NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and n vivo but fail to eliminate leukemiai nitiating cells

[Introduction]: Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation. [Methods]: In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells’ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality. [Results]: In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells. [Discussion]: The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.This work was supported by a grant from the Instituto de Salud Carlos III to LF PI21/01049, the II and V awards from UNOENTRECIENMIL Foundation, and a grant from CRIS FOUNDATION to Beat Cancer as part of the projects “Cell therapy based on NKG2D-CAR for pediatric leukemia” and “NKG2D-CAR as treatment for pediatric patients suffering from acute leukemia and juvenile myelomonocytic leukemia”. AF, MI-N, AN-Z and CF have been supported by Personnel research grants from CRIS Foundation to beat cancer. CM has been supported by Personnel PhD student grants from the Instituto de Salud Carlos III (ISCIII), PFIS (FI19/00176). MVG is funded by grant PID2021-123795OB-I00 from the Spanish Ministry of Science and Innovation [Ministerio de Ciencia e Innovación (MCIN)/Agencia Estatal de Investigación (AEI) / 10.13039/501100011033 and European Regional Development Fund (ERDF)-A way of making Europe] and belongs to cancer-Hub CSIC. MI lab is funded by grant PID2020-114148RB-I00 from the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033,which was in part granted with FEDER funding (EC)

Host plant scent mediates patterns of attraction/repellence among predatory mites

[EN] In mite communities, behavioral and foraging decisions of individuals rely on semiochemicals that they gather from the environment, which contain odors from plants, herbivores, and predators. Because herbivorous mites commonly co-occur with several species of phytoseiid predatory mites, which may engage in intraguild predation (IGP), predator mite decision-making relies on their ability to recognize odors signaling the presence of the herbivore but also that of potential competitors/predators. Here the odor-related foraging decisions of three predatory mites, Euseius stipulatus (Athias-Henriot), Neoseiulus californicus (McGregor) and Phytoseiulus persimilis (Athias-Henriot) (Mesostigmata: Phytoseiidae), which co-occur in citrus, compete for the herbivore Tetranychus urticae Koch (Prostigmata: Tetranychidae), and can engage in IGP were investigated. The composition of the volatile blends associated with the three predators was characterized. Moreover, the effect of these odors on the predators foraging decisions was measured. Results revealed that (1) the volatile signature of the three predatory mites is species specific, (2) the predators¿ foraging behavior is affected by heterospecific predator odors, and (3) predator responses strongly depend on the host plant: mutual attraction and mutual repellence occurred in Cleopatra mandarin and sour orange, respectively. These findings have important consequences for the management of systems where these species occur. The odor blends that make predators that share pest species as prey avoid each other could be used to improve pest control by minimizing undesired negative interactions among predator species, and by locally increasing predation risk on herbivore pest species.The authors thank M. Piquer (UJI) for technical assistance and J. Calvo (Koppert Biological Systems) for the supply of N. californicus and P. persimilis. This study was partially funded by the Spanish Research State Agency (research grants AGL2014-55616-C3, AGL2015-64990-2R, PID2019-103863RB-I00 and BES-2015-074570).Cruz-Miralles, J.; Cabedo-Lopez, M.; Guzzo, M.; Vacas, S.; Navarro-Llopis, V.; Ibáñez-Gual, MV.; Flors, V.... (2022). Host plant scent mediates patterns of attraction/repellence among predatory mites. Entomologia Generalis. 42(2):217-229. https://doi.org/10.1127/entomologia/2021/1237S21722942

Relationship between D90 and D100 with Biochemical and Local Failure in Low-risk Prostate Cancer Treated with Low-rate Brachytherapy (LDR)

Low dose rate brachytherapy (LDR) is an accepted, effective treatment with few local side effects, used as monotherapy in patients with low-risk prostate cancer (PC). The aim of this paper is to analyse 245 patients treated with LDR in the Radiation Oncology Department of the Hospital Gómez Ulla, from 2004 to 2016, evaluating the relationship of dosimetric parameters with biochemical and local recurrence as well as genitourinary and gastrointestinal toxicity derived from the technique. The results obtained show a clear relationship between the dose used and biochemical and local failure

Descemet’s Membrane Detachment during Phacocanaloplasty: Case Series and In-Depth Literature Review

This article presents three cases of Descemet’s membrane detachment (DMD) occurring during ‘ab externo’ phacocanaloplasty procedures in three patients with uncontrolled primary open-angle glaucoma (OAG) and discusses the management of this condition by reviewing the available literature. Following a successful 360° cannulation of Schlemm’s canal (SC), the microcatheter was withdrawn while an ophthalmic viscosurgical device (OVD) was injected into the canal. During passage through the inferonasal quadrant, a spontaneous separation of the posterior layer of the cornea was observed. Each case was managed differently after diagnosis, with the third case being drained intraoperatively based on experience gained from the previous cases. On the first postoperative day, slit-lamp biomicroscopy (BMC) revealed multiple DMDs in case one and a hyphema in the lower third of a deep anterior chamber. In the other two cases, a single DMD was observed. The second case developed hemorrhagic Descemet membrane detachment (HDMD), while the other two were non-hemorrhagic. In all three cases, anterior segment optical coherence tomography (AS-OCT) revealed the presence of retrocorneal hyperreflective membranes indicative of DMDs. These membranes were located in the periphery of the cornea and did not impact the visual axis. After evaluation, a small incision was made in the inferotemporal DMD of the first case. However, for the two remaining cases, a strategy of watchful waiting was deemed appropriate due to the location and size of the DMDs, as they did not affect the best-corrected visual acuity (BCVA). Over time, the patients demonstrated progressive improvement with a gradual reduction in the size of the DMDs

NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells

Introduction Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation. Methods In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA ⁻ ) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells’ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality. Results In vitro , we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo , NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo , they exhibited functional properties of leukemia initiating cells. Discussion The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL

Las unidades del discurso oral. La propuesta Val.Es.Co. de segmentación de la conversación (coloquial)

El presente artículo resume y examina críticamente la propuesta de segmentación del discurso realizada en Briz y Grupo Val.Es.Co (2003). El modelo Val.Es.Co. consta de ocho unidades (discurso, diálogo, intercambio/ alternancia de turnos, intervención/turno, acto y subacto), tres órdenes (social, estructural e informativo) y cuatro posiciones (inicial, media, final e independiente); se caracteriza, además, por ser jerárquico y recursivo. La aplicación del modelo Val.Es.Co. permite la segmentación de una conversación coloquial sin residuos, así como un adecuado tratamiento de diversos fenómenos conversacionales (actos truncados, solapamientos, elementos suprasegmentales o marcadores discursivos)This paper summarizes and critically reviews the model of discourse segmentation made by Briz and Grupo Val.Es.Co (2003). This model is made up of eight units (discourse, dialogue, exchange/ turn taking, intervention/turn, act and subact), three orders (social, structural and informative) and four positions (initial, medial, final and independent). The Val.Es.Co model is also hyerarchical and recursive. By applying the Val.Es.Co model, a conversation can be divided into parts and subparts without any element remaining unanalyzed. Also, some specific features occurring in conversations such as false starts, overlappings, the segmentation value of prosodic features or discourse markers, can be successfully analyze

DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted bloodbrain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes− cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1G395A, an essential biomarker in the current management of human gliomaWe are grateful for the financial support from the ‘Fondo de Investigaciones Sanitarias’ (FIS) (PI10/01069 and PI14/00077) and the ‘Miguel Servet Program’ (CP11/00147) from the ‘Instituto de Salud Carlos III’ (AAS), RTC-2015-3846-1 from Ministerio de Economía y Competitividad and FEDER fund

A Single-Run Next-Generation Sequencing (NGS) Assay for the Simultaneous Detection of Both Gene Mutations and Large Chromosomal Abnormalities in Patients with Myelodysplastic Syndromes (MDS) and Related Myeloid Neoplasms

Chromosomal abnormalities and somatic mutations are found in patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in around 50-80% of cases. The identification of these alterations is important for the accurate diagnosis and prognostic classification of these patients. Often, an apparently normal or failed karyotype might lead to an inadequate estimation of the prognostic risk, and several strategies should be combined to solve these cases. The aim of this study was to introduce a novel next-generation sequencing (NGS)-based strategy for the simultaneous detection of all the clinically relevant genetic alterations associated with these disorders. We validated this approach on a large cohort of patients by comparing our findings with those obtained with standard-of-care methods (i.e., karyotype and SNP-arrays). We show that our platform represents a significant improvement on current strategies in defining diagnosis and risk stratification of patients with MDS and myeloid-related disorders. Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms are clonal disorders that share most of their cytogenetic and molecular alterations. Despite the increased knowledge of the prognostic importance of genetics in these malignancies, next-generation sequencing (NGS) has not been incorporated into clinical practice in a validated manner, and the conventional karyotype remains mandatory in the evaluation of suspected cases. However, non-informative cytogenetics might lead to an inadequate estimation of the prognostic risk. Here, we present a novel targeted NGS-based assay for the simultaneous detection of all the clinically relevant genetic alterations associated with these disorders. We validated this platform in a large cohort of patients by performing a one-to-one comparison with the lesions from karyotype and single-nucleotide polymorphism (SNP) arrays. Our strategy demonstrated an approximately 97% concordance with standard clinical assays, showing sensitivity at least equivalent to that of SNP arrays and higher than that of conventional cytogenetics. In addition, this NGS assay was able to identify both copy-neutral loss of heterozygosity events distributed genome-wide and copy number alterations, as well as somatic mutations within significant driver genes. In summary, we show a novel NGS platform that represents a significant improvement to current strategies in defining diagnosis and risk stratification of patients with MDS and myeloid-related disorder

Herramientas de comunicación y divulgación musical orientadas a la transferencia: entornos digitales 2.0

Este proyecto tiene como objeto la formación sobre recursos y herramientas de comunicación y divulgación musical en espacios 2.0, con el fin de utilizarlas en el aula y fomentar la transferencia y el emprendimiento en el ámbito de la musicología