A simple approximation for the evaluation of the photon isoeffective dose in Boron Neutron Capture Therapy based on dose-independent weighting factors

The current methodology for determining the biological effect of Boron Neutron Capture Therapy (BNCT) has recently been questioned, and a more accurate framework based in the photon isoeffective dose has been proposed. In this work we derive a first order approximation to this quantity than can be easily evaluated even from limited data, as is the current situation in the radiobiology of BNCT. This procedure removes the main drawbacks of the current method and it is based on new weighting factors that, as a difference with the previously used, are true constants (dose independent). In addition to this, we apply the formalism to allow the comparison to a fractionated conventional radiotherapy treatment, for which there is a lot of knowledge from clinical practice. As an application, the photon isoeffective dose of a BNCT treatment for a brain tumor is estimated. An excel sheet used for these calculations is also provided as supplementary material and can be used also with user-provided input data for the estimation of the photon isoeffective dose for comparison with conventional radiotherapy, both to single and fractionated treatments.Departamento de Física Atómica, Molecular y Nuclear, Universidad de Granada, Granada, Spain. Institut Laue-Langevin. Grenoble, Rhône-Alpes, France. Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spai

The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells

Epigenetic therapies have emerged as promising anticancer approaches, since epigenetic modifications play a major role in tumor initiation and progression. Hydralazine, an approved vasodilator and antihypertensive drug, has been recently shown to act as a DNA methylation inhibitor. Even though hydralazine is already tested in clinical cancer trials, its mechanism of antitumor action remains undefined. Here, we show that hydralazine induced caspase-dependent apoptotic cell death in human p53-mutant leukemic T cells. Moreover, we demonstrate that hydralazine triggered the mitochondrial pathway of apoptosis by inducing Bak activation and loss of the mitochondrial membrane potential. Hydralazine treatment further resulted in the accumulation of reactive oxygen species, whereas a superoxide dismutase mimetic inhibited hydralazine-induced cell death. Interestingly, caspase-9-deficient Jurkat cells or Bcl-2- and Bcl-xL-overexpressing cells were strongly resistant to hydralazine treatment, thereby demonstrating the dependence of hydralazine-induced apoptosis on the mitochondrial death pathway. Furthermore, we demonstrate that hydralazine treatment triggered DNA damage which might contribute to its antitumor effect.Consejería de Economía, Innovación y Ciencia, Junta de Andalucía (Grant CTS-6183, Proyectos de Investigación de Excelencia 2010)University of Granada (Grant PP2012-PI13, Proyectos de Investigación Precompetitivos del Plan Propio

Plan de cuidados para la prevención y tratamiento del alcoholismo en mujeres con depresión

Introducción: Los pacientes que sufren de patología dual (comorbilidad de una enfermedad mental y un trastorno por abuso de sustancias), presentan mayores riesgos y peor calidad de vida que los que presentan solamenteuna de las patologías.Varios estudios han demostrado que la comorbilidad de depresión y alcoholismo supone una elevada prevalencia y un aumento de la severidad de ambas patologías, lo que la convierte en un importante problema de salud.Las causas de la patología dual de depresión y alcoholismo son, los factores de riesgo que tienen en común, la angustia provocada por la sintomatología depresiva, que puede llevar a los enfermos a usar el alcohol como vía de escape y desarrollar alcoholismo, o que el consumo patológico de alcoholprovoque una depresión.Objetivo: Debido a la frecuencia con la que se presenta, en este trabajo mehe centrado en cómo prevenir y tratar el alcoholismo en mujeres con depresión, ya que en ellas la depresión suele ser la desencadenante del alcoholismo.Metodología: Para ello, he realizado una búsqueda bibliográfica para obtener información sobre estas patologías, y elaborar un plan de cuidados estandarizado. En él he analizado los problemas de salud, establecido objetivos y elaborado estrategias para mejorar la calidad de vida de los pacientes con esta comorbilidad o riesgo de ella.Conclusión: La falta de reconocimiento de la enfermedad y de adherencia terapéutica, son obstáculos que suelen presentar los pacientes alcohólicos y los que padecen depresión. Para resolverlos, es importante conocer los factores de riesgo y problemas de salud existentes en estos pacientes para detectar a las personas vulnerables y aplicarles la valoración diagnóstica y tratamiento que proceda. Es imprescindible crear una relación terapéutica positiva, entre el enfermo y el equipo sanitario multidisciplinar que le acompañará en su tratamiento, lo que fomentará una adecuada adherencia terapéutica.<br /

Neutron radiobiology studies with a pure cold neutron beam

Data on the radiobiological effects of thermal neutrons are usually obtained from irradiations in a mixed field of neutrons of different energies and gamma rays or from conversion of proton data with similar energies to those created in the neutron capture on nitrogen. Experimental data from irradiations in a pure thermal or cold neutron beam can help to find new values for neutron relative biological effectiveness (RBE) factors, which are useful for BNCT (Boron Neutron Capture Therapy) and radiation protection applications. We present a new experimental setup for radiobiological studies at a cold neutron beam at Institut Laue-Langevin, a beam without fast neutron component and almost no gamma ray contribution. After the irradiation, survival assays are performed to obtain the survival curves. Finally, comparing with a reference photon irradiation, the thermal neutron RBE factors can be calculated. The methodology is outlined at the example of A375 melanoma cells for which new radiobiological data were obtained.We acknowledge financial support for this work from the Fundación Científica de la Asociación Española Contra el Cáncer (AECC) under grant PS16163811PORR, Junta de Andalucía (Andalusian Regional Government), under contract P11-FQM-8229, Spanish MINECO and FEDER funds under contract FIS2015-69941-C2-1-P, the grant agreement ILL-UGR and the founders of the University of Granada Chair Neutrons for Medicine: Spanish Fundación ACS and Capitán Antonio. M.P. acknowledges a grant under the program Becas de Iniciación a la Investigación from the Universidad de Granada (Plan Propio de Investigación). The open access fee was covered by FILL2030, a European Union project within the European Commission’s Horizon 2020 Research and Innovation programme under grant agreement N°731096

The DNA-methyltransferase inhibitors zebularine and decitabine induce mitochondria-mediated apoptosis and DNA damage in p53 mutant leukemic T cells

DNA methyltransferase (DNMT)-inhibiting nucleoside analogs reactivate the expression of tumor suppressor genes and apoptosis-related genes silenced by methylation, thus favoring the induction of apoptosis in tumor cells. Moreover, induction of DNA damage seems to contribute to their antitumor effect. However, the apoptotic signaling pathway induced by these demethylating drugs is not well understood. Here, we have investigated the induction of apoptosis by two nucleoside DNMT inhibitors, decitabine and zebularine, in leukemic T cells. Both inhibitors induced caspase-dependent apoptosis in Jurkat, CEM-6 and MOLT-4 leukemia T cell lines, all with mutant p53, whereas resting and activated normal T lymphocytes were highly resistant to these demethylating agents. Although decitabine and zebularine showed different ability to induce apoptosis and cell cycle arrest among the three cell lines, they similarly activated the intrinsic apoptotic pathway by inducing mitochondrial alterations such as Bak activation, loss of transmembrane potential and generation of reactive oxygen species (ROS). Accordingly, Bcl-2- and Bcl-xL-overexpressing Jurkat cells, as well as caspase-9-deficient Jurkat cells, were resistant to apoptosis induced by decitabine and zebularine. Interestingly, ROS production seemed to be necessary for the induction of apoptosis. Apoptotic events, such as Bak and caspase activation, started as soon as 20 hr after treatment with either decitabine or zebularine. In addition, progression of apoptosis triggered by both DNMT inhibitors was paralleled by the induction of DNA damage. Our results suggest that the mitochondrial apoptotic pathway activated by decitabine and zebularine in p53 mutant leukemic T cells depends mainly on the induction of DNA damage.Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo; Grant number: PI06071

Influence of the ectopic location on the antigen expression and functional characteristics of endometrioma stromal cells

Research question: Are the alterations observed in the endometriotic cells, such as progesterone resistance, already present in the eutopic endometrium or acquired in the ectopic location? Design: The response to decidualization with progesterone and cyclic AMP for up to 28 days was compared in different endometrial stromal cell (EnSC) lines established from samples of endometriomas (eEnSC), eutopic endometrium from women with endometriosis (eBEnSC), endometrial tissue from healthy women (BEnSC) and menstrual blood from healthy donors (mEnSC). Results: Usual features of decidualized cells, such as changes in cell morphology and expression of prolactin, were similarly observed in the three types of eutopic EnSC studied, but not in the ectopic cells upon decidualization. Among the phenotypic markers analysed, CD105 was down-regulated under decidualization in all cell types (mEnSC, P = 0.005; BEnSC, P = 0.029; eBEnSC, P = 0.022) except eEnSC. mEnSC and BEnSC underwent apoptosis during decidualization, whereas eBEnSC and eEnSC were resistant to the induction of cell death. Lastly, migration studies revealed that mEnSC secreted undetermined factors during decidualization that inhibited cell motility, whereas eEnSC showed a significantly lower ability to produce those migration-regulating factors (P < 0.0001, P  < 0.001 and P = 0.0013 for the migration of mEnSC at 24, 48 and 72 h, respectively; P  < 0.0001 for the migration of eEnSC at all times studied). Conclusions: This study provides novel insights into the differences between endometriotic and eutopic endometrial cells and reinforces the idea that the microenvironment in the ectopic location plays additional roles in the acquisition of the alterations that characterize the cells of the endometriotic foci.This work was supported by the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016, ISCIII Subdirección General de Evaluación y Fomento de la Investigación, Ministerio de Economía y Competitividad, Spain (Grant PI16/01642); the European Regional Development Fund (ERDF/634 FEDER funding); and the Plan Propio, Universidad de Granada (Grant PP2021.PP-12)

The implementation of Small Private Online Courses (SPOC) as a new approach to education

This article presents a study of the participants of a Small Private Online Course (SPOC) entitled “The Didactic Programming: Elements and Process of Elaboration” at the University of Málaga (Spain). Since the concept was first introduced in 2013, SPOCs have been progressively implemented in higher education. They were conceived to succeed where Massive Open Online Courses (MOOCs) failed, namely in the high drop-out rate. Using a descriptive method, a questionnaire was designed to collect data on the individual characteristics of the University students participating in the SPOC, the degree of satisfaction they expressed at the end of the training process and their opinion regarding class-based courses. The completion rate was 78.7%, and 70.6% of them had previously undertaken online training activities. All the sections of the course (objectives, contents, evaluation, etc.) were favourably evaluated by more than 85% of the participants, as well as their preference for online training

Menstrual blood‑derived stromal cells modulate functional properties of mouse and human macrophages

Menstrual blood-derived stromal cells (MenSCs) are emerging as a strong candidate for cell-based therapies due to their immunomodulatory properties. However, their direct impact on innate immune populations remains elusive. Since macrophages play a key role in the onset and development of inflammation, understanding MenSCs implication in the functional properties of these cells is required to refine their clinical effects during the treatment of inflammatory disorders. In this study, we assessed the effects that MenSCs had on the recruitment of macrophages and other innate immune cells in two mouse models of acute inflammation, a thioglycollate (TGC)-elicited peritonitis model and a monobacterial sepsis model. We found that, in the TGC model, MenSCs injection reduced the percentage of macrophages recruited to the peritoneum and promoted the generation of peritoneal immune cell aggregates. In the sepsis model, MenSCs exacerbated infection by diminishing the recruitment of macrophages and neutrophils to the site of infection and inducing defective bacterial clearance. Additional in vitro studies confirmed that co-culture with MenSCs impaired macrophage bactericidal properties, affecting bacterial killing and the production of reactive oxygen intermediates. Our findings suggest that MenSCs modulate the macrophage population and that this modulation must be taken into consideration when it comes to future clinical applications.Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, Ministerio de Economía y Competitividad, Spain PI16/01642 PI10/01096European Union (EU)Catedra de Investigación Antonio Chamorro-Alejandro Otero, Universidad de Granada CACH2017-

Decidualization modulates the mesenchymal stromal/stem cell and pericyte characteristics of human decidual stromal cells. Effects on antigen expression, chemotactic activity on monocytes and antitumoral activity

Decidual stromal cells (DSCs) are the most abundant cellular component of human decidua and play a central role in maternal–fetal immune tolerance. Antigen phenotyping and functional studies recently confirmed the relationship of DSCs with mesenchymal stem/stromal cells (MSCs) and pericytes, the latter two cell types being closely related or identical. The present study investigated the effect of decidualization, a process of cell differentiation driven by progesterone (P4) and other pregnancy hormones, on the MSC/pericyte characteristics of DSCs. To this end we isolated undifferentiated DSC (preDSC) lines that were decidualized in vitro (dDSC) by the effect of P4 and cAMP. Using flow cytometry, we found significant downmodulation of the expression of the MSC/pericyte markers α-smooth muscle actin, nestin, CD140b, CD146 and SUSD2 in dDSCs. The dDSCs did not differ, compared to preDSCs, in the expression of angiogenic factors (characteristic of pericytes) HGF, FGF2, ANGPT1 or VEGF according to RT-PCR results, but had significantly increased PGF expression. In migration assays, preDSC-conditioned media had a chemotactic effect on the THP-1 monocytic line (characteristic of pericytes), and this effect was significantly greater in dDSCconditioned media. Media conditioned with dDSC, but not with preDSC, induced apoptosis in 4 out of 6 different tumor cell lines (characteristic of MSCs) according to propidium iodide staining and flow cytometry results. Our findings show that decidualization induces phenotypic and functional changes in the MSC/pericyte properties of DSCs that may have a role in the normal development of pregnancy.This article contributes to COST Action CA17116 “International Network for Translating Research on Perinatal Derivatives into Therapeutic Approaches (SPRINT)”, supported by COST (European Cooperation in Science and Technology)

Decidualized human decidual stromal cells inhibit chemotaxis of activated T cells: a potential mechanism of maternal-fetal immune tolerance

Numerous lines of evidence confirm that decidual stromal cells (DSCs) play a key role in maternal–fetal immune tolerance. Under the influence of progesterone and other hormones, the DSCs go through a process of differentiation (decidualization) during normal pregnancy. In mice, DSCs inhibit the expression of chemokines that attract abortigenic Th1 and Tc cells to the decidua. We have studied this phenomenon in humans. Methods: We established human DSC lines and decidualized these cells in vitro with progesterone and cAMP. We determined the expression of the chemokines CXCL9, CXCL10 and CXCL11, whose receptor CXCR3 is expressed by Th1 and Tc cells, in undifferentiated DSCs and decidualized DSCs by qRT-PCR. Activated CD3+CXCR3+ cells, including CD4+ Th1 cells and CD8+ Tc cells, were induced in vitro. The migration capacity of these activated lymphocytes was investigated in Transwell chambers with conditioned media from undifferentiated and decidualized DSCs. Results: We demonstrated that CXCL9 was not expressed by DSCs, whereas the expression of CXCL10 and CXCL11 was inhibited in decidualized cells. Conditioned media from decidualized cells significantly inhibited the migration of Th1 and Tc cells.Wefound that decidualized cells secrete factors ofMWless than 6000–8000 Da, which actively inhibit the chemotaxis of these lymphocytes. Discussion: These results confirm in humans that decidualization of DSCs inhibits the expression by these cells of chemokines that attract Th1 and Tc cells and induces the secretion by DSCs of factors that inhibit the chemotaxis of these lymphocytes, thus preventing the arrival of abortigenic T cells in the decidua.Financial support was provided by Proyectos de I+D+I through the Programa Operativo Feder Andalucı́a (Grant B-CTS-228-UGR20