Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Altres ajuts: This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias cofinanced by the European Regional Development Fund (ERDF); Fundación Asociación Española Contra el Cáncer (M.C. and P.A.) and Gilead Fellowships (GLD16/00144, GLD18/00047, F.B). M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades. S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero.Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential. The online version of this article (10.1007/s11060-020-03580-y) contains supplementary material, which is available to authorized users

Cubik: Una herramienta de apoyo en la enseñanza de la programación

Se presenta un entorno para el desarrollo de Algoritmos. Este entorno controla con naturalidad la edición de forma tal que no se incurra en errores sintácticos ni errores semánticos. Permite usar del nombre de otros Algoritmos como primitivas lo que promueve el concepto de modularidad. Además el entorno soporta que los Algoritmos pueden ser traducidos a programas en lenguaje Pascal los cuales luego pueden ser ejecutados. Esta característica permite la prueba de los Algoritmos editados. El Editor maneja datos de entrada, salida, y datos locales. Asimismo maneja acciones para modificar los datos, estas acciones son representaciones abstractas de las sentencias existentes en la mayoría de los Lenguajes de Programación Estructurados.Eje: 4to. ateneo de profesores universitarios de computación y sistemasRed de Universidades con Carreras en Informática (RedUNCI

Cubik: Una herramienta de apoyo en la enseñanza de la programación

Se presenta un entorno para el desarrollo de Algoritmos. Este entorno controla con naturalidad la edición de forma tal que no se incurra en errores sintácticos ni errores semánticos. Permite usar del nombre de otros Algoritmos como primitivas lo que promueve el concepto de modularidad. Además el entorno soporta que los Algoritmos pueden ser traducidos a programas en lenguaje Pascal los cuales luego pueden ser ejecutados. Esta característica permite la prueba de los Algoritmos editados. El Editor maneja datos de entrada, salida, y datos locales. Asimismo maneja acciones para modificar los datos, estas acciones son representaciones abstractas de las sentencias existentes en la mayoría de los Lenguajes de Programación Estructurados.Eje: 4to. ateneo de profesores universitarios de computación y sistemasRed de Universidades con Carreras en Informática (RedUNCI

Factor Structure of the AUDIM-M Dimensional Self-Concept Questionnaire in Mexican Adolescents

Self-concept is one of the most relevant variables in the field of personality, and a negative self-perception can pose a risk to the adolescent’s development. The present study aimed to analyze the psychometric properties proposed by Aguirre and collaborators for the dimensional self-concept questionnaire (AUDIM-M). The total sample was 560 adolescents from the city of Chihuahua, Chihuahua, with a mean age of 12.96 ± 0.88 years. The factor structure of the questionnaire was analyzed using confirmatory factor analysis. The analyses show that a four-factor structure is viable and adequate (GFI 0.964; RMSEA 0.057; CFI 0.950). The four-factor structure (personal self-concept, physical self-concept, social self-concept, and academic self-concept), according to statistical and substantive criteria, shows adequate indicators of reliability and validity adjustment. The model obtained coincides with that proposed by Aguirre et al. Improving adolescents’ self-concept undoubtedly contributes to their quality of life, hence the need for valid and reliable instruments for its measurement; this study could be a first approach for future research

Bactericidal Activity of Silver Nanoparticles on Oral Biofilms Related to Patients with and without Periodontal Disease

Background and Objectives: Periodontal disease (PD) is a multifactorial oral disease regularly caused by bacterial biofilms. Silver nanoparticles (AgNP) have offered good antimicrobial activity; moreover, there is no available scientific information related to their antimicrobial effects in biofilms from patients with PD. This study reports the bactericidal activity of AgNP against oral biofilms related to PD. Materials and Methods: AgNP of two average particle sizes were prepared and characterized. Sixty biofilms were collected from patients with (30 subjects) and without PD (30 subjects). Minimal inhibitory concentrations of AgNP were calculated and the distribution of bacterial species was defined by polymerase chain reaction. Results: Well-dispersed sizes of AgNP were obtained (5.4 ± 1.3 and 17.5 ± 3.4 nm) with an adequate electrical stability (−38.2 ± 5.8 and −32.6 ± 5.4 mV, respectively). AgNP showed antimicrobial activities for all oral samples; however, the smaller AgNP had significantly the most increased bactericidal effects (71.7 ± 39.1 µg/mL). The most resistant bacteria were found in biofilms from PD subjects (p P. gingivalis, T. denticola, and T. forsythia were present in all PD biofilms (100%). Conclusions: The AgNP showed efficient bactericidal properties as an alternative therapy for the control or progression of PD

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Altres ajuts: This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias cofinanced by the European Regional Development Fund (ERDF); Fundación Asociación Española Contra el Cáncer (M.C. and P.A.) and Gilead Fellowships (GLD16/00144, GLD18/00047, F.B). M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades. S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero.Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential. The online version of this article (10.1007/s11060-020-03580-y) contains supplementary material, which is available to authorized users

Adoptive transfer of ex vivo expanded SARS‐CoV‐2‐specific cytotoxic lymphocytes: A viable strategy for COVID‐19 immunosuppressed patients?

Cellular and humoral response to acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections is on focus of research. We evaluate herein the feasibility of expanding virus‐specific T cells (VST) against SARS‐CoV‐2 ex vivo through a standard protocol proven effective for other viruses. The experiment was performed in three different donors' scenarios: (a) SARS‐CoV‐2 asymptomatic infection/negative serology, (b) SARS‐CoV‐2 symptomatic infection/positive serology, and (c) no history of SARS‐CoV‐2 infection/negative serology. We were able to obtain an expanded VST product from donors 1 and 2 (1.6x and 1.8x increase of baseline VST count, respectively) consisting in CD3 + cells (80.3% and 62.7%, respectively) with CD4 + dominance (60% in both donors). Higher numbers of VST were obtained from the donor 2 as compared to donor 1. T‐cell clonality test showed oligoclonal reproducible peaks on a polyclonal background for both donors. In contrast, VST could be neither expanded nor primed in a donor without evidence of prior infection. This proof‐of‐concept study supports the feasibility of expanding ex vivo SARS‐CoV‐2‐specific VST from blood of convalescent donors. The results raise the question of whether the selection of seropositive donors may be a strategy to obtain cell lines enriched in their SARS‐CoV‐2‐specificity for future adoptive transfer to immunosuppressed patients.The neutralization antibody assay was supported by Valencian government grant Covid_19-SCI as well as the Spanish National Research Council grants CSIC-COV19-082 and CSIC-COV-19-104 to RG.Peer reviewe