light distribution analysis with dSiPMs and monolithic crystals

[Otros] Monolithic scintillation crystals offer the possibility to preserve the scintillation light distribution, specially when black painted. Furthermore, the statistical moments of that distribution can provide accurate information about the three spatial components. Nevertheless, for monolithic crystal the moments estimation has an associated error due to the symmetry truncation of the light distribution towards the crystal borders. For the 2-D impact coordinates determination, this error is called compression as it is accentuated near the edges. The computation of all centered moments is, therefore, affected by this error. Digital SiPMs (dSiPMs) can offer complete information about the light distribution, since all cells are purely digital detectors, so that other ways to obtain ¿-impact coordinates can be performed. In this work, a comparison between the statistical moments analysis and an alternative fitting the light distribution for each event to a theoretical distribution has been made. With the fitted approach, compression is avoided and an approximately constant spatial resolution is obtained for the entire photodetection area. Moreover, DOI information is improved and preserved all over the crystal.This work was supported by the Spanish Plan Nacional de Investigacion Científica, Desarrollo e Innovación Tecnologica (I+D+I) under Grant No. FIS2010-21216-CO2-01 and Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013Conde, P.; González Martínez, AJ.; Hernández, L.; Bellido, P.; Crespo, E.; Iborra, A.; Moliner, L.... (2013). Statistical moments of scintillation light distribution analysis with dSiPMs and monolithic crystals. IEEE. 10-13. https://doi.org/10.1109/NSSMIC.2013.6829086S101

Time reconstruction study using tubes of response backprojectors in List Mode algorithms, applied to amonolithic crystals based breast PET

[Otros] The LM-EM algorithm has the advantage to calculate the emission probabilities needed for the reconstruction process on the fly, without the need of a pre-calculated system matrix. The reconstruction time for this algorithm strongly depends on the used backprojector and the available statistics. This algorithm when implemented in systems using monolithic crystals to detect gamma radiation allows one to extensively exploit the virtual pixilation feature, not available for systems based on pixilated crystals. In this work we present a backprojector for LM-EM, the TOR method, which achieves a tradeoff between computational efficiency and image quality. Its temporal subset algorithm optimization (LM-OS) has also been implemented in order to achieve real-time reconstructions. To evaluate the performances of LM-OS algorithm with the TOR method backprojector and only with one iteration on the datasets, studies based on the system spatial resolution, uniformity, and contrast coefficients were carried out and they were compared with those obtained with LM-EM and MLEM algorithms using twelve iteration. Finally, a study on reconstruction time using LM-OS has been performed with breast patients dataProject funded by the Spanish Ministry of Economy and Competitiveness and co-funded with FEDER's funds within the INNPACTO 2011 program. This work was supported by the Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+i) under Grant No. FIS2010-21216-CO2-01 and the Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013Moliner, L.; Correcher, C.; González Martínez, AJ.; Conde, P.; Crespo, E.; Hernandez, L.; Rigla, JP.... (2013). Time reconstruction study using tubes of response backprojectors in List Mode algorithms, applied to amonolithic crystals based breast PET. IEEE. 14-18. https://doi.org/10.1109/NSSMIC.2013.6829372S141

Time-of-Flight Detector for the Characterisation of Laser-Accelerated Protons

[Otros] Lasers of ultra-high intensity focused on thin targets can form plasmas and release large numbers of charged particles with kinetic energies in the MeV region. The characterization of the accelerated particles requires suitable detectors. We present a time-of-flight detector based on a plastic scintillator optimized for the spectral analysis of laser-accelerated protons. All details of the detector layout are adapted to the expected properties of the proton beam. Particle energies will be separated by the time-of-flight technique over 200 cm path length. The active area (25 mm width) corresponds to a few mrad opening angle. With 5 mm thickness the detector is capable of absorbing protons up to 22.5 MeV. A very thin, aluminized mylar foil shields the scintillator from outer light while absorbing very little particle energy. The scintillation photons are measured with a photomultiplier tube coupled through a bundle of optical fibres. The coupling of these fibres via a PMMA light guide has been previously optimized in simulations with Litrani. A critical aspect of the detection of virtually large numbers of protons emitted in femtosecond pulses is the saturation of the PMT. The latter can be avoided by use of appropriate optical filters. With these the effective dynamic range starts from single particles over several orders of magnitude. Our time-of-flight detector has been calibrated at the Spanish National Accelerator Centre at Sevilla. Proton beams from 0.46 to 5.6 MeV from a tandem accelerator have been used to measure the relation between particle energy and pulse heights. Further tests have been performed with a pulsed electron beam to simulate many-particle hits.Project funded by the Spanish Ministry of Economy and Competitiveness and co-funded with FEDER¿s funds within the INNPACTO 2011 program, Grant No. IPT-2011-0862- 900000. This work was supported by the Spanish Plan Nacional de Investigacion Científica, Desarrollo e Innovacion Tecnológica (I+D+i) under Grant No. FIS2010-21216-CO2-01 and the Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013Seimetz, M.; Bellido, P.; Soriano, A.; Huertas, C.; García Lopez, J.; Jimenez-Ramos, MC.; Fernandez, B.... (2013). Time-of-Flight Detector for the Characterisation of Laser-Accelerated Protons. IEEE. 25-28. https://doi.org/10.1109/NSSMIC.2013.6829804S252

Dosimetric Calibration of Radiochromic Film For Laser-accelerated Proton Beams

[Otros] When an ultra-intense and ultra-short laser pulse interacts with solid matter a fraction of the laser pulse can be converted into kinetic energy of a beam of charged particles. Radiochromic film (RCF), widely used as radiation detector in the field of conventional radiotherapy, can be used as detector for laser-accelerated protons. If used in stack configuration it is a useful and versatile tool to obtain 2D spatial distribution and energetic information of proton beams. In order to obtain dosimetric information from RCF it must be properly calibrated. Irradiating film pieces under well known conditions allows us to establish a relation between the optical density (OD) of the radiochromic film, which is measured through a flat bed scanner operating in transmission mode, and the deposited energy in the active layer. A calibration curve over a large dynamic range (3 orders of magnitude) has been obtained for few MeV protons. Our calibration process has been performed at the Spanish National Accelerator Center at Sevilla. We have irradiated several areas of a single RCF with a constant 50 pA beam current and fixed 4 MeV energy from a 3 MV tandem accelerator. We have calculated the deposited energy in the films under the same conditions. We demonstrate that this technique can be used to measure the spectrum and total energy of a laser-accelerated mixed-energy proton beam. This detector has been calibrated for a near future application at the Center of Pulsed, Ultra-short, Ultra-intense Lasers (CLPU) at Salamanca (Spain). We present the calibration procedure and results, the design optimization, and a comparison with similar experiments.Project funded by the Spanish Ministry of Economy and Competitiveness and co-funded with FEDERs funds within the INNPACTO 2011 program. This work was supported by the Spanish Plan Nacional de Investigacion Cientifica, Desarrollo e InnovacionTecnologica (I+D+i) under Grant No. FIS2010-21216-CO2-01 and the Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013.Bellido, P.; Seimetz, M.; Soriano, A.; Huertas, C.; García Lopez, J.; Jimenez-Ramos, MC.; Fernandez, B.... (2013). Dosimetric Calibration of Radiochromic Film For Laser-accelerated Proton Beams. IEEE. 20-23. https://doi.org/10.1109/NSSMIC.2013.6829806S202

Performance Evaluation of the Dual Ring MAMMI breast PET

[Otros] MAMMI is a dedicated breast positron emission tomograph (PET) based on monolythic LYSO crystals, with a transaxial field of view (FOV) of 170 mm. It has been upgraded by adding a second ring of detectors that extends the axial FOV from 40 mm to 94.4 mm, in order to improve its sensitivity and reduce the acquisition time. In this work we present the performance evaluation of the dual ring MAMMI breast PET and a discussion about the contribution of the addition of a second ring of detectors, the compensation of the detector blur and the increase of the scintillator thickness. Experimental measurements suggested on NEMA NU 4-2008 and NEMA NU 2-2007 have been conveniently adapted to the dimensions of the MAMMI. The addition of the second ring of detectors leads to a rise of the sensitivity from 1.8% to 3.6%. The spatial resolution at one-fourth of the axial FOV (1.5 mm axial, 1.6 mm tangential, 1.7 mm radial) is slightly better than that measured at the axial center (1.9 mm axial, 1.8 mm tangential and radial), because of the 14 mm gap in between detection rings. The results obtained after the evaluation reflect a substantial performance improvement, specially in the absolute sensitivity, because of the changes introduced in the MAMMI PET.This work was supported in part bythe Spanish Plan Nacional de Investigacion Científica, Desarrollo e Innovación Tecnologica (I+D+I) under Grant No. FIS2010-21216-CO2-01 and Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013Soriano, A.; Sánchez, F.; Carrilero, V.; Pardo, A.; Vidal San Sebastian, LF.; Vazquez, C.; Barbera, J.... (2013). Performance Evaluation of the Dual Ring MAMMI breast PET. IEEE. 1-4. https://doi.org/10.1109/NSSMIC.2013.6829103S1