Towards Automated Management and Analysis of Heterogeneous Data Within Cannabinoids Domain

Cannabinoid research requires the cooperation of experts from various field biochemistry and chemistry to psychological and social sciences. The data that have to be managed and analysed are highly heterogeneous, especially because they are provided by a very diverse range of sources. A number of approaches focused on data collection and the corresponding analysis, restricting the scope to a sub-domain. Our goal is to elaborate a solution that would allow for automated management and analysis of heterogeneous data within the complete cannabinoids domain. The corresponding integration of diverse data sources would increase the quality and preciseness of the analysis. In this paper, we introduce the core ideas of the proposed framework as well as present the implemented prototype of a cannabinoids data platform.Comment: Preprint. Accepted to the 14th International Conference on Evaluation of Novel Approaches to Software Engineering (ENASE 2019). Final version published by SCITEPRES

Recent Changes in Drug Abuse Scenario: The Novel Psychoactive Substances (NPS) Phenomenon

copyright 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND.Final Published versio

Systemic medications and other risk factors of open-angle glaucoma

Het onderzoek in dit proefschrift is ontworpen om de werking van sommige systemische geneesmiddelen te ontcijferen en een aantal andere risicofactoren van open-kamerhoek glaucoom (OKG) te onderzoeken. De studies gepresenteerd in de eerste drie hoofdstukken zijn gebaseerd op het Erasmus Rotterdam Gezondheids Onderzoek (ERGO/ Rotterdamstudie), een prospectief populatie-gebaseerde cohort studie van ouderdomgerelateerde aandoeningen. Onze studie populatie bestaat uit 3939 van de oorspronkelijke 7983 deelnemers van 55 jaar en ouder uit het Rotterdamse onderzoek. In hoofdstuk een hebben we onderzocht of het gebruik van cholesterol- verlagende geneesmiddelen geassocieerd is met een verlaagd risico op (OKG). We hebben de relatie tussen het gebruik van corticosteroïden en incident OKG onderzocht in hoofdstuk twee. In hoofdstuk 3 is onderzocht of antitrombotica het risico van OKG kan verminderen. Het centrale thema van de hoofdstukken 4, 5 en 6 is het gebruik van statistische methodologie, systematische review en meta-analyse om andere risicofactoren van OKG te verhelderen. Hoofdstuk 4 beschrijft de risico's die samenhangen met visuele veldprogressie in OKG door het vergelijken van verschillende statistische benaderingen in de Groningen Longitudinal Glaucoma Study (GLGS), een prospectieve cohort studie in een klinische setting. Hoofdstuk 5 presenteert in een systematische review en meta-analyse de relatie tussen bijziendheid en OKG. Hoofdstuk 6 biedt een overzicht van de huidige stand van kennis van het effect van systemische geneesmiddelen op OKG. The research presented in this thesis was designed to decipher the effect of some systemic medications and some other risk factors of OAG. The studies presented in the first three chapters are based on the Rotterdam Study, a prospective population-based cohort study of age related disorders in the elderly. Our study population comprised of 3939 of the original 7983 participants aged 55 years and older from the Rotterdam study. In chapter 1 we studied whether the use of cholesterol-lowering drugs is associated with a reduced risk of OAG. In chapter 2 we explored the association between corticosteroid use and incident OAG. In chapter 3 we studied whether antithrombotics could reduce the risk of OAG. The central theme of chapters 4, 5 and 6 is the use of statistical methodology, systematic review and meta-analysis to elucidate other risk factors of OAG. Chapter 4 describes the risk factors associated with visual field progression in OAG by comparing different statistical approaches in the Groningen Longitudinal Glaucoma Study (GLGS), a prospective cohort study in a clinical setting. Chapter 5 presents a systematic review and meta-analysis to examine the association between myopia and OAG. Chapter 6 reviews the current state of knowledge of the effect of systemic medications on OAG.

Targeting tumor microenvironment crosstalk through GPCR receptors and PI3K pathway

[eng] The tumor microenvironment (TME) is gaining momentum due to its contribution to cancer progression and therapy resistance. This TME has a direct crosstalk with tumor cells that involves the activation of different pathways. Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although FL is generally characterized by slow progression and high response rates to therapy, it is still considered incurable, because almost virtually all the patients relapse. FL is probably the NHL with the highest dependence on microenvironment. PI3K is a common denominator transducing the signaling from FL crosstalk with the TME and plays an important role in multiple cellular functions, and also contributes to cancer promoting aspects of the TME, such as angiogenesis and inflammatory cell recruitment. Idelalisib is a first-in-class δ isoform- specific PI3K inhibitor that receive regulatory approval for relapsed CLL, SLL and FL in 2014. Idelalisib blocks PI3K δ which is restricted to leukocytes. BCL2 deregulation is paramount in the pathogenesis of FL, as a consequence of the t(14;18), and therefore it is an attractive target for novel therapeutic approaches. Venetoclax (ABT-199, AbbVie) is a small BCL-2 inhibitors. Even though 85% of FL patients harbor the t(14;18), the results of the first clinical trial with venetoclax were not satisfactory (overall response 38%). From this first study we conclude that Idelalisib modulates key pathways in the germinal center and shapes the FL immune microenvironment by decreasing the recruitment of TFH and Treg to the tumor site leading to less immunesuppresive phenotype. Furthermore Idelalisib induces a moderate cytotoxic effect on FL cells in co-cultures. This co-culture decrease FL dependence on BCL-2 and consequently, venetoclax cytotoxicity, but Idelalisib sensitizes FL co-cultures to venetoclax. In summary, Idelalisib interferes with the crosstalk of FL and its immune microenvironment and potentiates the activity of venetoclax targeting the tumor cells, thus representing a promising combination therapy that may improve FL outcome. Colorectal cancer (CRC) is the third most common cancer in males and the second in females, and the fourth most common cause of cancer-related death worldwide. Patients with advanced and distal metastatic disease (stage IV), the survival rate drops to 10%, which accounts for approximately 18% of cases. The TME in CRC, is a complex structure composed by different type of cells, which are interacting each other’s and secreting a variety of growth factors and other molecules, such as cytokines and chemokines. Tumor development is based on the crosstalk between tumor cells and their surrounding microenvironment, and this crosstalk is mediated by the receptors and its ligand expression in both types of cells. G protein-coupled receptors (GPCRs) are an important family of membrane signaling receptors, which have an important role in cancer growth and development. Originally, GPCRs were considered as monomeric functional entities, nevertheless, in recent years has become evident that GPCRs form dimers and this dimers formation may modify the cellular response. In cancer, CXCR4 (has been studied extensively) plays an important role at different stages of cancer development, and is involved in the metastasis process of tumor cells. The up- regulation of CXCR4 in CRC correlates with a poor prognosis. Another GPCR, CB2 receptor modulates the downstream signaling and it is able to activate a wide range of signaling pathways, including extracellular signal-regulated kinases 1/2 (ERK1/2). In CRC, it has been described an up-regulation of CB2 receptor expression. GPCRs show differential expression in cancer cells and tissues, and they are highly druggable sites. From this second study we concluded that CXCR4 and CB2 expression is increased in primary colon tumor cells and in metastasis cells compared to normal epithelial cells from colon mucosa, and they formed heterodimers in colon tumoral cells and are associated with more aggressive phenotypes. Moreover, a bidirectional cross-antagonism crosstalk is established between these receptors. These heterodimers regulate in vitro CXCL12-induced migration, and in vivo, the simultaneous inhibition of both receptors shows superior anti-tumoral and anti-metastatic activities than the single agent inhibition. In summary, targeting the heterodimerization of CXCR4 and CB2 that are biologically relevant in cancer can be an effective way to reduce proliferation and dissemination in CRC.[spa] El estudio del microambiente tumoral está ganando importancia en las últimas décadas debido a su contribución en la formación y desarrollo del cáncer, además de contribuir en la resistencia de las células tumorales a diferentes terapias. Este microambiente interactúa con las células tumorales y activa diferentes vías. El linfoma folicular (FL), es el linfoma no Hodgkin indolente más común y con mayor dependencia del microambiente tumoral, además es considerado incurable. PI3K desempeña un papel importante en la comunicación con el microambiente, y es importante en múltiples funciones celulares, además de contribuir en la angiogénesis, reclutamiento de células inflamatorias y promover el crecimiento tumoral. Idelalisib es un inhibidor de PI3K (específicamente de la isoforma δ), que se aprobó en 2014 por la FDA. Paralelamente la desregulación de BCL2 es primordial en la patogénesis de FL, como consecuencia de la t (14; 18), presente en un 85% de los pacientes, y por lo tanto es un objetivo atractivo para novedosos enfoques terapéuticos. Venetoclax (ABT-199, AbbVie) es un pequeño inhibidor de BCL2, que mostró unos resultados del primer ensayo clínico no satisfactorios (respuesta global del 38%). De este primer estudio concluimos que Idelalisib interfiere en la comunicación de FL y su microambiente inmune, además potencia la actividad de venetoclax atacando a las células tumorales, lo que representa una terapia de combinación prometedora que puede mejorar el resultado del tratamiento de FL

Spatial learning and memory in brain-injured and non-injured mice: investigating the roles of diacylglycerol lipase-α and -β.

A growing body of evidence implicates the importance of the endogenous cannabinoid 2-arachidonyl glycerol (2-AG) in memory regulation. The biosynthesis of 2-AG occurs primarily through the diacylglycerol lipases (DAGL-α and -β), with 2-AG serving as a bioactive lipid to both activate cannabinoid receptors and as a rate limiting precursor for the production of arachidonic acid and subsequent pro-inflammatory mediators. Gene deletion of DAGL-α shows decrements in synaptic plasticity and hippocampal neurogenesis suggesting this biosynthetic enzyme may be important for processes of normal spatial memory. Additionally, 2-AG is elevated in response to pathogenic events such as traumatic brain injury (TBI), suggesting its regulatory role may extend to conditions of neuropathology. As such, this dissertation investigates the in vivo role of DAGL-α and -β to regulate spatial learning and memory in the healthy brain and following neuropathology (TBI). The first part of this dissertation developed a mouse model of learning and memory impairment following TBI, using hippocampal-dependent tasks of the Morris water maze (MWM). We found modest, but distinct differences in MWM performance between left and right unilateral TBI despite similar motor deficits, histological damage, and glial reactivity. These findings suggest that laterality in mouse MWM deficit might be an important consideration when modeling TBI-induced functional consequences. The second part of this dissertation work evaluated DAGL-β as a target to protect against TBI-induced learning and memory deficit given its selective expression on microglia and the role of 2-AG as a precursor for eicosanoid production. The gene deletion of DAGL-β did not protect against TBI-induced MWM or motor deficits, but unexpectedly produced a survival protective phenotype. These findings suggest that while DAGL-β does not contribute to injury-induced memory deficit, it may contribute to TBI-induced mortality. The third and final set of experiments investigated the role of DAGL-α in mouse spatial learning and memory under physiological conditions (given the predominantly neuronal expression of DAGL-α). Complementary pharmacological and genetic manipulations produced task specific impaired MWM performance, as well as impaired long-term potentiation and alterations to endocannabinoid lipid levels. These results suggest that DAGL-α may play a selective role in the integration of new spatial information in the normal mouse brain. Overall, these data point to DAGL-α, but not DAGL-β, as an important contributor to hippocampal-dependent learning and memory. In contrast, DAGL-β may contribute to TBI-induced mortality