Recent advances in the targeting of epigenetic regulators in b-cell non- Hodgkin lymphoma

B-cell lymphoma; DNMT; EZH2Linfoma de células B; DNMT; EZH2Limfoma de cèl·lules B; DNMT; EZH2In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field.The authors received financial support from Fondo de Investigacion Sanitaria PI15/00102 and PI18/01383, European Regional Development Fund (ERDF) "Una manera de hacer Europa" (to GR). The authors received fundings from TG Therapeutics and Celgene Corp to support researches unrelated to the present work. Funders were involved neither in the design, nor in the writing of this review

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies

Enhancing adult hippocampal neurogenesis with lysophosphatidic acid: a proposal for erasing cocaine contextual memory

Stimulating adult hippocampal neurogenesis (AHN) has been uncovered as a promising approach in the manipulation of retrograde memories. This work aims to study whether increasing AHN with lysophosphatidic acid (LPA, an endogenous lysophospholipid with proneurogenic actions) promotes the forgetting of previously established cocaine-contextual associations. C57BL/6J mice previously trained in a cocaine-induced conditioned place preference (CPP) paradigm were submitted to 23 days of withdrawal, during which they received repeated intracerebroventricular infusions of LPA, ki16425 (a selective LPA1/3 receptors antagonist), or vehicle solution. Then, CPP maintenance was assessed, and the causal role of AHN in this process was evaluated using a mediation analysis. In a complementary experiment, wild-type and LPA1-null mice were acutely infused with LPA or ki16425 to determine the involvement of the LPA1 receptor in the in vivo proneurogenic actions of LPA. The chronic LPA treatment significantly weakened the long-term retention of a previously acquired cocaine-CPP memory, an effect clearly mediated by a LPA-induced increase in the number of adult-born dentate granule cells. In contrast, the ki16425-treated mice displayed aberrant responses of initially decreased CPP retention that progressively increased CPP across the extinction sessions, in absence of effects on AHN. The histological studies suggested that the proneurogenic actions of LPA were related to the enhancement of cell proliferation and critically depended on the LPA1 receptor function. Our results suggest that the LPA/LPA1-pathway acts as a potent in vivo modulator of AHN, and highlight the usefulness of a post-learning increase of adult-born hippocampal neurons as a strategy to promote the forgetting of cocaine-context associations.Plan Propio de Investigación y Transferencia. Campus de Excelencia Internacional Andalucía Tech. Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), co‐funded by the European Research Development Fund (AEI/FEDER, UE) (PSI2013‐44901‐P and PSI2017‐82604‐R to L.J.S. and PSI2015‐73156‐JIN to E.C.O.); by the National System of Health‐Instituto de Salud Carlos III, which is co‐funded by AEI/FEDER, UE (Red de Trastornos Adictivos; RD16/0017/0001 to F.R.d.F.); and by the Andalusian R&D&I Programme, Regional Ministry of Economy and Knowledge (PAIDI CTS643 to G.E.T.). D.L.G.M. hold a FPU grant from the Spanish Ministry of Education, Culture and Sports (FPU13/04819 ). F.R.d.F. and G.E.T. are supported by Nicolas Monardes Programme, from the Andalusian Regional Ministry of Health. E.C.O. holds a ‘Jóvenes Investigadores’ grant (code: PSI2015‐73156‐JIN) from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), which is co‐funded by the AEI/FEDER, UE

Construcción de un sistema de información y de ayuda a la decisión mediante lógica difusa para el cultivo del olivar en Andalucía

In Southern Spain, olive (Olea europaea L.) growing is an important part of the economy, especially in the provinces of Jaén, Córdoba and Granada. This work proposes the first stages of an Information and Decision-Support System (IDSS) for providing different types of users (farmers, agricultural engineers, public services, etc.) with information on olive growing and the environment, and also assisting in decision-making. The main purposes of the project reported in this paper are to process uncertain or imprecise data, such as those concerning the environment or crops, and combine user data with other scientific-experimental data. The possibility of storing agricultural and ecological information in fuzzy relational databases, vital to the development of an IDSS is described. The information will be processed using knowledge extraction tools (fuzzy data-mining) that will allow rules on expert knowledge for assessing suitability of land to be developed and making thematic maps with the aid of Geographic Information Systems. Flexible querying will allow the users to collect information interactively from databases, while user information is constantly added. Flexible querying of databases, land suitability and thematic maps may be used to help in decisionmaking.El cultivo del olivo (Olea europaea L.) tiene una enorme importancia económica en la zona sur de España y concretamente en las provincias de Jaén, Córdoba y Granada. En este trabajo se propone la construcción de un sistema de información y ayuda a la toma de decisión (IDSS) que permita en el futuro a distintos tipos de usuarios (agricultores, agrónomos, administraciones públicas, etc.) obtener y manejar información sobre el cultivo de olivar y el soporte ambiental del mismo, así como ayudar en la toma de decisiones. Los principales objetivos desarrollados en este trabajo son el tratamiento de datos inciertos e imprecisos, como es el caso de la información ambiental y sobre cultivos, y la fusión de datos sobre cultivo y otros de carácter científico-experimental. Se describe la posibilidad de almacenar la información de carácter agronómico y ecológico en bases de datos relacionales, que es vital para el desarrollo de un IDSS. La información será procesada a través de herramientas de extracción de conocimiento (minería de datos difusa) y permitirá sobre la base del conocimiento experto el desarrollo de reglas para la clasificación de aptitud del terreno y para la obtención de mapas temáticos con la ayuda de Sistemas de Información Geográfica. La consulta flexible permitirá a los distintos usuarios la consulta interactiva de toda la información almacenada en las bases de datos, así como una implementación constante de las mismas. La consulta flexible de bases de datos, la idoneidad de los terrenos y los mapas temáticos pueden ser de gran utilidad en la toma de decisiones.This work is part of the research projects 1FD97-0244-CO3-2 (financed with FEDER funds) and CGL2004-02282BTE (Spanish Ministry of Education and Science)

More adult-born dentate gyrus neurons to weaken cocaine-related retrograde memories: an in vivo strategy employing exogenous lysophosphatidic acid

The post-training enhancement of adult hippocampal neurogenesis (AHN) has been receiving growing interest as a potential method to manipulate retrograde memories. Recent hypothesis suggest that the addition of adult-born dentate granule cells might promotes remodeling of pre-existing hippocampal circuits, which might both clear cocaine-related memories and facilitate the learning of new adaptive information. Here, we study the effect of stimulating AHN in vivo with exogenous lysophosphatidic acid (LPA) on the maintenance of retrograde cocaine-contextual associative memories. Male C57BL/6J mice trained in a cocaine-induced Conditioned Place Preference (CPP) model were later submitted to repeated intracerebroventricular (i.c.v.) injections of LPA, Ki16425 or vehicle solution during withdrawal. Afterwards, the long-term persistence of the cocaine-CPP was assessed and the mediational role of AHN in this process was evaluated. In addition, wild-type and mice lacking the LPA1 receptor received a single i.c.v. injection of LPA, Ki16425 or vehicle to assess the role of the LPA1 receptor in the LPA-induced increase of AHN. Our results revealed that the chronic administration of LPA decreased the retention of a previously acquired cocaine-induced CPP. This effect was mediated by an LPA-induced increase of AHN. In contrast, mice treated with Ki16425 showed reduced cocaine-CPP retention, but they increased their preference for the cocaine-paired compartment throughout CPP extinction. Besides, no effects of Ki16425 on AHN were found. Immunohistochemical studies suggested that LPA stimulated cell proliferation and promoted neuronal maturation with a key role of the LPA1 receptor. These findings emphasize the relevance of LPA and its LPA1 receptor as an in vivo modulator of AHN and the utility of the post-training increase of adult-born hippocampal neurons to weaken cocaine-context associations.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

LPA1/3 receptor antagonist KI16425 as a novel treatment for the neurobehavioural effects of the ethanol

Aims. The lysophosphatidic acid (LPA) is an ubiquitous lysophospholipid that acts through G-protein coupled receptors (LPA1-6), and it is involved in the modulation of emotional and motivational behaviors. Recent literature suggests a relevant role of the LPA signaling system in alcoholism, specially through the LPA1 receptor. This work aims to elucidate whether systemic LPA1/3 receptor blockade with ki16425 would modulate ethanol effects on the brain and behavior. Methods. This study consisted of four experiments assessing the effect of intraperitoneal ki16425 administration (20 mg/kg) on ethanol-related behaviors. Male Wistar rats or mice (Swiss, C57BL/6J or hybrid C57BL/6J×129X1/SvJ background) were employed in various procedures: I) oral ethanol selfadministration; II) loss of righting reflex; III) ethanol-induced conditioned place preference (CPP) and IV) ethanol-withdrawal behavioral symptoms (by assessing nest building, physical signs and spatial working memory). Immunohistochemistry was carried out in order to evaluate basal neuronal activity (c-Fos) in the medial prefrontal cortex (mPFC) and in the hippocampus, as well as adult hippocampal neurogenesis (AHN) using proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) markers. Results. Systemic Ki16425 administration reduced oral self-administration of ethanol in previously trained rats. Likewise, ki16425 pretreatment in mice attenuated the sedation induced by ethanol, blocked ethanol rewarding effect in a CPP paradigm and reduced behavioral symptoms induced by ethanol withdrawal. Immunohistochemistry revealed a protective effect of ki16425 against ethanol actions on basal neuronal activity in the mPFC and on AHN. Conclusions. Our results suggest a potential usefulness of systemic LPA1/3 receptors antagonists as a novel treatment for alcohol-related disorders.Universidad de Málaga, Campus de Excelencia Internacional Andalucía Tech

Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory

Author manuscriptErasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (a LPA1/3 receptor antagonist), or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an ~two-fold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1 receptor-deficient mice were acutely infused with LPA, which revealed that LPA1-mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA1-pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), which is cofunded by the European Research Development Fund AEI/FEDER, UE- (PSI2013-44901-P and PSI2017-82604-R to LJS and PSI2015-73156-JIN to ECO); by the National System of Health-Instituto de Salud Carlos III, which is co-funded by AEI/FEDER, UE (Red de Trastornos Adictivos; RD16/0017/0001 to FRdF); and by the Andalusian R&D&I Programme, Regional Ministry of Economy and Knowledge (PAIDI CTS643 to GET). DLGM and RDMF hold FPU grants from the Spanish Ministry of Education, Culture and Sports (FPU13/04819 and FPU14-01610, respectively). CRV received a ‘Plan Propio’ grant from the University of Malaga. FJP and AS hold ‘Miguel Servet’ grants (CP14/00212 and CP14/00173, respectively) from the National System of Health-Instituto de Salud Carlos III, which is co-funded by AEI/FEDER, UE. FRdF and GET are supported by Nicolas Monardes Programme, from the Andalusian Regional Ministry of Health. ECO holds a ‘Jóvenes Investigadores’ grant (code: PSI2015- 73156-JIN) from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación) which is co-funded by the European Research Development Fund (AEI/FEDER, UE)

Year-long evaluation of microalgae production in wastewater using pilot-scale raceway photobioreactors: Assessment of biomass productivity and nutrient recovery capacity

The production of Scenedesmus sp. using wastewater was validated with pilot-scale raceway photobioreactors during a complete annual cycle in Almería (Spain). Three different dilution rates (0.1, 0.2, or 0.3 day-1) were evaluated. Biomass productivity was significantly affected by season (temperature and solar radiation) achieving a maximum value of 25.1 g·m-2·day-1 when operating at a dilution rate of 0.2 day-1 in summer. Up to 96% of the N-NH4+ present in the media was either assimilated by microalgae to produce biomass, converted to N-NO3+ by the action of nitrifying bacteria, or desorbed (stripping). Maximum nitrogen removal rates reached 4286.6 mg·m-2·day-1 in summer. In terms of P-PO43+, up to 75% was removed, with removal rates ranging from 147.5 mg·m-2·day-1 in winter to 227.2 mg·m-2·day-1 in summer. Data reported herein was used to validate the ABACO model, which demonstrated to be robust enough to accurately predict biomass productivity in pilot-scale outdoor open raceways throughout the year (R2=0.929; 0.05). The current study demonstrates the potential of raceway reactors and Scenedesmus sp. to recover nutrients from unprocessed wastewater with an exceptionally high content of N-NH4+ at pre-industrial scale. Keywords: Bioremediation, microalgae, biomass, photobioreacto

Optimización de Campus Virtual. Ampliación y ordenación del archivo/repositorio en red bajo el parámetro “estrategias artísticas"

Proyecto dedicado a ampliar e introducir un orden en la herramienta realizada en el Proyecto de Innovación y Mejora de la Calidad Docente, PIMCD nº 216, realizado durante el curso 2017-2018, y cuyo título fue: “Optimización de Campus Virtual: archivo/repositorio en red de referencias artísticas desde 1900 hasta la actualidad”. La ordenación se ha realizado mediante el parámetro "estrategias artísticas"

PERSPECTIVA PSICOSOCIAL DE LOS DERECHOS HUMANOS

Hoy en día es imprescindible abordar el problema de los derechos desde una perspectiva holística que integre la posición que el individuo ocupa en la sociedad y el impacto de los hechos sociales sobre su persona. Esta perspectiva va por lo tanto más allá del enfoque clásico de las violaciones a los derechos civiles y políticos de los ciudadanos sino, también incluye sus derechos económicos, sociales y culturales. Cualquier enfoque de tipo holístico debe entender al ser humano en su ambiente, social, cultural, natural y en función a todas las estructuras existentes, por más sutiles que sean o invisibles que parezcan. Precisamente este libro permite apreciar la dimensión amplia y compleja del ser en sociedad y las interacciones que de ambas partes se generan y las ramificaciones que producen. No es un ejercicio fácil y los editores de este volumen han logrado un salto cuántico al poder congregar en un solo espacio miradas que en otras circunstancias podrían haber sido opuestas y hasta contrarias a nuestra comprensión de problemas que, en efecto, tienen raíces comunes. El libro está dividido en 5 secciones, El espíritu de los tiempos actuales y los Derechos Humanos, Construcción ciudadana y ejercicio de los Derechos Humanos, Violaciones a Derechos Humanos, victimizaciones y su atención, Ejercicio de los Derechos Humanos y situaciones disruptivas y Defensa y defensores de Derechos Humanos.Manuel Gutiérrez Romero Jessica Ruiz Magañ