LIF as a metabolic messenger: study of glucose sensing by NSCLC and LIF-mediated nutrient stress responses

[eng] Tumours grow in a self-imposed hypoglycaemic microenvironment due to their exacerbated metabolic needs. To thrive in these harsh conditions, malignant cells must adapt their own metabolic routes and hijack the host nutrient supply infrastructure through extracellular signalling. This study aimed at characterising the secretory response of tumoral cells in response to glucose deprivation, both the molecular signalling leading to this response and the consequences of this response for the tumour. In particular, this study focused on a cytokine never before linked to glucose deprivation: LIF. Through use of in silico, in vitro, and in vivo approaches we made two novel findings: firstly, we determined that LIF induction happens through non-canonical N-glycosylation dependent signalling, in the context of glucose deprivation. Furthermore, we have determined that the signalling mechanism leading to LIF production encompasses a complex combination of transcriptional and post-transcriptional signals that involve PERK but none of its canonical transcription factors. Secondly, we discovered a novel pro-tumorigenic role for this cytokine as an angiogenic. Our findings addressed the gap in literature regarding the mechanism for LIF production in tumours, providing insight relevant to future development of therapeutic approaches. And most importantly, we provide an integrative view of not only how glucose deprivation leads to production of LIF, but also how this cytokine could lead to the resolution of the local hypoglycaemia via angiogenesis.[spa] Los tumores imponen un microambiente de constante hipoglicemia debido a su rápida proliferación y al exacerbado consumo de metabolitos que esto conlleva. Para prosperar en estas circunstancias, las células cancerosas alteran su metabolismo y sus rutas de señalización de forma que puedan abusar de la infraestructura de aporte de nutrientes del organismo. El objetivo de este estudio es caracterizar la respuesta secretora del tumor en respuesta a la falta de glucosa, tanto al nivel de la señalización molecular que integra esta respuesta como al nivel de las consecuencias externas que estas señales tienen para el tumor. En particular, este estudio se centra en una citoquina que nunca antes se había relacionado con la falta de glucosa: LIF (por sus siglas en inglés: Factor Inhibidor de la Leucemia). A través del uso de técnicas in silico, in vitro e in vivo hemos alcanzado dos descubrimientos. En primer lugar, hemos determinado que la producción de LIF está inducida a través de una ruta no-canónica de detección de la falta de glucosa basada en la falta de N-glicosilación. Además, hemos determinado que el mecanismo que sigue a este fallo en la glicosilación incluye una compleja combinación de señales transcripcionales y postranscripcionales dependientes de PERK, pero no de los factores de transcripción tradicionalmente asociados a esta quinasa. En segundo lugar, hemos descubierto un nuevo rol pro-tumorigénico de esta citoquina como factor pro-angiogénico. Nuestros hallazgos cubren un vacío en la literatura en lo relativo al mecanismo que causa la producción de LIF por parte del tumor, lo cual podría servir de base para nuevas aproximaciones terapéuticas. Además, hemos desarrollado una visión unificada que explica cómo la falta de glucosa resulta en la producción de esta citoquina, y cómo LIF a su vez puede actuar para resolver la hipoglicemia local restaurando el riego sanguíneo mediante la angiogénesis

Impact of COVID-19 lockdown in telecommunications engineering competency-based alumni ranking

[EN] Higher education, as other social and economic sectors in Spain, was disrupted on 15th March 2020 following health emergency Laws enacted related to COVID-19. Non-presential lecturing was stablished country-wide until the end of the academic year 2019-20, as society was set in lockdown. In this context, it is necessary to evaluate the impact of the mandatory changes implemented in the education paradigm in order to assess the degree of acquisition of general and specific competencies altogether the acquisition of transversal competencies, as an important factor for the alumni career. This paper reports a comprehensive study on the competencies degree of acquisition considering the lockdown scenario in Spain. The results from the last four academic years have been comparatively evaluated in the core subject `Teoría de la Comunicación¿, lectured in the fourth semester of the Telecommunications Engineering Integrated Program (Bachelor and Master) in the Universitat Politècnica de València, Spain, comprising data from 745 alumni. The results indicate that the degree of acquisition of technical competencies in this scenario has been adequate, being marginally better compared to previous academic year, probably due to new lecturing materials prepared. Nevertheless, the acquisition of the transversal competency `analysis and problem solving¿ exhibits degraded results, indicating inhomogeneous acquisition probably due to limitations in the group-based problem-solving practice. The results suggest that specific materials and remote lecturing strategies should be developed and implemented to guarantee adequate acquisition levels.The support by the 2020 Science Parks program from the Consellería de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana, Spain, is acknowledged.Llorente, R.; Rodríguez-Hernández, MA.; Hernandez Franco, CA.; Sastre, J.; Carrión García, A.; Madrigal-Madrigal, J. (2020). Impact of COVID-19 lockdown in telecommunications engineering competency-based alumni ranking. IATED Academy. 9599-9607. https://doi.org/10.21125/iceri.2020.2139S9599960

Temporal headache and jaw claudication may be the key for the diagnosis of giant cell arteritis

Temporal artery biopsy (TAB) is a surgical procedure with a low positive yield. The purpose of this study is to determine which variables are the most important in the giant cell arteritis (GCA) diagnosis. The objective of this evaluation is to improve the percentage of positive temporal artery biopsy and if possible, avoid the biopsy in some cases. A retrospective clinical study consisted of 90 patients who had undergone TAB at the Río Hortega Hospital (Spain) from January 2009 to December 2016. Clinical findings, erythrocyte sedimentation rates (ESR) and other laboratory parameters, American College of Rheumatology (ACR) criteria for GCA score and biopsy results were recorded. Nineteen (21.1%) biopsies were positive for GCA. The mean age in positive TAB was 78.6 years old (SD 7.93), and 73.7% were female. Presence of temporal headache (p = 0.003), jaw claudication (p = 0.001), abnormal artery exploration (p = 0.023), elevated erythrocyte sedimentation rate (p = 0.035), CRP (p = 0.018) and platelets (p = 0.042), were significantly associated with GCA. Multivariate logistic regression revealed that the best predictors for the diagnosis of GCA are headache and jaw claudication, adjusted by sex, age, and temporal exploration. TAB has benefit only for patients who score a 2 or 3 on the ACR criteria for GCA without biopsy. These findings highlight the need for a better diagnostic strategy for patients with suspected temporal arteritis

TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma

Interleukin-8 (IL-8/CXCL8) is a pro-angiogenic and pro-inflammatory chemokine that plays a role in cancer development. Non-small cell lung carcinoma (NSCLC) produces high amounts of IL-8, which is associated with poor prognosis and resistance to chemo-radio and immunotherapy. However, the signaling pathways that lead to IL-8 production in NSCLC are unresolved. Here, we show that expression and release of IL-8 are regulated autonomously by TRAIL death receptors in several squamous and adenocarcinoma NSCLC cell lines. NSCLC constitutively secrete IL-8, which could be further enhanced by glucose withdrawal or by treatment with TRAIL or TNF alpha. In A549 cells, constitutive and inducible IL-8 production was dependent on NF-kappa B and MEK/ERK MAP Kinases. DR4 and DR5, known regulators of these signaling pathways, participated in constitutive and glucose deprivation-induced IL-8 secretion. These receptors were mainly located intracellularly. While DR4 signaled through the NF-kappa B pathway, DR4 and DR5 both regulated the ERK-MAPK and Akt pathways. FADD, caspase-8, RIPK1, and TRADD also regulated IL-8. Analysis of mRNA expression data from patients indicated that IL-8 transcripts correlated with TRAIL, DR4, and DR5 expression levels. Furthermore, TRAIL receptor expression levels also correlated with markers of angiogenesis and neutrophil infiltration in lung squamous carcinoma and adenocarcinoma. Collectively, these data suggest that TRAIL receptor signaling contributes to a pro-tumorigenic inflammatory signature associated with NSCLC

Preparación y caracterización de bioplástico a partir de almidón del fruto de pan de sopa (Artocarpus altilis (s. park) fosberg)

Objective: Obtain and characterize a biodegradable material, using as raw material the breadfruit (Artocarpus altillis (s. park) fosberg) starch. Desing/methodology/approach: The breadfruit starch was extracted using wet method. The dried starch was mixed with glycerol, water and HCl 1N approx. at 75 °C until obtaining the bioplastic, which was characterized by FT-IR and SEM-EDX spectroscopy. Results: The highest starch content is obtained in the intermediate stage of fruit development (mature-green) with a 10% yield. Infrared and SEM-EDX tests were performed on both the starch and the bioplastic obtained. The SEM-EDX showed that for the starch the average granule diameter is between 2.5 ± 0.2 to 8.4 ± 0.2 µm with a spherical geometry, with cuts in random directions. Limitations on study/implications: There are no significant technological limitations, but there are implications that impact the accelerated development of the bioplastics trade. Findings/conclusions: Breadfruit starch was isolated and characterized with Infrared and SEM-EDX techniques. A bioplastic material was obtained from starch, using glycerol and water as plasticizer, finding that the ratio (1:10, starch: water) generates a material with the best thermoplastic characteristics.Objetivo: Obtener y caracterizar un material biodegradable, utilizando como materia prima el almidón del fruto del pan de sopa (Artocarpus altillis (s. park) fosberg) Diseño/metodología/aproximación: Se extrajo el almidón del fruto del pan de sopa por el método húmedo. El almidón seco, se mezcló con glicerol, agua y HCl 1N aproximadamente a 75 °C hasta obtener un bioplástico, el cual se caracterizó por espectroscopia de FT-IR y SEM-EDX. Resultados: El mayor contenido de almidón se obtiene en la etapa intermedia de desarrollo del fruto (verde-maduro) con un 10% de rendimiento. Se realizaron pruebas de infrarrojo y SEM-EDX, tanto del almidón como del bioplástico obtenido. El SEM-EDX mostró que para el almidón el diámetro de granulo promedio es entre 2.5 ± 0.2 a 8.4 ± 0.2 µm con una geometría de tipo esférica, con cortes en direcciones aleatorias. Limitaciones del estudio/implicaciones: No se observan limitaciones tecnológicas importantes, pero si implicaciones que impactan en el desarrollo acelerado del comercio de bioplásticos. Hallazgos/conclusiones: Se aisló almidón del fruto pan de sopa y se caracterizó con técnicas de Infrarrojo y SEM-EDX. Se obtuvo un material bioplástico a partir del almidón, empleando como plastificante glicerol y agua, encontrándose que la proporción (1:10, almidón:agua)  genera un material con las mejores características de termoplástico

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

Background There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. Methods We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Results Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice. Conclusions Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM

Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review

Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3-47.5] mg/day at ANK onset to 5 [0-10] at 12 months. After a median [IQR] follow-up of 16 [5-50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations