Search

Existe una gran variabilidad en la realización de la colonoscopia como método de cribado del carcinoma colorrectal. En los últimos años, se han propuesto indicadores de calidad con el objetivo de estandarizar y mejorar esta técnica. OBJETIVOS El objetivo general de nuestro estudio es mejorar la calidad de las colonoscopias del Programa de Cribado del Cáncer Colorrectal, llevado a cabo en el Área VI del Sistema Murciano de Salud por el Hospital General Universitario José María Morales Meseguer. Los objetivos específicos son: evaluar la calidad de estas colonoscopias; identificar, seleccionar y definir indicadores de calidad para su evaluación; diseñar un conjunto de actividades para mejorar la calidad y; por último, evaluar la efectividad de las medidas de mejora. MATERIALES Y MÉTODOS Se trata de un estudio antes y después, utilizando la metodología de un ciclo de mejora de la calidad. El instrumento de medida, es un conjunto de indicadores de calidad del Programa de Cribado. Primero, es llevado a cabo por un grupo de trabajo un proceso de identificación, selección, y posteriormente, definición de los términos de los indicadores de calidad a evaluar. Se realiza un estudio observacional, descriptivo, retrospectivo y unicéntrico para analizar, el grado de cumplimiento de los indicadores de calidad seleccionados. Se analizan las posibles causas que han podido influir en los resultados observados, empleando herramientas y métodos de la calidad: análisis de los campos de fuerza, diagrama de causa-efecto y un diagrama de Pareto. Son clasificadas las categorías causales identificadas en función de la capacidad de actuación que podemos ejercer. Finalmente, las actividades para lograr la mejora, son representadas en un Diagrama de afinidades. La segunda evaluación se desarrolla como un subestudio observacional, descriptivo, prospectivo postintervención y unicéntrico acerca de los mismos indicadores. RESULTADOS Se seleccionaron y definieron 20 indicadores de calidad para evaluar las colonoscopias de cribado. En la primera evaluación se seleccionaron aleatoriamente 110 de 665 colonoscopias, salvo para los indicadores 3.3, 3.4, 3.6 y 3.7, en los que el tamaño muestral era mayor. No se cumplían los estándares de calidad establecidos en 10 de los 20 indicadores de calidad. No se registró en ningún caso el tiempo de retirada, siendo muy deficiente el registro en el informe endoscópico de la tasa de limpieza colónica, así como la tasa de intubación cecal, que en ambos casos fue menor del 90 %. La tasa de detección de adenomas fue del 63,81 %. Tras el diseño e implementación de las actividades para la mejora, en la segunda evaluación, se seleccionaron 110 de 298 colonoscopias, cumpliendo los estándares de calidad establecidos en todos los indicadores, salvo en tres. Se consiguió mejorar la cumplimentación de todos los indicadores de calidad, salvo en los que el nivel de cumplimiento ya era muy alto: tasa de detección de adenomas, que fue del 63,6 %; tasa de recuperación de pólipos ≥ 5 mm; tasa de hemorragia post-polipectomía; y la tasa de complicaciones que requirieran reingreso en ≤ 7 días. CONCLUSIONES Se han definido un grupo de indicadores representativos de la calidad del proceso colonoscopia de cribado de carcinoma colorrectal. Globalmente considerada, la calidad de las colonoscopias es elevada, cumpliendo con los estándares de calidad propuestos por las principales sociedades científicas salvo para tres de los indicadores evaluados, principalmente, por un deficiente registro de la actividad. Tras el análisis de situación y los resultados obtenidos se ha diseñado e implementado un plan de mejora de la calidad de la colonoscopia de cribado. Se ha logrado mejorar de forma significativa el resultado de los indicadores de calidad en la mayoría de los indicadores, siendo menor la mejora en aquellos que partían con resultados buenos en la primera evaluación. There is a great variability in the performance of colonoscopy as a method of screening for colorectal carcinoma. During the last years, criteria or indicators of quality with the objective have seted out to standardize and to improve this technique. OBJECTIVES The general mission of our study is to improve the quality of the colonoscopy procedures in the Program of Screening of the Colorrectal Cancer, carried out in the Area VI of the Murrcian System of Health by the Hospital General Universitario José María Morales Meseguer. The specific objectives are: to evaluate the quality of these procedures; to identify, to select and to define indicators of quality for its evaluation; to design a set of activities to improve the quality and; finally, to evaluate the effectiveness of the improvement measures. METHODS This is a before-and-after study, using the methodology of a quality improvement cycle. The measuring instrument is a set of quality indicators of the Screening Program. Firs, a process of identification, selection is carried out by a work group, and later, a definition of the terms of the indicators of quality to evaluate. An observational, descriptive, retrospective and single-center study is carried out to analyze the degree of compliance with the selected quality indicators. The possible causes that have influenced the observed results are analyzed, using quality tools and methods: analysis of the force fields; cause-effect diagram and a Pareto diagram. The identified causal categories are classified according to the capacity to act that we can exercise. Finally, the activities to achieve the improvement are represented in an Affinity Diagram. The second evaluation is developed as an observational, descriptive, prospective post-intervention and single-center substudy about the same indicators. RESULTS 20 indicators of quality to evaluate the screening colonoscopies had been selected and defined. In the first evaluation, 110 of 665 colonoscopies were randomly selected, except for indicators 3.3, 3.4, 3.6 and 3.7, where the sample size was greater. The established standars of quality in 10 of the 20 indicators of quality were not fulfilled. In no case was the withdrawal time recorded, with very poor compliance with the colonic cleaning rate, as well as the rate of cecal intubation, which in both cases, was less than 90 %. The detection rate of adenomas was 63.81 %. After the design and implementation of the activities for improvement, in the second evaluation, 110 of 298 colonoscopies were selected, complying with the quality standards established in all indicators, except three. It was possible to improve the completion of all quality indicators, except: adenoma detection rate, which was 63.6 %; polyp recovery rate ≥ 5 mm; post-polypectomy bleeding rate; and the rate of complications requiring re-entry in ≤ 7 days. CONCLUSIONS A group of indicators representative of the quality o the colorectal carcinoma screening colonoscopy process has been defined. Globally considered, the quality of colonoscopies is high, complying with the quality standards proposed by the main scientific societies except for three of the indicators evaluated, mainly due to a poor record of activity. Following the analysis of the situation and the results obtained, a plan has been designed and implemented to improve the quality of the screening colonoscopy. The results of the quality indicators has been significantly improved in most of the indicators, with less improvement in those that started with good results in the first evaluation.

[ES] En este Trabajo de Fin de Grado se presenta el diseño e implementación realizado al crear un sistema de alerta que avise de tweets que contengan discurso de odio en su publicación. Para ello, se emplearán diversos tipos de modelos, utilizando técnicas relacionadas con el Aprendizaje Automático, para hacer una clasificación automática de dichas publicaciones. Estos modelos se explicarán y compararán para escoger el que obtenga mejores resultados sobre tweets reales ya etiquetados., [EN] In this Final Degree Project, the design and implementation of an alert system that warns of tweets containing hate speech in their publication is presented. For this purpose, different types of models will be used, using techniques related to Automatic Learning, to make an automatic classification of these publications. These models will be explained and compared to choose the one that obtains better results on real and tagged tweets., [CA] En aquest Treball de Fi de Grau, es presenta el disseny i implementació realitzat al crear un sistema d’alerta que avise de tweets que continguen discurs d’odi en la seua publicació. Per a això, s’empraran diversos tipus de models, utilitzant tècniques relacionades amb el Aprenentatge Automàtic, per a fer una classificació automàtica d’aquestes publicacions. Aquests models s’explicaran i compararan per a triar el que obtinga millors resultats sobre tweets reals ja etiquetats.

Figure S1. Chemical inhibition of SHP1 and SHP2 favors the differentiation of HEL cells. Levels of CD41 and CD61 surface markers in HEL cells 48 h after 4h incubation with the indicated inhibitors of SHP1 and SHP2. Figure S2. Chemical inhibition of SHP1 and SHP2 potentiates morphological changes of PMA in HL-60 cells. Representative pictures of May-Grünwald-Giemsa stained cytospins of HL-60 cells after 48 h treatment with PRS, NSC and their combination. Scale bar: 10 μm. Figure S3. AML cell lines are differentially responsive to PRS and NSC. A) Dose-response curves of HL-60 cells treated with PRS and NSC during 48 h. B) Dose-response curves of AML cell lines different from HL-60 treated with PMA and NSC during 48 h. (DOCX 509 kb)

[EN]Haematopoiesis is a very relevant differentiation process in adult humans where a multipotent cell, the haematopoietic stem cell (HSC), generates a widely varied, fully differentiated progeny, with immune defence, nutrient exchange and volume homeostasis functions. The regulatory cues governing the biology of HSCs must be tightly regulated in order to ensure their own self-renewal, as well as the proper turnover of differentiated cells. These signals are provided by the surrounding environment, known as niche, integrated by both haematopoietic and non-haematopoietic cells. The disruption of this fine equilibrium by alteration of either the external signals or their intracellular transduction in haematopoietic stem and progenitor cells (HSPCs) leads to the development of haematologic malignancies, including leukaemia. Two important blood disorders affecting the myeloid lineage are acute and chronic myeloid leukaemia (AML and CML, respectively). They are especially recurrent among the elderly, with a median age at diagnosis of 65 years for CML and 70 for AML, a fact to be considered due to the increasing life expectancy in Western countries. AML is a highly heterogeneous and aggressive disease with poor prognosis and, in general, no significant therapeutic improvements beyond chemotherapy over the last four decades. An exception to this scenario is the treatment of acute promyelocytic leukaemia (APL), which is highly responsive to pro-differentiative therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Unlike AML, CML is highly homogeneous in terms of molecular biology, with the expression of the fusion oncokinase breakpoint cluster region-ABL proto-oncogene 1, non-receptor tyrosine kinase (BCR-ABL) as the main pathogenic driver. In the early 2000s, the clinical use of tyrosine kinase inhibitors (TKI) targeting this protein revolutionised the management of CML due to great improvements in treatment response and survival rates. However, this disease remains challenging in particular cases. Despite its heterogeneous nature, AML displays a differentiation blockage as a hallmark. This feature, together with the example of the differentiation-based APL treatment, has prompted the development of an important line of research focusing on the molecular mechanisms governing cell differentiation during haematopoiesis. This knowledge would lead to a better understanding of the dysregulated processes leading to pathogenesis and their subsequent pharmacological targeting to treat the disease. In line with this, the present work sought to assess in detail the involvement of SRC homology 2 domain containing protein tyrosine phosphatases 1 (SHP1) and 2 (SHP2) in the differentiation of leukaemic cells and the potential of these molecules as pharmacological targets for AML. Herein, it was demonstrated the cooperative function of both phosphatases in phorbol ester-induced cell differentiation, with an enhanced differentiated phenotype of cells subjected to simultaneous downregulation of these proteins. In addition, the kinase SRC was identified as a downstream target of SHP2 in this process, which appeared to influence the extent of the differentiation stimulus triggered by phorbol 12-myristate-13-acetate (PMA). Besides, the role of both phosphatases on cell differentiation showed to be partially overlapping through the regulation of β-catenin protein levels. Based on this evidence, the chemical inhibitor of SHP1 and SHP2 NSC 87877 (NSC) was successfully tested to boost the differentiation-inducing effect of phorbol esters in the AML cell line HL-60. Moreover, this compound synergised with the phorbol ester 13-O-acetyl-12-deoxyphorbol or prostratin (PRS) to prevent proliferation of not only in HL-60 cells, but also additional cell lines used as AML models (NB-4, OCI-AML2 and THP-1). Most importantly, the anti-leukaemic activity of this combination was corroborated in vivo with a xenograft mouse model and in primary cells from AML patients ex vivo. On the other hand, the management of CML still requires further improvement, since the success of TKI relies on long-term administration to patients due to the existence of quiescent BCR-ABL independent leukaemic stem cells (LSCs). This is associated with intolerances in patients and great costs for national health systems. Moreover, selective pressure on leukaemic blasts can lead to the emergence of point mutations in BCR-ABL that confer acquired resistance to TKI. To overcome this issue, novel therapeutic approaches based on co-targeting BCR-ABL and other important contributors to CML pathogenesis are subject of intense research. Based on this idea and the involvement of SHP1 and SHP2 in the disease, NSC was tested in combination with TKI in different models of CML. This compound enhanced the effect of the TKI imatinib (IM) and nilotinib (NL) in different CML cell lines (K-562, KCL-22 and BV-173). Immunoblotting analyses allowed the observation of a strong decrease in β-catenin levels upon NSC treatment and a moderate downregulation of c-MYC induced by both IM and NSC. Further gene expression studies identified CCND1, CCND2, CDKN1C and TLE2 as targets of either one or both drugs that might mediate the anti-leukaemic activity of their combination. Additionally, NSC also displayed anti-proliferative potential in patient-derived induced pluripotent stem cells (iPSCs), intrinsically resistant to IM at moderate doses. Treatment of these cells with NSC exerted a dramatic cell cycle arrest concomitant with the downregulation of CTNNB1, encoding β-catenin, as well as CCND1 and CCND2. Additionally, some members of TLE family were modulated by this drug. In summary, the results described in the present work support a promising therapeutic potential of the chemical inhibitor NSC 87877 in different myeloid malignancies where SHP1 and SHP2 are deeply involved. Furthermore, some mechanistic insight on the molecules connected to these phosphatases in both disease biology and pharmacological mode of action of the inhibitor has been provided.

Introducción La pancreatitis aguda (PA) continúa siendo una importante causa de morbimortalidad en el mundo, debido en parte a la ausencia de un tratamiento específico. En su manejo, uno de los pilares sobre el que se asienta es la resucitación intensiva precoz con sueroterapia. Los últimos estudios parecen apuntar en la dirección de una mayor efectividad del Ringer lactate (RL), pero no ha podido asentarse en las últimas guías clínicas como la fluidoterapia de elección. Objetivo Determinar si la fluidoterapia inicial con RL en los pacientes con PA, respecto a la resucitación con Suero salino fisiológico (SSF), disminuye la incidencia de fallo orgánico transitorio o persistente. Además se valorará si repercute en un menor desarrollo de syndrome de respuesta inflamatoria sistémica (SRIS); acidosis metabólica; alteraciones iónicas; menor elevación de proteína C reactiva (PCR); necrosis pancreática o peripancreática; gravedad de la PA; tratamiento invasivo; ingreso en Unidad de Cuidados Intensivos (UCI); soporte nutricional; y de sobrecarga de volumen. Material y métodos Ensayo clínico aleatorizado simple ciego. Son elegibles pacientes de 18 años o mayores que acuden al Servicio de Urgencias (SU) del Hospital Universitario Morales Meseguer (HUMM) siendo diagnosticados de PA de cualquier etiología y que no cumplan ninguno de los criterios de exclusión. Los pacientes son aleatorizados a recibir en las primeras 72 horas RL o SSF. Se recogerán las variables necesarias para la definición de fracaso orgánico tras la aleatorización y a las 72 horas. Además, se recogerán las variables necesarias para la evaluación de los objetivos secundarios.

[EN]Haematopoiesis is a very relevant differentiation process in adult humans where a multipotent cell, the haematopoietic stem cell (HSC), generates a widely varied, fully differentiated progeny, with immune defence, nutrient exchange and volume homeostasis functions. The regulatory cues governing the biology of HSCs must be tightly regulated in order to ensure their own self-renewal, as well as the proper turnover of differentiated cells. These signals are provided by the surrounding environment, known as niche, integrated by both haematopoietic and non-haematopoietic cells. The disruption of this fine equilibrium by alteration of either the external signals or their intracellular transduction in haematopoietic stem and progenitor cells (HSPCs) leads to the development of haematologic malignancies, including leukaemia. Two important blood disorders affecting the myeloid lineage are acute and chronic myeloid leukaemia (AML and CML, respectively). They are especially recurrent among the elderly, with a median age at diagnosis of 65 years for CML and 70 for AML, a fact to be considered due to the increasing life expectancy in Western countries. AML is a highly heterogeneous and aggressive disease with poor prognosis and, in general, no significant therapeutic improvements beyond chemotherapy over the last four decades. An exception to this scenario is the treatment of acute promyelocytic leukaemia (APL), which is highly responsive to pro-differentiative therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Unlike AML, CML is highly homogeneous in terms of molecular biology, with the expression of the fusion oncokinase breakpoint cluster region-ABL proto-oncogene 1, non-receptor tyrosine kinase (BCR-ABL) as the main pathogenic driver. In the early 2000s, the clinical use of tyrosine kinase inhibitors (TKI) targeting this protein revolutionised the management of CML due to great improvements in treatment response and survival rates. However, this disease remains challenging in particular cases. Despite its heterogeneous nature, AML displays a differentiation blockage as a hallmark. This feature, together with the example of the differentiation-based APL treatment, has prompted the development of an important line of research focusing on the molecular mechanisms governing cell differentiation during haematopoiesis. This knowledge would lead to a better understanding of the dysregulated processes leading to pathogenesis and their subsequent pharmacological targeting to treat the disease. In line with this, the present work sought to assess in detail the involvement of SRC homology 2 domain containing protein tyrosine phosphatases 1 (SHP1) and 2 (SHP2) in the differentiation of leukaemic cells and the potential of these molecules as pharmacological targets for AML. Herein, it was demonstrated the cooperative function of both phosphatases in phorbol ester-induced cell differentiation, with an enhanced differentiated phenotype of cells subjected to simultaneous downregulation of these proteins. In addition, the kinase SRC was identified as a downstream target of SHP2 in this process, which appeared to influence the extent of the differentiation stimulus triggered by phorbol 12-myristate-13-acetate (PMA). Besides, the role of both phosphatases on cell differentiation showed to be partially overlapping through the regulation of β-catenin protein levels. Based on this evidence, the chemical inhibitor of SHP1 and SHP2 NSC 87877 (NSC) was successfully tested to boost the differentiation-inducing effect of phorbol esters in the AML cell line HL-60. Moreover, this compound synergised with the phorbol ester 13-O-acetyl-12-deoxyphorbol or prostratin (PRS) to prevent proliferation of not only in HL-60 cells, but also additional cell lines used as AML models (NB-4, OCI-AML2 and THP-1). Most importantly, the anti-leukaemic activity of this combination was corroborated in vivo with a xenograft mouse model and in primary cells from AML patients ex vivo. On the other hand, the management of CML still requires further improvement, since the success of TKI relies on long-term administration to patients due to the existence of quiescent BCR-ABL independent leukaemic stem cells (LSCs). This is associated with intolerances in patients and great costs for national health systems. Moreover, selective pressure on leukaemic blasts can lead to the emergence of point mutations in BCR-ABL that confer acquired resistance to TKI. To overcome this issue, novel therapeutic approaches based on co-targeting BCR-ABL and other important contributors to CML pathogenesis are subject of intense research. Based on this idea and the involvement of SHP1 and SHP2 in the disease, NSC was tested in combination with TKI in different models of CML. This compound enhanced the effect of the TKI imatinib (IM) and nilotinib (NL) in different CML cell lines (K-562, KCL-22 and BV-173). Immunoblotting analyses allowed the observation of a strong decrease in β-catenin levels upon NSC treatment and a moderate downregulation of c-MYC induced by both IM and NSC. Further gene expression studies identified CCND1, CCND2, CDKN1C and TLE2 as targets of either one or both drugs that might mediate the anti-leukaemic activity of their combination. Additionally, NSC also displayed anti-proliferative potential in patient-derived induced pluripotent stem cells (iPSCs), intrinsically resistant to IM at moderate doses. Treatment of these cells with NSC exerted a dramatic cell cycle arrest concomitant with the downregulation of CTNNB1, encoding β-catenin, as well as CCND1 and CCND2. Additionally, some members of TLE family were modulated by this drug. In summary, the results described in the present work support a promising therapeutic potential of the chemical inhibitor NSC 87877 in different myeloid malignancies where SHP1 and SHP2 are deeply involved. Furthermore, some mechanistic insight on the molecules connected to these phosphatases in both disease biology and pharmacological mode of action of the inhibitor has been provided.