Osteosarcoma en la infancia y adolescencia: factores pronósticos e identificación de nuevas dianas terapéuticas

Introduction Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Current management of high-grade osteosarcoma consists of administration of neoadjuvant/adjuvant chemotherapy and complete surgical removal of all tumour sites. The most important prognostic factors for long-term survival are: disease extension (localized/metastatic), primary tumour location (extremity/axial), histologic response to first-line induction chemotherapy and surgical removal of all detectable lesions. The addition of chemotherapy to surgery in the 1970s and 80s increased substantially long-term survival of osteosarcoma patients. However, no further improvement of survival has been observed since then, with currently 5-year overall survival of 60-70% for localized and 20-30% for metastatic osteosarcoma. Therefore, there is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. General objective: - To identify prognostic factors, at diagnosis and relapse, for children and adolescents with high-grade osteosarcoma and identify new therapeutic targets. Specific objectives: - To identify prognostic factors and survival of children and adolescents with highgrade osteosarcoma at diagnosis and relapse. - To determine the incidence and cancer distribution, treatment setting and provider specialty of children and adolescents in the Comunidad Valenciana. - To identify new therapeutic targets in paediatric and adolescent osteosarcoma Methods: This PhD thesis consists of four papers of which the candidate is the first author: 1. Pablo Berlanga, Adela Cañete, Roberto Díaz, Marta Salom, Francisco Baixauli, Jacinto Gómez, Margarita Llavador, Victoria Castel. Presentation and Long-term Outcome of High-grade Osteosarcoma: A Single-institution Experience. J Pediatric Hematol Oncol 2015; 37: e272-e277. 2. Pablo Berlanga, Adela Cañete, Marta Salom, Joaquin Montalar, María Guasp, Alfredo Marco, Victoria Castel. Postrelapse Prognostic Factors in Nonmetastatic Osteosarcoma: A Single-Institution Experience. J Pediatric Hematol Oncol 2016; 38: 176-181. 3. Pablo Berlanga, María Luisa Vicente, Adela Cañete, Carmen Alberich, Victoria Castel. Cancer in cancer in children and adolescents in Spain: incidence, treatment setting and provider specialty. Clin Transl Oncol 2016; 18: 27-32. 4. Pablo Berlanga, Lisandra Muñoz, Marta Piqueras, Antoni Sirerol, María Dolors Sánchez-Izquierdo, David Hervás, Miguel Hernández, Margarita Llavador, Isidro Machado, Antonio Llombart-Bosch, Adela Cañete, Victoria Castel, Jaime Font de Mora. miR-200c and Akt predict osteosarcoma progression and lung metastasis. Mol Oncol. 2016; 10: 1043-53. This work was supported by a Predoctoral Research Fellowship from the Instituto de Investigación Sanitaria La Fe (2011/0319) Results and conclusions: Five-year overall survival (OS), event-free survival (EFS) and main prognostic factors for high-grade osteosarcoma patients in our cohort are similar to those previously described: A) At diagnosis: metastatic disease, poor histologic response to first-line induction chemotherapy and incomplete surgical removal of all detectable lesions are the main negative prognostic factors. B) At first relapse: good histologic response to neoadjuvant first-line chemotherapy and complete surgical removal of all lesions at relapse are the main favourable prognostic factors. Chemotherapy and surgery are the cornerstone of osteosarcoma treatment. Despite the important role of chemotherapy in the treatment of metastatic disease,surgical removal of all tumour lesions at first-line treatment and relapse is necessary for long-term survival. The improvement of imaging techniques, such as the computed tomography (TC) scan, has increased its sensitivity while decreasing its specificity in the identification of pulmonary metastases and a new definition of “pulmonary metastases” at diagnosis with current imaging techniques is needed. In order to maintain chemotherapy intensity, a delay in the resumption of chemotherapy after primary tumour surgery needs to be avoided. Osteosarcoma incidence is higher during adolescence. Adolescents are a unique group, with patterns of disease and healthcare challenges distinctly different than those faced by younger children and adults. In our region, childhood and adolescent cancer incidence is similar to other European countries, with higher overall incidence of malignancy in adolescents than children. Of importance, our results show an important dispersion of treatment of adolescents compared to children in the Comunidad Valenciana. We suggest the centralization of care of adolescents with cancer with the creation of specific teenager and young adult cancer centres in which these patients can benefit from the shared expertise of medical and paediatric specialists. There is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. PI3K/AKT/mTOR activation, determined by phopho-AKT immunostaining, is associated with lower overall survival in osteosarcoma primary tumours. MiR-200 is overexpressed in lung metastases and plays a role in the molecular processes of lung metastasis. Therefore, PI3k/AKT/mTOR and miR-200c inhibitors are potential therapeutic targets to prevent progression and metastasis of paediatric osteosarcomas.Introduction Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Current management of high-grade osteosarcoma consists of administration of neoadjuvant/adjuvant chemotherapy and complete surgical removal of all tumour sites. The most important prognostic factors for long-term survival are: disease extension (localized/metastatic), primary tumour location (extremity/axial), histologic response to first-line induction chemotherapy and surgical removal of all detectable lesions. The addition of chemotherapy to surgery in the 1970s and 80s increased substantially long-term survival of osteosarcoma patients. However, no further improvement of survival has been observed since then, with currently 5-year overall survival of 60-70% for localized and 20-30% for metastatic osteosarcoma. Therefore, there is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. General objective: - To identify prognostic factors, at diagnosis and relapse, for children and adolescents with high-grade osteosarcoma and identify new therapeutic targets. Specific objectives: - To identify prognostic factors and survival of children and adolescents with highgrade osteosarcoma at diagnosis and relapse. - To determine the incidence and cancer distribution, treatment setting and provider specialty of children and adolescents in the Comunidad Valenciana. - To identify new therapeutic targets in paediatric and adolescent osteosarcoma Methods: This PhD thesis consists of four papers of which the candidate is the first author: 1. Pablo Berlanga, Adela Cañete, Roberto Díaz, Marta Salom, Francisco Baixauli, Jacinto Gómez, Margarita Llavador, Victoria Castel. Presentation and Long-term Outcome of High-grade Osteosarcoma: A Single-institution Experience. J Pediatric Hematol Oncol 2015; 37: e272-e277. 2. Pablo Berlanga, Adela Cañete, Marta Salom, Joaquin Montalar, María Guasp, Alfredo Marco, Victoria Castel. Postrelapse Prognostic Factors in Nonmetastatic Osteosarcoma: A Single-Institution Experience. J Pediatric Hematol Oncol 2016; 38: 176-181. 3. Pablo Berlanga, María Luisa Vicente, Adela Cañete, Carmen Alberich, Victoria Castel. Cancer in cancer in children and adolescents in Spain: incidence, treatment setting and provider specialty. Clin Transl Oncol 2016; 18: 27-32. 4. Pablo Berlanga, Lisandra Muñoz, Marta Piqueras, Antoni Sirerol, María Dolors Sánchez-Izquierdo, David Hervás, Miguel Hernández, Margarita Llavador, Isidro Machado, Antonio Llombart-Bosch, Adela Cañete, Victoria Castel, Jaime Font de Mora. miR-200c and Akt predict osteosarcoma progression and lung metastasis. Mol Oncol. 2016; 10: 1043-53. This work was supported by a Predoctoral Research Fellowship from the Instituto de Investigación Sanitaria La Fe (2011/0319) Results and conclusions: Five-year overall survival (OS), event-free survival (EFS) and main prognostic factors for high-grade osteosarcoma patients in our cohort are similar to those previously described: A) At diagnosis: metastatic disease, poor histologic response to first-line induction chemotherapy and incomplete surgical removal of all detectable lesions are the main negative prognostic factors. B) At first relapse: good histologic response to neoadjuvant first-line chemotherapy and complete surgical removal of all lesions at relapse are the main favourable prognostic factors. Chemotherapy and surgery are the cornerstone of osteosarcoma treatment. Despite the important role of chemotherapy in the treatment of metastatic disease,surgical removal of all tumour lesions at first-line treatment and relapse is necessary for long-term survival. The improvement of imaging techniques, such as the computed tomography (TC) scan, has increased its sensitivity while decreasing its specificity in the identification of pulmonary metastases and a new definition of “pulmonary metastases” at diagnosis with current imaging techniques is needed. In order to maintain chemotherapy intensity, a delay in the resumption of chemotherapy after primary tumour surgery needs to be avoided. Osteosarcoma incidence is higher during adolescence. Adolescents are a unique group, with patterns of disease and healthcare challenges distinctly different than those faced by younger children and adults. In our region, childhood and adolescent cancer incidence is similar to other European countries, with higher overall incidence of malignancy in adolescents than children. Of importance, our results show an important dispersion of treatment of adolescents compared to children in the Comunidad Valenciana. We suggest the centralization of care of adolescents with cancer with the creation of specific teenager and young adult cancer centres in which these patients can benefit from the shared expertise of medical and paediatric specialists. There is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. PI3K/AKT/mTOR activation, determined by phopho-AKT immunostaining, is associated with lower overall survival in osteosarcoma primary tumours. MiR-200 is overexpressed in lung metastases and plays a role in the molecular processes of lung metastasis. Therefore, PI3k/AKT/mTOR and miR-200c inhibitors are potential therapeutic targets to prevent progression and metastasis of paediatric osteosarcomas

Conducta Antisocial Delictiva y Asertividad en estudiantes de nivel secundaria de una Institución Educativa Nacional, Bambamarca, 2017

RESUMEN La presente investigación tuvo como objetivo determinar la relación entre la Conducta Antisocial Delictiva y la Asertividad en estudiantes de nivel secundaria de una Institución Educativa Nacional, Bambamarca, 2017. La población, objeto de estudio, estuvo conformada por 460 estudiantes, hombres y mujeres, de entre 12 y 17 años de edad, del nivel secundario de una institución educativa nacional de la ciudad de Bambamarca. En tanto la muestra estuvo conformada por 319 estudiantes, los mismos que fueron seleccionados aleatoriamente de la referida población. Los instrumentos empleados fueron: el cuestionario de conductas antisociales-delictivas de Seisdedos Cubero (1988), y la Escala Multidimensional de Asertividad (EMA) de Flores Galaz y Díaz-Loving (2004). Al finalizar la investigación se determinó que el 44.8% de los estudiantes presentan un nivel medio de conducta antisocial, siendo el nivel predominante. Asimismo que en los estudiantes predomina el nivel medio de conducta delictiva donde se ubican el 43.9% de los referidos estudiantes. Referentes a las categorías de asertividad se observa que el 37.0% de los estudiantes registraron una categoría asertiva, el 33.5% una categoría no asertiva y el 29.5% presenta una categoría asertiva indirecta, predominando ligeramente la categoría asertiva. Además se evidencia la existencia de una correlación altamente significativa y negativa, entre la Conducta Antisocial y la asertividad, en tanto que existe una correlación altamente significativa y positiva entre la Conducta Antisocial y la Asertividad Indirecta y la No Asertividad en dichos estudiantes. Finalmente se observa que existe una correlación altamente significativa y negativa, entre la Conducta Delictiva y la Asertividad, en tanto que existe una correlación altamente significativa y positiva entre la Conducta Delictiva y la Asertividad Indirecta y la No Asertividad en estudiantes del nivel de educación secundaria de la población investigada. Palabras Claves: Conducta Antisocial, Conducta Delictiva, Asertividad.ABSTRACT The present investigation had as objective to determine the relation between the Antisocial Conduct Crime and the Assertiveness in students of secondary level of the I.E. Hno Miguel Carducci Ripiani, Bambamarca, 2017. The study population consisted of 460 students, male and female, between 12 and 17 years of age, of the secondary level of the I.E. Brother Miguel Carducci Ripiani from the city of Bambamarca. The sample consisted of 319 students, who were randomly selected from the population. The instruments used were: the antisocial-criminal behavior questionnaire of Seisdedos Cubero (1988) and the Multidimensional Assertiveness Scale (EMA) of Flores Galaz and Díaz-Loving (2004). At the end of the investigation it was determined that 44.8% of the students present an average level of antisocial behavior, being the predominant level. Likewise, in the secondary education level, the average level of criminal behavior predominates where 43.9% of the students are located. Regarding assertiveness categories, 37.0% of the students registered an assertive category, 33.5% a nonassertive category and 29.5% presented an indirect assertive category, with a predominance of the assertive category. In addition, there is evidence of a highly significant and negative correlation between Antisocial Behavior and assertiveness, while there is a highly significant and positive correlation between Antisocial Behavior and Indirect Assertiveness and Non Assertiveness in such students. Finally, there is a highly significant and negative correlation between Delicate Behavior and Assertiveness, while there is a highly significant and positive correlation between Delicate Behavior and Indirect Assertiveness and Non Assertiveness in students at the secondary level of education The population investigated. Key Words: Antisocial Behavior, Delicate Behavior, Assertiveness

Mejora de la comprensión lectora para la inclusión mediante figuras retóricas

Actualmente, en España se calcula que aproximadamente el 1 % de la población sufre algún tipo de discapacidad intelectual. Para estas personas, la realización de tareas tan sencillas y cotidianas como ir a comprar o leer un libro pueden resultar muy complicadas, ya que tienen dificultad de comprensión para comprender muchos de los términos empleados en el día a día. Una posible solución para entender un concepto es la consulta del mismo en un diccionario. Pero esta no es una solución viable para estos colectivos, ya que las definiciones ofrecidas suelen tener un lenguaje complicado y difícil de entender para ellos. Para ayudar a estas personas con sus problemas de comprensión, se ha implementado una aplicación web que dada una palabra la define en base a otras palabras relacionadas con ella más fáciles y que el usuario conoce. Para dar estas definiciones se emplearon metáforas y símiles. Al tratarse de una aplicación web, está al alcance de cualquier usuario que disponga de un dispositivo con conexión a internet. Para diseñar la aplicación se ha hecho un diseño centrado en el usuario, contando con las opiniones de expertos. Se quiere conseguir una aplicación que se adapte a las necesidades reales del colectivo objetivo. La aplicación está compuesta por varios servicios web, para obtener tanto las palabras relacionadas como para generar los símiles y las metáforas. Además, para facilitar la comprensión del usuario, se han implementado varios servicios web complementarios. Uno que obtiene el pictograma asociado a una palabra, y otro que proporciona una descripción y un ejemplo. La aplicación ha sido evaluada por usuario finales. De esta evaluación se pudo concluir que el trabajo es útil para personas cuyo grado de discapacidad no fuese muy elevado, y que queda trabajo por hacer si queremos que la aplicación sea útil para personas con un grado de discapacidad mayor

Análisis del perfil de lo usuarios mayores de edad del Centro Deportivo J10, en Huesca.

En la actualidad, el sector del fitness ha adquirido mucha demanda por parte de la sociedad, cada vez son más las personas que deciden ocupar su tiempo libre con la actividad física, asimismo existe en este sector una salida profesional para nosotros los graduados en Ciencias de la Actividad Física y el Deporte. Por lo comentado anteriormente, este sector se ha transformado en una parte importante de la economía española, donde se ofrecen servicios muy diversos con distintos objetivos para los diferentes perfiles de usuario que se pueden dar. La finalidad de este estudio es analizar el perfil de la población que asiste al Centro Deportivo J10, para conocer cuáles son las actividades más demandadas y las motivaciones, los gustos, y los hábitos deportivos de sus usuarios

HIV- 1 Protease Inhibits Cap- and Poly(A)-Dependent Translation upon eIF4GI and PABP Cleavage

A number of viral proteases are able to cleave translation initiation factors leading to the inhibition of cellular translation. This is the case of human immunodeficiency virus type 1 protease (HIV-1 PR), which hydrolyzes eIF4GI and poly(A)-binding protein (PABP). Here, the effect of HIV-1 PR on cellular and viral protein synthesis has been examined using cell-free systems. HIV-1 PR strongly hampers translation of pre-existing capped luc mRNAs, particularly when these mRNAs contain a poly(A) tail. In fact, HIV-1 PR efficiently blocks cap- and poly(A)-dependent translation initiation in HeLa extracts. Addition of exogenous PABP to HIV-1 PR treated extracts partially restores the translation of polyadenylated luc mRNAs, suggesting that PABP cleavage is directly involved in the inhibition of poly(A)-dependent translation. In contrast to these data, PABP cleavage induced by HIV-1 PR has little impact on the translation of polyadenylated encephalomyocarditis virus internal ribosome entry site (IRES)-containing mRNAs. In this case, the loss of poly(A)-dependent translation is compensated by the IRES transactivation provided by eIF4G cleavage. Finally, translation of capped and polyadenylated HIV-1 genomic mRNA takes place in HeLa extracts when eIF4GI and PABP have been cleaved by HIV-1 PR. Together these results suggest that proteolytic cleavage of eIF4GI and PABP by HIV-1 PR blocks cap- and poly(A)-dependent initiation of translation, leading to the inhibition of cellular protein synthesis. However, HIV-1 genomic mRNA can be translated under these conditions, giving rise to the production of Gag polyprotein

The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Precision Medicine; Pediatric and Adolescent Patients; Recurrent MalignanciesMedicina de Precisión; Pacientes pediátricos y adolescentes; Neoplasias malignas recurrentesMedicina de precisió; Pacients pediàtrics i adolescents; Neoplasmes malignes recurrentsMAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/ refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA)

Next-Generation Sequencing Identifies Potential Actionable Targets in Paediatric Sarcomas

Background: Bone and soft-tissue sarcomas represent 13% of all paediatric malignancies. International contributions to introduce next-generation sequencing (NGS) approaches into clinical application are currently developing. We present the results from the Precision Medicine program for children with sarcomas at a reference centre. Results: Samples of 70 paediatric sarcomas were processed for histopathological analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) with a consensus gene panel. Pathogenic alterations were reported and, if existing, targeted recommendations were translated to the clinic. Seventy paediatric patients with sarcomas from 10 centres were studied. Median age was 11.5 years (range 1-18). Twenty-two (31%) had at least one pathogenic alteration by NGS. Thirty pathogenic mutations in 18 different genes were detected amongst the 22 patients. The most frequent alterations were found in TP53, followed by FGFR4 and CTNNB1. Combining all biological studies, 18 actionable variants were detected and six patients received targeted treatment observing a disease control rate of 78%. Extrapolating the results to the whole cohort, 23% of the patients would obtain clinical benefit from this approach. Conclusions: Paediatric sarcomas have a different genomic landscape when compared to adult cohorts. Incorporating NGS targets into paediatric sarcomas' therapy is feasible and allows personalized treatments with clinical benefit in the relapse setting

A new sports garment with elastomeric technology optimizes physiological, mechanical, and psychological acute responses to pushing upper-limb resistance exercises

This study aimed to compare the mechanical (lifting velocity and maximum number of repetitions), physiological (muscular activation, lactate, heart rate, and blood pressure), and psychological (rating of perceived exertion) responses to upper-body pushing exercises performed wearing a sports elastomeric garment or a placebo garment. Nineteen physically active young adults randomly completed two training sessions that differed only in the sports garment used (elastomeric technology or placebo). In each session, subjects performed one set of seated shoulder presses and another set of push-ups until muscular failure. The dependent variables were measured immediately after finishing the set of each exercise. Compared to the placebo garment, the elastomeric garment allowed participants to obtain greater muscular activation in the pectoralis major (push-ups: p = 0.04, d = 0.49; seated shoulder press: p < 0.01, d = 0.64), triceps brachialis (push-ups, p < 0.01, d = 0.77; seated shoulder press: p < 0.01, d = 0.65), and anterior deltoid (push-ups: p < 0.01, d = 0.72; seated shoulder press: p < 0.01, d = 0.83) muscles. Similarly, participants performed more repetitions (push-ups: p < 0.01; d = 0.94; seated shoulder press: p = 0.03, d = 0.23), with higher movement velocity (all p ≤ 0.04, all d ≥ 0.47), and lower perceived exertion in the first repetition (push-ups: p < 0.01, d = 0.61; seated shoulder press: p = 0.05; d = 0.76) wearing the elastomeric garment compared to placebo. There were no between-garment differences in most cardiovascular variables (all p ≥ 0.10). Higher diastolic blood pressure was only found after the seated shoulder press wearing the elastomeric garment compared to the placebo (p = 0.04; d = 0.49). Finally, significantly lower blood lactate levels were achieved in the push-ups performed wearing the elastomeric garment (p < 0.01; d = 0.91), but no significant differences were observed in the seated shoulder press (p = 0.08). Overall, the findings of this study suggest that elastomeric technology integrated into a sports garment provides an ergogenic effect on mechanical, physiological, and psychological variables during the execution of pushing upper-limb resistance exercises

Pharmacogenetics in Neuroblastoma: What Can Already Be Clinically Implemented and What Is Coming Next?

Pharmacogenetics is one of the cornerstones of Personalized Precision Medicine that needs to be implemented in the routine of our patients' clinical management in order to tailor their therapies as much as possible, with the aim of maximizing efficacy and minimizing toxicity. This is of great importance, especially in pediatric cancer and even more in complex malignancies such as neuroblastoma, where the rates of therapeutic success are still below those of many other types of tumors. The studies are mainly focused on germline genetic variants and in the present review, state of the art is presented: which are the variants that have a level of evidence high enough to be implemented in the clinic, and how to distinguish them from the ones that still need validation to confirm their utility. Further aspects as relevant characteristics regarding ontogeny and future directions in the research will also be discussed

Uncertainty Determination Methodology, Sampling Maps Generation and Trend Studies with Biomass Thermogravimetric Analysis

This paper investigates a method for the determination of the maximum sampling error and confidence intervals of thermal properties obtained from thermogravimetric analysis (TG analysis) for several lignocellulosic materials (ground olive stone, almond shell, pine pellets and oak pellets), completing previous work of the same authors. A comparison has been made between results of TG analysis and prompt analysis. Levels of uncertainty and errors were obtained, demonstrating that properties evaluated by TG analysis were representative of the overall fuel composition, and no correlation between prompt and TG analysis exists. Additionally, a study of trends and time correlations is indicated. These results are particularly interesting for biomass energy applications