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Background. Monte Carlo simulation of radiation transport for medical linear accelerators (linacs) requires accurate knowledge of the geometrical description of the linac head. Since the geometry of Varian TrueBeam machines has not been disclosed, the manufacturer distributes phase-space files of the linac patient-independent part to allow researchers to compute absorbed dose distributions using the Monte Carlo method. This approach limits the possibility of achieving an arbitrarily small statistical uncertainty. This work investigates the use of the geometry of the Varian Clinac 2100, which is included in the Monte Carlo system PRIMO, as a surrogate. Methods. Energy, radial and angular distributions extracted from the TrueBeam phase space files published by the manufacturer and from phase spaces tallied with PRIMO for the Clinac 2100 were compared for the 6, 8, 10 and 15 MV flattened-filtered beams. Dose distributions in water computed for the two sets of PSFs were compared with the Varian Representative Beam Data (RBD) for square fields with sides ranging from 3 to 30 cm. Output factors were calculated for square fields with sides ranging from 2 to 40 cm. Results. Excellent agreement with the RBD was obtained for the simulations that employed the phase spaces distributed by Varian as well as for those that used the surrogate geometry, reaching in both cases Gamma ( , 2 mm) pass rates larger than , except for the 15 MV surrogate. This result supports previous investigations that suggest a change in the material composition of the TrueBeam 15 MV flattening filter. In order to get the said agreement, PRIMO simulations were run using enlarged transport parameters to compensate the discrepancies between the actual and surrogate geometries. Conclusions. This work sustains the claim that the simulation of the 6, 8 and 10 MV flattening-filtered beams of the TrueBeam linac can be performed using the Clinac 2100 model of PRIMO without significant loss of accuracy., Open Access funding enabled and organized by Projekt DEAL. The authors acknowledge support by the Open Access Publication Fund of the University of Duisburg-Essen. MR acknowledges funding by the Sistema Nacional de Investigación de Panamá (SNI). JS thanks the Spanish Ministerio de Ciencia e Innovación, project PID2019-104714GB-C22. LB acknowledges funding by the HARMONIC project. The HARMONIC project (Health effects of cArdiac fluoRoscopy and MOderN radIotherapy in paediatriCs) has received funding from the Euratom research and training programme 2014-2018 under grant agreement number 847707., Postprint (published version)

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

MicroRNAs (miRNAs) are small non-coding endogenous RNAs, which are attracting a growing interest as therapeutic molecules due to their central role in major diseases. However, the transformation of these biomolecules into drugs is limited due to their unstability in the bloodstream, caused by nucleases abundantly present in the blood, and poor capacity to enter cells. The conjugation of miRNAs to nanoparticles (NPs) could be an effective strategy for their clinical delivery. Herein, the engineering of non-liposomal lipid nanovesicles, named quatsomes (QS), for the delivery of miRNAs and other small RNAs into the cytosol of tumor cells, triggering a tumor-suppressive response is reported. The engineered pH-sensitive nanovesicles have controlled structure (unilamellar), size (<150 nm) and composition. These nanovesicles are colloidal stable (>24 weeks), and are prepared by a green, GMP compliant, and scalable one-step procedure, which are all unavoidable requirements for the arrival to the clinical practice of NP based miRNA therapeutics. Furthermore, QS protect miRNAs from RNAses and when injected intravenously, deliver them into liver, lung, and neuroblastoma xenografts tumors. These stable nanovesicles with tunable pH sensitiveness constitute an attractive platform for the efficient delivery of miRNAs and other small RNAs with therapeutic activity and their exploitation in the clinics.

Purpose The Transit-Guided Radiation Therapy (TGRT) technique is a novel technique aimed to quantify the position error of a patient by using the transit portal images (TPI) of the treatment fields. Despite of the promising preliminary results, about 4% of the cases would have led to position overcorrections. In this work, the TGRT formalism is refined to improve its accuracy and, especially, to decrease the risk of overcorrections. Methods A second free parameter accounting for beam hardening has been added to the attenuation model of the TGRT formalism. Five treatment plans combining different delivery techniques and tumour sites have been delivered to an anthropomorphic phantom. TPIs have been obtained under a set of random couch shifts for each field. For each TPI, both the original and the refined TGRT formalism have been used to estimate the underlying true shift. Results With respect the original formalism, the refined formalism: (i) decreased both the number (from 5% to 1%) and the magnitude of the overcorrections; (ii) lowered the detection threshold (from approximately 1 mm to <0.3 mm); (iii) largely improved the accuracy in tumour sites with large mass thickness variations; and (iv) largely improved the accuracy for true shifts below 5 mm. For true shifts above 5 mm, the accuracy was slightly impaired. Conclusions The refined TGRT formalism performed globally better than the original TGRT formalism and it largely reduced the risk of overcorrections. Further refinements of the TGRT formalism should focus on true shifts above 5 mm., Postprint (author's final draft)

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.

MicroRNAs (miRNAs) are small non-coding endogenous RNAs, which are attracting a growing interest as therapeutic molecules due to their central role in major diseases. However, the transformation of these biomolecules into drugs is limited due to their unstability in the bloodstream, caused by nucleases abundantly present in the blood, and poor capacity to enter cells. The conjugation of miRNAs to nanoparticles (NPs) could be an effective strategy for their clinical delivery. Herein, the engineering of non-liposomal lipid nanovesicles, named quatsomes (QS), for the delivery of miRNAs and other small RNAs into the cytosol of tumor cells, triggering a tumor-suppressive response is reported. The engineered pH-sensitive nanovesicles have controlled structure (unilamellar), size (<150 nm) and composition. These nanovesicles are colloidal stable (>24 weeks), and are prepared by a green, GMP compliant, and scalable one-step procedure, which are all unavoidable requirements for the arrival to the clinical practice of NP based miRNA therapeutics. Furthermore, QS protect miRNAs from RNAses and when injected intravenously, deliver them into liver, lung, and neuroblastoma xenografts tumors. These stable nanovesicles with tunable pH sensitiveness constitute an attractive platform for the efficient delivery of miRNAs and other small RNAs with therapeutic activity and their exploitation in the clinics.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

Objective.Transitin vivodosimetry methods monitor that the dose distribution is delivered as planned. However, they have a limited ability to identify and to quantify the cause of a given disagreement, especially those caused by position errors. This paper describes a proof of concept of a simplein vivotechnique to infer a position error from a transit portal image (TPI).Approach.For a given treatment field, the impact of a position error is modeled as a perturbation of the corresponding reference (unperturbed) TPI. The perturbation model determines the patient translation, described by a shift vector, by comparing a givenin vivoTPI to the corresponding reference TPI. Patient rotations can also be determined by applying this formalism to independent regions of interest over the patient. Eight treatment plans have been delivered to an anthropomorphic phantom under a large set of couch shifts (<15 mm) and rotations (<10°) to experimentally validate this technique, which we have named Transit-Guided Radiation Therapy (TGRT).Main results.The root mean squared error (RMSE) between the determined and the true shift magnitudes was 1.0/2.4/4.9 mm for true shifts ranging between 0-5/5-10/10-15 mm, respectively. The angular accuracy of the determined shift directions was 12° ± 14°. The RMSE between the determined and the true rotations was 0.5°. The TGRT technique decoupled translations and rotations satisfactorily. In 96% of the cases, the TGRT technique decreased the existing position error. The detection threshold of the TGRT technique was around 1 mm and it was nearly independent of the tumor site, delivery technique, beam energy or patient thickness.Significance.TGRT is a promising technique that not only provides reliable determinations of the position errors without increasing the required equipment, acquisition time or patient dose, but it also adds on-line correction capabilities to existing methods currently using TPIs., Peer Reviewed, Objectius de Desenvolupament Sostenible::3 - Salut i Benestar, Postprint (published version)

The International Atomic Energy Agency (IAEA), jointly with the World Health Organization (WHO), has operated a postal dosimetry audit program for radiotherapy centers worldwide since 1969. In 2017 the IAEA introduced a new methodology based on radiophotoluminescent dosimetry (RPLD) for these audits. The detection system consists of a phosphate glass dosimeter inserted in a plastic capsule that is kept in measuring position with a PMMA holder during irradiation. Correction factors for this holder were obtained using experimental methods. In this work these methods are described and the resulting factors are verified by means of Monte Carlo simulation with the general-purpose code PENELOPE for a range of photon beam qualities relevant in radiotherapy. The study relies on a detailed geometrical representation of the experimental setup. Various photon beams were obtained from faithful modeling of the corresponding linacs. Monte Carlo simulation transport parameters are selected to ensure subpercent accuracy. The simulated correction factors fall in the interval 1.005–1.008 (±0.2%), with deviations with respect to experimental values not larger than 0.2(2)%. This study corroborates the validity of the holder correction factors currently used for the IAEA audits., Peer Reviewed, Postprint (author's final draft)

[ES] En este trabajo se desarrolla una aplicación web responsive, para la administración de empresas. Esta aplicación se ha realizado utilizando el framework Quasar para el frontend y Express para la API REST que publica los servicios web necesarios para dotar de funcionalidad a la plataforma, la cual implementa un sistema de seguridad basado en tokens. El resultado final es una aplicación capaz de adaptarse a ordenadores y dispositivos móviles que ofrece las funcionalidades de la plataforma de un modo sencillo e intuitivo para el usuario., [EN] This project consists of developing a responsive web application for business administration. The application has been developed using Quasar framework as frontend and Express as REST API which provides the web services that makes the platform functional. This API integrates a token-based security system. As a result, a responsive web application able to work on desktop computers and mobile devices is developed, and it offers all features of the platform in a user-friendly way., [CA] En aquest treball es desenvolupa una aplicació web adaptativa per a l'administració d'empreses. Aquesta aplicació s'ha realitzat utilitzant el framework Quasar per al frontend i Express per a l'API REST que publica els serveis web necessaris per a dotar de funcionalitat a l'aplicació web, la qual implementa un sistema de seguretat basat en tokens. El resultat final és una aplicació capaç d'adaptar-se a ordinadors i dispositius mòbils que ofereix les funcionalitats de la plataforma d'una manera senzilla i intuïtiva per a l'usuari.