The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the γ-secretase inhibitor PF-03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine-mediated activation of nuclear factor-κB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients.

Cell death targeting therapies in B lymphoid malignancies.

Programmed cell death, commonly associated with the term apoptosis, is an integrated intracellular program that plays a critical role in lymphoid tissue homeostasis. Alterations in this highly regulated process is a common feature of most lymphoid malignancies, thus facilitating tumor escape from traditional chemotherapeutic agents whose main endpoint is the induction of tumor cell death. In the last years, enormous progress has been made in understanding the deregulated signals that could lead to ineffective apoptosis in B lymphoid tumors. Consequently, several new strategies have been designed to modulate the key molecules of life-and-death decisions. Numerous novel approaches are being validated and some of them have progressed to clinical testing or have even been approved in a record time. In this review we will focus on current therapies that have demonstrated to trigger efficiently cell death in B lymphoid neoplasms, either by directly targeting the intracellular apoptotic machinery or by modulating different factors involved in its regulation.

Del escritorio a la tarima: una experiencia de formación en competencias transversales dentro de la licenciatura en biología / From the desk to the stand: a training experience in generic competences within the Biology Degree

Introducción. Se diseñó una asignatura de pregrado con el fin de desarrollar compentencias transversales en redacción científica y presentación oral. Materiales y métodos. Consistió en una asignatura de cuatro créditos en formato intensivo durante 2 semanas y al final se realizó una encuesta de evaluación de satisfacción, con una escala numérica (de 0 a 5, máxima satisfacción). Resultados. Los 20 alumnos dieron una puntuación de 4,4 a la asignatura en general, 4,5 a los contenidos teóricos y 4,8 a los prácticos sobre presentaciones orales. Consideraron que sus conocimientos y habilidades habían mejorado después de la asignatura. Conclusiones. El diseño de actividades dirigidas a la mejora de determinadas competencias transversales puede ser útil y es percibida satisfactoriamente por los estudiantes (AU)

Introduction. A new subject for undergraduates was desiged in order to develop generic competences on scientific writing and oral communication. Material and methods. It was organized as a 4 credit course in intensive format for 2 weeks. At the end of the course, an evaluation of the students´ satisfaction was carried out by means of a numerical scale ( from o= worst to 5 very good). Results. All twenty students scored the course in general as 4.4, 4.5 for lectures and 4.8 for the practical activities on oral presentations. Students felt that their abilities in scientific writing and oral communication have improved. Conclusions. The design of an education activity devoted to improve these cross-sectional competences could be useful and it is perceived positively by the students (AU)