Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers.

Chimeric antigen receptor (CAR)–modified T cells have revolutionized the treatment of CD19-positive hematologic malignancies. Although anti-CD19 CAR-engineered autologous T cells can induce remission in patients with B-cell acute lymphoblastic leukemia, a large subset relapse, most of them with CD19-positive disease. Therefore, new therapeutic strategies are clearly needed. Here, we report a comprehensive study comparing engineered T cells either expressing a second-generation anti-CD19 CAR (CART19) or secreting a CD19/CD3-targeting bispecific T-cell engager antibody (STAb-T19). We found that STAb-T19 cells are more effective than CAR-T19 cells at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo. We observed that leukemia escape in vitro is associated with rapid and drastic CAR-induced internalization of CD19 that is coupled with lysosome-mediated degradation, leading to the emergence of transiently CD19-negative leukemic cells that evade the immune response of engineered CAR-T19 cells. In contrast, engineered STAb-T19 cells induce the formation of canonical immunologic synapses and prevent the CD19 downmodulation observed in anti- CD19 CAR-mediated interactions. Although both strategies show similar efficacy in short-term mouse models, there is a significant difference in a long-term patient-derived xenograft mouse model, where STAb-T19 cells efficiently eradicated leukemia cells, but leukemia relapsed after CAR-T19 therapy. Our findings suggest that the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued antibody secretion, allows an efficient recruitment of the endogenous T-cell pool, resulting in fast and effective elimination of cancer cells that may prevent CD19-positive relapses frequently associated with CAR-T19 therapies.post-print1691 K

Obligaciones de medios y obligaciones de resultado: ¿tiene relevancia jurídica su distinción?

La idea fundamental a la que responde la distinción entre obligaciones de medios y obliga-ciones de resultado, consiste en examinar aquella prestación que ha prometido el deudor y que el acreedor puede razonablemente esperar. En unos casos que se denominan convencionalmente obligaciones de resul-tado (o contrato de obra), el deudor se compromete a proporcionar al acreedor un resultado preciso. En otros, por el contrario, que se denominan obligaciones de medios (o de arrendamiento de servicios), el deudor se compromete únicamente a emplear los medios apropiados en la realización de una tarea de modo que el acree-dor pueda conseguir el resultado deseado que le llevó a contratar. Pero ese resultado no está garantizado por el deudor. Si bien esta distinción tiene detractores en la doctrina y algunas Sentencias del Tribunal Supremo (SSTS) niegan la misma, nosotros pondremos de manifiesto en este trabajo que las críticas no obstaculizan su admisión. Tras el estudio del concepto y la distinción de ambos tipos de obligaciones dado por doctrina y jurisprudencia, a falta de regulación legal expresa, analizaremos si en realidad diferenciar una obligación de medios de otra de resultado tiene virtualidad jurídica. A pesar de existir un sector doctrinal y alguna STS que no encuentran relevancia alguna a la distinción, veremos que, en efecto, la caracterización de una obligación como de medios o como de resultado tiene una importante relevancia jurídica, cual es la de determinar el alcance de las obligaciones del deudor y, por tanto, para identificar los supuestos de incumplimiento contrac-tual. Por último, veremos la perspectiva de esta distinción en los instrumento de armonización.Palabras clave: Obligaciones de medios y de resultado. Clases de obligaciones. Naturaleza de las obligaciones. Obligaciones.Abstract: The main reason for the distinction between obligations of means and obligations of result consists on the appraisal of the performance promised by the debtor that the creditor can reasonably ex-pect.  In cases conventionally referred to as obligations of result (or construction contracts) the debtor un-dertakes to achieve a particular result.  On the contrary, in other cases referred to as obligations of means (or provision of services) the debtor only undertakes to use the appropriate means in the performance of a duty so that the creditor can achieve the expected result that made him enter into the contract.  But that result is not guaranteed by the debtor.  If it is true that this difference has detractors among scholars and some decisions of the Spanish Supreme Court deny it, we are going to show in this paper that such critics do not hinder its admission. After the study of the concept and the distinction between the two types of obligations made by scholars and the jurisprudence, and lacking an express regulation, we shall analyse if it is legally relevant to distinguish between an obligation of means and an obligation of result.  Not-withstanding the opinion of some scholars and some decisions of the Supreme Court that do not find the difference relevant, we shall see that the characterization of an obligation as an obligation of means or an obligation of result is of great legal importance; mainly to determine the scope of the debtor’s obligations and, therefore, to identify the cases of breach of contract.  Finally, we shall see the perspective of such a difference in the instruments of harmonization.Keywords: Obligations of means and obligations of result. Types of obligations. The nature of ob-ligations. Obligations

Percepción del profesor de una propuesta de enseñanza, utilizando analogías, sobre de los estados de agregación de la materia

Se presenta la valoración de cinco profesores de una propuesta de enseñanza, implementada en nueve grupos de 3º de ESO, sobre los estados de agregación de la materia que utiliza diferentes analogías, como recurso didáctico, del modelo cinético particular. El profesorado considera las analogías empleadas como una herramienta útil para los estudiantes pues les ayuda no solo a imaginar el modelo cinético sino a comprender y explicar las propiedades y cambios de estado de la materi

Fluorinated vs Nonfluorinated PR2(biaryl) Ligands and Their [AuCl(L)] Complexes: Synthesis, X-ray Structures, and Computational Study of Weak Interactions. Bond, No Bond, and Beyond

Producción CientíficaSix fluorinated PR2(biaryl) phosphines, Ln, with R = Ph, Cy and biaryl = C6H4–C6F5, C6F4–C6H5, C6F4–C6F5, have been prepared. Their [AuCl(Ln)] complexes and H congeners with PhJohnPhos or CyJohnPhos have been studied in order to examine the interactions that bring the distal aryl close to the Au–Cl bond region. X-ray, DFT structure optimization, QTAIM, and NCI methods allow for some understanding of the forces involved. The “no bond” noncovalent distal-aryl/Au–Cl weak interactions are produced at forced short distances achieved under intramolecular structural ligand pressure. Enhanced vdW distal-aryl/Au interactions at “no bond” distances shorter than the sum of Au and C vdW radii and weaker distal-aryl/Cl interactions at “no bond” distances beyond the sum of Cl and C vdW radii counterbalance the unfavorable structural distortion of the free ligand, providing some extra stability of the molecule on the order of 2–10 kcal mol–1. The F substituents in the distal aryl induce shorter aryl distances to the Au–Cl zone, pointing overall to stronger π-aryl polarization as being mainly responsible for the NCIs with gold. The interactions in the C···Cl zone, where the distances are larger than the sum of vdW radii, contribute only about 5%, according to energy estimations using NBOs.Ministerio de Economía, Industria y Competitividad (Projects CTQ2016-80913-P and CTQ2017-89217-P)Junta de Castilla y León (Projects VA051P17 and VA062G18)Ministerio de Economía, Industria y Competitividad FPI scholarship (BES-2017-080726

Perception of teachers and students at 3th year of Secondary School about they use analogies to understand the states of the matter

Se presenta la valoración que 5 profesores y 218 estudiantes de 3º ESO hacen de las analogías incluidas en una propuesta de enseñanza para el estudio de los estados de agregación. Con las analogías como recurso didáctico se pretendía que los alumnos comprendieran el modelo cinético molecular de la materia necesario para justificar las propiedades de sólidos, líquidos y gases, y su comportamiento durante los cambios de estado. Se utilizaron diferentes analogías (batallón militar, pista de baile, partido de fútbol y clase de educación física), con una estrategia didáctica que evoluciona desde la presentación de la analogía por el profesor a la construcción de la analogía por los estudiantes. Para valorar las analogías se ha diferenciado el grado en que se comprenden y se consideran adecuadas, viables e interesantes para la enseñanza de las ciencias. Tanto profesores como alumnos han valorado positivamente las analogías empleadas; los primeros comparten su intencionalidad y dificultad didáctica, y los segundos consideran que las analogías son una herramienta útil que les ayuda no solo a comprender el modelo cinético molecular sino a explicar las propiedades y cambios de los estados de agregación de la materia, es decir, el fenómeno en sí mismo.In this study we show the perception of 5 teachers and 218 students at 3th year of Secondary School about the analogies included in an educational unit to understand the states of matter. We expected our students understood the molecular kinetic model of matter with analogies, since it is necessary to explain the properties of the solid, liquid and gaseous state of matter and to prove their performance during the change of state. Different types of analogies were used: a battalion, a dance floor, a football match and a PE class, with an evolving didactic strategy starting with the presentations of analogies by the teacher and ending by the fulfilment of analogies by the students. To evaluate these analogies it has been distinguished the degree by which they are understood, suitable, viable and interesting for the study of Science. The analogies used have been considered positive by both, teachers and students. Teachers share their wilfulness and didactic difficulty and students think analogies are useful tools which help them to understand the molecular kinetic model to explain the properties and the changes of the states of matter, that is to say, to understand the phenomenon itself

Antibiotic resistance genes in phage particles from Antarctic and Mediterranean seawater ecosystems

Anthropogenic activities are a key factor in the development of antibiotic resistance in bacteria, a growing problem worldwide. Nevertheless, antibiotics and resistances were being generated by bacterial communities long before their discovery by humankind, and might occur in areas without human influence. Bacteriophages are known to play a relevant role in the dissemination of antibiotic resistance genes (ARGs) in aquatic environments. In this study, five ARGs (blaTEM, blaCTX-M-1, blaCTX-M-9, sul1 and tetW) were monitored in phage particles isolated from seawater of two different locations: (i) the Mediterranean coast, subjected to high anthropogenic pressure, and (ii) the Antarctic coast, where the anthropogenic impact is low. Although found in lower quantities, ARG-containing phage particles were more prevalent among the Antarctic than the Mediterranean seawater samples and Antarctic bacterial communities were confirmed as their source. In the Mediterranean area, ARG-containing phages from anthropogenic fecal pollution might allow ARG transmission through the food chain. ARGs were detected in phage particles isolated from fish (Mediterranean, Atlantic, farmed, and frozen), the most abundant being -lactamases. Some of these particles were infectious in cultures of the fecal bacteria Escherichia coli. By serving as ARG reservoirs in marine environments, including those with low human activity, such as the Antarctic, phages could contribute to ARG transmission between bacterial communities

Propuesta de evaluación del Trabajo Fin de Grado de Biología basada en competencias

La formación del profesorado para las tareas de evaluación y tutorización de los Trabajos Fin de Grado (TFG) constituye uno de los factores importantes a tener en cuenta para su exitosa implantación. Así, el objetivo de este trabajo es presentar las experiencias de formación que se están desarrollando en la Universidad de Málaga para apoyar al profesorado en estas tareas, mostrando su diseño y los resultados obtenidos. Se han impartido tres ediciones de un curso sobre evaluación y tutorización de los TFG, con la participación de 127 profesores de dieciséis Facultades diferentes, que imparten TFG en más de 20 Titulaciones, habiéndose realizado 23 trabajos diferentes relacionados con la temática de los cursos. Abstract Teacher training for the tasks of assessment and tutoring is one of the key factors to consider for a successful implementation of the Final Year Proyect (FYP). The aim of this paper is to present the Universidad de Málaga teacher training experiences to support the teachers for these tasks, showing its design and results obtained with them. Three courses have been held on evaluation and tutoring of FYP. One hundred and twenty seven teachers from 16 different Faculties, who teach FYP in more than 20 official Degrees, have participated. Twenty-three reports, related with the aim of the course, have been developed by the participants.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech