Editorial: Engineered immune cells in cancer immunotherapy (EICCI)

Adoptive Cell Therapy (ACT) to treat cancer represents a rapidly evolving field. New approaches for the genetic engineering of immune effector cells with either a T cell receptor (TCR) or a chimeric antigen receptor (CAR) (Figure 1 Panels A and B, respectively) have led to the increase of the clinical efficacy, the reduction or better control of toxicities and the expansion of the indications of these therapies. The Research Topic “Engineered Immune Cells in Cancer Immunotherapy (EICCI)” represents the venue for collecting studies, new evidence, advances in the technologies and the greatest knowledge for the translational application on the topic of cellular therapy for cancer. The great success of this Research Topic with the publication of total 46 articles, including 18 original articles, 20 reviews, 5 mini reviews, 2 case reports and 1 methodology manuscript, and the contributions of 360 authors, testify to the huge interest of the scientific community in this field and the numerous advancements

Proceedings From the First International Workshop at Sidra Medicine: “Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development”, 15th–16th February 2019, Doha, Qatar

The progress in the isolation and characterization of tumor antigen (TA)-specific T lymphocytes and in the genetic modification of immune cells allowed the clinical development of adoptive cell therapy (ACT). Several clinical studies highlighted the striking clinical activity of T cells engineered to express either Chimeric Antigen (CAR) or T Cell (TCR) Receptors to target molecularly defined antigens expressed on tumor cells. The breakthrough of immunotherapy is represented by the approval of CAR-T cells specific for advanced or refractory CD19+ B cell malignancies by both the Food and Drug Administration (FDA) and the European Medicinal Agency (EMA). Moreover, advances in the manufacturing and gene editing of engineered immune cells contributed to the selection of drug products with desired phenotype, refined specificity and decreased toxicity. An important step toward the optimization of CAR-T cell therapy is the development of “off-the shelf” T cell products that allow to reduce the complexity and the costs of the manufacturing and to render these drugs available for a broad number of cancer patients. The Engineered Immune Cells in Cancer Immunotherapy (EICCI) workshop hosted in Doha, Qatar, renowned experts, from both academia and industry, to present and discuss the progress on both pre-clinical and clinical development of genetically modified immune cells, including advances in the “off-the-shelf” manufacturing. These experts have addressed also organizational needs and hurdles for the clinical grade production and application of these biological drugs.Qatar National Research Fund (QNRF)-Conference Workshop Sponsorship Program CWSP15-W-0911-18001Associazione Italiana per la Ricerca sul Cancro (AIRC) Ig 18458Associazione Italiana per la Ricerca sul Cancro (AIRC) 22737Ministry of Education, Universities and Research (MIUR) PRIN 2017WC8499Italian Ministry of Health (Research project on CAR T cells for hematological malignancies and solid tumors

Role of Hospital Exemption in Europe: position paper from the Spanish Advanced Therapy Network (TERAV)

Instituto de Salud Carlos IIIEuropean Union - NextGenerationEU, Recovery, Transformation and Resilience Plan RD21/0017/000

Null paths on a toroidal topological black hole in conformalWeyl gravity

The motion of massless particles on the background of a toroidal topological black hole is analyzed in the context of conformal Weyl gravity. Null geodesics, in terms of the Jacobi elliptic functions, are found analytically. In addition, the Sagnac effect in this space-time is characterized, and we find a strong condition in the theory's parameters that is required for its existence.Comment: 8 pages, 7 figure

Sophus Lie: un matemático visionario

A diferencia de una mera exposici´on de datos puramente biogr´aficos, este art´ıculo pretende dar a conocer a cualquier persona en general, y a los matem´aticos y cient´ıficos en particular, aquellas an´ecdotas menos conocidas, leyendas m´as o menos ajustadas a la realidad, correspondencia enviada y recibida, y sobre todo, opiniones de otras personas sobre la vida y obra de Sophus Lie

Legitimidad en el emprendimiento. Estructura intelectual y tendencias de investigación

[EN] From the beginning of the xxi century, research on organizational legitimacy has been frequently used to explain the survival of new companies. The need of being considered legitimated for new companies to improve their access to necessary resources to survive has called the researchers attention. This situation has favored the increase in the research about organizational legitimacy in the entrepreneurship field, which has augmented the complexity of obtaining a global understanding of the field´s current context. The aim of this research is to identify and visualize the intellectual structure of the research and the emerging trends regarding organizational legitimacy in the entrepreneurship field. The database is made up of the sources of knowledge and references on which the scientific articles published in the data base of the Web of Science (WOS) were based. Through a bibliometric methodology based on co-citation, we identify the main research areas, the most active ones, the main contributors, dissemination paths and emerging trends in the research field. This research paper contributes to the development of organizational legitimacy in the entrepreneurship field offering a comprehensive view of the situation of this domain, a starting point as well as a theoretical base for the researchers to build new developments.[ES] Desde principios del siglo xxi, la investigación sobre la legitimidad organizacional se ha utilizado con frecuencia para explicar la supervivencia de las nuevas empresas. La necesidad de ser consideradas legitimas las nuevas empresas para mejorar su acceso a los recursos necesarios para sobrevivir ha llamado la atención de los investigadores. Esta situación ha favorecido el aumento de la investigación sobre la legitimidad organizacional en el campo del emprendimiento, lo que ha aumentado la complejidad de obtener una comprensión global de la situación actual en el campo. El objetivo de esta investigación es identificar y visualizar la estructura intelectual de la investigación y las tendencias emergentes en el campo de la legitimidad organizacional en el emprendimiento. La base de datos está formada por las fuentes de conocimiento o referencias en que se basan los artículos científicos publicados en la base de datos de Web of Science (WOS). Mediante una metodología bibliométrica basada en co-citas, identificamos las principales áreas de investigación, las más activas, los principales contribuyentes, las vías de difusión y las tendencias emergentes en el campo de la investigación. Este trabajo de investigación contribuye al desarrollo del campo de la legitimidad organizacional en el emprendimiento ofreciendo una visión integral de la situación de este dominio, tanto un punto de partida como una base teórica para que los investigadores construyan nuevos desarrollos

LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis

Leucine-rich repeat kinase 2 (LRRK2) has been linked to dopaminergic neuronal vulnerability to oxidative stress (OS), mitochondrial impairment, and increased cell death in idiopathic and familial Parkinson’s disease (PD). However, how exactly this kinase participates in the OS-mitochondria-apoptosis connection is still unknown. We used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 LRRK2 knockout (KO) in the human embryonic kidney cell line 293 (HEK-293) to evaluate the cellular response to the mitochondrial inhibitor complex I rotenone (ROT), a well-known OS and cell death inducer. We report successful knockout of the LRRK2 gene in HEK-293 cells using CRISPR editing (ICE, approximately 60%) and flow cytometry (81%) analyses. We found that HEK-293 LRRK2 WT cells exposed to rotenone (ROT, 50 μM) resulted in a significant increase in intracellular reactive oxygen species (ROS, +7400%); oxidized DJ-1-Cys106-SO3 (+52%); phosphorylation of LRRK2 (+70%) and c-JUN (+171%); enhanced expression of tumor protein (TP53, +2000%), p53 upregulated modulator of apoptosis (PUMA, +1950%), and Parkin (PRKN, +22%); activation of caspase 3 (CASP3, +8000%), DNA fragmentation (+35%) and decreased mitochondrial membrane potential (ΔΨm, −58%) and PTEN induced putative kinase 1 (PINK1, −49%) when compared to untreated cells. The translocation of the cytoplasmic fission protein dynamin-related Protein 1 (DRP1) to mitochondria was also observed by colocalization with translocase of the outer membrane 20 (TOM20). Outstandingly, HEK-293 LRRK2 KO cells treated with ROT showed unaltered OS and apoptosis markers. We conclude that loss of LRRK2 causes HEK-293 to be resistant to ROT-induced OS, mitochondrial damage, and apoptosis in vitro. Our data support the hypothesis that LRRK2 acts as a proapoptotic kinase by regulating mitochondrial proteins (e.g., PRKN, PINK1, DRP1, and PUMA), transcription factors (e.g., c-JUN and TP53), and CASP3 in cells under stress conditions. Taken together, these observations suggest that LRRK2 is an important kinase in the pathogenesis of PD.Committee for Development and Research-UdeA” (Comité para el Desarrollo y la Investigacion-CODI, Universidad de Antioquia-UdeA) grants (#2017- 15829)The Spanish ISCIII Health Research Fund and the European Regional Development Fund (FEDER)Grants PI15/02015 and PI18/00337. The APC was funded by Committee for Development and Research-UdeA

La Influencia de los Productos Hidrofugantes en la Succión del Ladrillo Cerámico Cara Vista

Boletín de la Sociedad Española de Cerámica y Vidrio

Rnd3 Expression is Necessary to Maintain Mitochondrial Homeostasis but Dispensable for Autophagy

Autophagy is a highly conserved process that mediates the targeting and degradation of intracellular components to lysosomes, contributing to the maintenance of cellular homeostasis and to obtaining energy, which ensures viability under stress conditions. Therefore, autophagy defects are common to different neurodegenerative disorders. Rnd3 belongs to the family of Rho GTPases, involved in the regulation of actin cytoskeleton dynamics and important in the modulation of cellular processes such as migration and proliferation. Murine models have shown that Rnd3 is relevant for the correct development and function of the Central Nervous System and lack of its expression produces several motor alterations and neural development impairment. However, little is known about the molecular events through which Rnd3 produces these phenotypes. Interestingly we have observed that Rnd3 deficiency correlates with the appearance of autophagy impairment profiles and irregular mitochondria. In this work, we have explored the impact of Rnd3 loss of expression in mitochondrial function and autophagy, using a Rnd3 KO CRISPR cell model. Rnd3 deficient cells show no alterations in autophagy and mitochondria turnover is not impaired. However, Rnd3 KO cells have an altered mitochondria oxidative metabolism, resembling the effect caused by oxidative stress. In fact, lack of Rnd3 expression makes these cells strictly dependent on glycolysis to obtain energy. Altogether, our results demonstrate that Rnd3 is relevant to maintain mitochondria function, suggesting a possible relationship with neurodegenerative diseases.MINECO (SAF 2013-49176-C2-1- R)Conselleria d’ Educació, Investigació, Cultura i Esport (AICO/2016/047)FUSP-CEU-UCH (FUSP-PPC-19- 28A751CC)Instituto de Salud Carlos III (ISCIII) (PI18/ 00337)WKZ Fonds (R4376)ReumaNederland (16-1-2-1)Nicolas Monardes regional Ministry of Health contrac

Neuronal apoptosis inhibitory protein (NAIP) localizes to the cytokinetic machinery during cell division

The neuronal apoptosis inhibitory protein (NAIP) is a constituent of the inflammasome and a key component of the innate immune system. Here we use immunofluorescence to position NAIP within the cytokinetic apparatus, contiguous to chromosomal passenger complex (CPC), Centralspindlin, PRC1 and KIF4A. During metaphase, NAIP accumulates in the mitotic spindle poles and is shown in spindle microtubules; in anaphase NAIP is detected in the middle of the central spindle. At the end of cytokinesis, NAIP is localized in the outlying region of the stem body, the center of the intercellular bridge formed between daughter cells prior to cellular abscission. We also describe the sustained presence of NAIP mRNA and protein throughout the cell cycle with a significant increase observed in the G2/M phase. Consistent with a role for NAIP in cytokinesis, NAIP overexpression in HeLa cells promotes the acquisition of a multinuclear phenotype. Conversely, NAIP siRNA gene silencing results in an apoptotic lethal phenotype. Our confocal and super resolution stimulated-emission-depletion (STED) examination of mammalian cell cytokinesis demonstrate a potential new role for NAIP in addition to anti-apoptotic and innate immunology functions.This work was supported by operating grants from FightSMA, The SMA Foundation, The Canadian Gene Cure Foundation, CIHR and Families of SMA to A.M