Estudio del papel de la neuropilina-1 en el desarrollo, pronóstico y la respuesta celular a lenvatinib en el carcinoma hepatocelular humano

191 p.[EN] Hepatocellular carcinoma (HCC), the main type of primary liver cancer, constitutes the sixth most common and third most deadly cancer worldwide, respectively. Due to the late diagnosis and the molecular heterogeneity of this tumor, the clinical onset of HCC patients remains complex, with a high rate of therapeutic failure and recurrence. Although novel findings have been accomplished in recent years, the precise mechanisms underlying the processes of tumor development, progression and drug responsiveness remain unclear. In this line, autophagy, responsible for the maintenance of cell homeostasis, acts as a double-edged process in cancer, displaying a key function in the progression and cellular response to targeted drugs. Furthermore, increasing evidence highlights the crucial role of the hypoxic microenvironment in the chemoresistance development in solid tumors, and mainly in HCC, where the hypoxia-inducible factor 1α (HIF-1α) acts as the main mediator of the cellular response to hypoxia. The interplay between these mechanisms is closely associated to the therapeutic use of tyrosine kinase inhibitors (TKIs), such as lenvatinib, that primarily act by disrupting tumor angiogenesis through inhibition of tyrosine kinase receptors (RTKs) activity. The transmembrane glycoprotein neuropilin-1 (NRP1) has exhibited an interesting function in the modulation of tumor-associated signaling pathways and processes by interacting with key RTKs, such as vascular endothelial growth factor receptor (VEGFR) or platelet-derived growth factor receptors (PDGFR) among others, and their corresponding ligands. Despite the interesting role that NRP1 seems to have in cancer cell survival and drug efficacy, fewer studies have evaluated the potential value of NRP1 as a tumor biomarker or therapeutic target in HCC. For this reason, we aimed at assessing the clinical significance of the receptor NRP1 in the prognosis, diagnosis and other tumor-associated features in HCC patients, as well as to determine the role of NRP1 in the underlying mechanisms of lenvatinib efficacy with potential implication in the loss of cellular sensitivity to lenvatinib. To accomplish these purposes, we conducted a systematic review with meta-analysis including all the articles that evaluate the clinical correlation of NRP1 overexpression with tumor prognosis, development and/or other clinicopathological features in patients diagnosed with HCC. On the other hand, we confirmed these results using datasets of human HCC samples from publicly available databases, and we also assessed the potential role of NRP1 in the lenvatinib efficacy employing three HCC cell lines, HepG2, Hep3B and Huh-7 as the in vitro model for the experimental study. Initially, a total of 1305 patients from seven articles were included in the quantitative analysis, where approximately 53.81% of patients exhibited NRP1 overexpression. After meta-analysis, increased levels of NRP1 showed to be significantly correlated with poor prognosis, represented by shorter overall survival (OS), as well as with tumor pathogenesis by observing higher NRP1 expression in tumor tissue samples from 692 HCC patients. In addition, a significant association was found between NRP1 overexpression and patient’s age, younger than 50 years old, and increased risk of venous invasion, highlighting the potential of NRP1 as a tumor biomarker in HCC. Meanwhile, results from the experimental study showed higher NRP1 levels in HCC samples from public databases compared to normal liver tissue, and a strong correlation with advanced tumor stages and nodal metastasis status. When analyzed in an in vitro model of HCC, NRP1 was overexpressed in the Hep3B and Huh-7 cell lines in comparison to the HepG2 HCC line, also showing a higher susceptibility to lenvatinib the Hep3B and Huh-7 cells. Analysis of cell proliferation and migration revealed that NRP1 downregulation derived from lenvatinib treatment was involved in the antitumor effects of this drug. To deeply evaluate the potential role of NRP1 in the underlying mechanisms of the lenvatinib effectiveness, we further analyzed the modulation exerted by lenvatinib in NRP1 expression. The double-edged process of autophagy was revealed as the main mechanism responsible for the lenvatinib-derived downregulation of NRP1 in the Hep3B and Huh-7 cell lines, where autophagy blockade restrained the lenvatinib efficacy, being prevented by specific NRP1 targeting. Furthermore, after hypoxia induction, protein levels of NRP1 were significantly diminished through a hypoxia-related autophagy increase. Interestingly, NRP1 expression was also modulated by HIF-1α, showing lower levels of NRP1 after HIF-1α silencing. Even though autophagy blockade increased cell survival even after hypoxia induction and lenvatinib treatment, gene silencing of HIF-1α achieved to prevent this loss of lenvatinib effectiveness and the recovery of protein NRP1 expression in Hep3B and Huh-7 cell lines. Altogether, results from this study suggest that NRP1 might constitute a valuable biomarker for prognosis, diagnosis and risk of invasion in patients with HCC, together with the potential role that NRP1 seems to play in the underlying mechanisms of the lenvatinib efficacy in HCC cells, where both the double-edged autophagy and the HIF-1α-related hypoxia response are involved. Therefore, NRP1 could be a novel tumor biomarker and therapeutic target for improving the clinical landscape of advanced HCC

Precision of Digital Volume Correlation Approaches for Strain Analysis in Bone Imaged with Micro-Computed Tomography at Different Dimensional Levels

Accurate measurement of local strain in heterogeneous and anisotropic bone tissue is fundamental to understand the pathophysiology of musculoskeletal diseases, to evaluate the effect of interventions from preclinical studies, and to optimize the design and delivery of biomaterials. Digital volume correlation (DVC) can be used to measure the three-dimensional displacement and strain fields from micro-computed tomography (μCT) images of loaded specimens. However, this approach is affected by the quality of the input images, by the morphology and density of the tissue under investigation, by the correlation scheme, and by the operational parameters used in the computation. Therefore, for each application, the precision of the method should be evaluated. In this paper, we present the results collected from datasets analyzed in previous studies as well as new data from a recent experimental campaign for characterizing the relationship between the precision of two different DVC approaches and the spatial resolution of the outputs. Different bone structures scanned with laboratory source μCT or synchrotron light μCT (SRμCT) were processed in zero-strain tests to evaluate the precision of the DVC methods as a function of the subvolume size that ranged from 8 to 2,500 µm. The results confirmed that for every microstructure the precision of DVC improves for larger subvolume size, following power laws. However, for the first time, large differences in the precision of both local and global DVC approaches have been highlighted when SRμCT or in vivo μCT images were used instead of conventional ex vivo μCT. These findings suggest that in situ mechanical testing protocols applied in SRμCT facilities should be optimized to allow DVC analyses of localized strain measurements. Moreover, for in vivo μCT applications, DVC analyses should be performed only with relatively course spatial resolution for achieving a reasonable precision of the method. In conclusion, we have extensively shown that the precision of both tested DVC approaches is affected by different bone structures, different input image resolution, and different subvolume sizes. Before each specific application, DVC users should always apply a similar approach to find the best compromise between precision and spatial resolution of the measurements

High incidence of extended-spectrum β-lactamases among outpatient clinical isolates of Escherichia coli: a phenotypic assessment of NCCLS guidelines and a commercial method

The production of extended-spectrum beta-lactamases (ESBLs) among 357 clinical isolates of Escherichia coli and 175 of Klebsiella spp. was studied using both the National Committee for Clinical Laboratory Standards disk diffusion method and the semiautomated Wider system. We highlight the predominance of E. coli (50, 92.6%) among positive samples and the largely outpatient origin of these (40, 80%), including 39 samples of urine (97.5%) and one of urethral exudate. There were only four ESBL-producing isolates of Klebsiella spp. (7.4%), and three were in outpatient urine samples (75%, 2 K. oxytoca and 1 K. pneumoniae). The positive and negative predictive values for the Wider system were 81% and 98.5%, respectively. We stress the high incidence of ESBL in our setting, the predominance of cases in the outpatient setting, and the acceptable detection of ESBL by means of the Wider system in E. coli and Klebsiella spp

Inhibidores tirosín quinasa en el tratamiento del hepato - carcinoma avanzado

El hepatocarcinoma o carcinoma hepatocelular (CHC) se ha convertido en el tipo de neoplasia más común dentro del cáncer hepático. Este tipo de cáncer presenta una elevada tasa de mortalidad, siendo actualmente el tercer cáncer con mayor mortalidad a nivel mundial. Los receptores tirosín quinasa (RTKs) son glicoproteínas de membrana que participan en la activación de numerosas vías de señalización, relacionadas principalmente con procesos de proliferación, migración, angiogénesis, crecimiento, supervivencia y diferenciación celular. Las vías activadas por RTKs aparecen desreguladas con frecuencia en CHC y contribuyen al desarrollo y progresión tumoral. Por ello, estos receptores se han convertido en importantes dianas para la búsqueda de nuevos tratamientos eficaces frente a este tipo de cáncer. Los inhibidores tirosín quinasa (TKIs) son moléculas que bloquean de forma selectiva la activación de los RTKs. El amplio espectro de acción de estos inhibidores y su demostrada eficacia han llevado a la aprobación de varios TKIs como tratamiento sistémico del CHC en estadio avanzado. No obstante, a pesar de los resultados prometedores obtenidos, en ocasiones el tratamiento fracasa y se desarrolla resistencia a estos TKIs. Por esta razón, se continúa trabajando en la búsqueda de nuevas moléculas que actúen como TKIs más eficaces y seguros

Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence

[EN] Hepatic fibrosis is a reversible response to either acute or chronic cellular injury froma wide variety of etiologies, characterized by excessive deposition of extracellularmatrix resulting in liver dysfunction and cirrhosis. Melatonin (N‐acetyl‐5‐methoxytryptamine), the main product secreted by the pineal gland, is a multitaskingindolamine with important physiological functions such as anti‐inflammatory andantioxidant actions, modulation of circadian rhythms, and immune system enhance-ment. Among the numerous biological activities of melatonin, its antifibrotic effectshave received increasingly more attention. In this study, we performed a systematicreview of publications of the last 10 years evaluating the mechanisms of action ofmelatonin against liver fibrosis. The study protocol was registered at PROSPERO(CRD42022304744). Literature research was performed employing PubMed,Scopus, and Web of Science (WOS) databases, and after screening, 29 articleswere included. Results from the selected studies provided denoted the usefulactions of melatonin on the development, progression, and evolution of liver fibrosis.Melatonin antifibrotic effects in the liver involved the reduction of profibrogenicmarkers and modulation of several cellular processes and molecular pathways,mainly acting as an antioxidant and anti‐inflammatory agent. In addition, theindolamine influenced different molecular processes, such as hepatocyte apoptosis,modulation of autophagy and mitophagy, restoration of circadian rhythms, andmodulation of microRNAs, among others. Although some limitations have beenfound regarding variability in the study design, the findings here summarized displaythe potential role of melatonin in ameliorating the development of liver fibrosis andits possible progression to liver cirrhosis and hepatocarcinomaS

Real-time agreement and fulfilment of SLAs in Cloud Computing environments

A Cloud Computing system must readjust its resources by taking into account the demand for its services. This raises the need for designing protocols that provide the individual components of the Cloud architecture with the ability to self-adapt and to reach agreements in order to deal with changes in the services demand. Furthermore, if the Cloud provider has signed a Service Level Agreement (SLA) with the clients of the services that it offers, the appropriate agreement mechanism has to ensure the provision of the service contracted within a specified time. This paper introduces real-time mechanisms for the agreement and fulfilment of SLAs in Cloud Computing environments. On the one hand, it presents a negotiation protocol inspired by the standard WSAgreement used in web services to manage the interactions between the client and the Cloud provider to agree the terms of the SLA of a service. On the other hand, it proposes the application of a real-time argumentation framework for redistributing resources and ensuring the fulfilment of these SLAs during peaks in the service demand.This work is supported by the Spanish government Grants CONSOLIDER-INGENIO 2010 CSD2007-00022, TIN2011-27652-C03-01, TIN2012-36586-C03-01 and TIN2012-36586-C03-03.De La Prieta, F.; Heras Barberá, SM.; Palanca Cámara, J.; Rodríguez, S.; Bajo, J.; Julian Inglada, VJ. (2014). Real-time agreement and fulfilment of SLAs in Cloud Computing environments. 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Deadline Prediction Scheduling based on Benefits

This paper describes a scheduling algorithm that composes a scheduling plan which is able to predict the completion time of the arriving tasks. This is done by performing CPU booking. This prediction is used to establish a temporal commitment with the client that invokes the execution of the task. This kind of scheduler is very useful in scenarios where Service-Oriented Computing is deployed and the execution time is used as a parameter for QoS. This scheduler is part of an architecture that is based on the Distributed Goal-Oriented Computing paradigm, which allows agents to express their own goals and to reach them by means of service compositions. Moreover, the scheduler is also able to prioritize those tasks which provide greater benefits to the OS. In this work, the scheduler has been designed in several iterations and tested by means of a set of experiments that compare the scheduler algorithm with a representative set of scheduling algorithms. © 2012 Elsevier B.V. All rights reserved.This work is supported by the TIN2009-13839-C03-01 project of the Spanish government, PROMETEO/2008/051 project, FEDER funds and CONSOLIDER-INGENIO 2010 under grant CSD2007-00022.Palanca Cámara, J.; Navarro Llácer, M.; García-Fornes, A.; Julian Inglada, VJ. (2013). Deadline Prediction Scheduling based on Benefits. Future Generation Computer Systems. 29(1):61-73. https://doi.org/10.1016/j.future.2012.05.007S617329

Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients

Semillas en el tiempo : el latinoamericanismo filosófico contemporáneo

Los trabajos que conforman este Iibro giran en torno a un eje: los filósofos latinoamericanistas contemporáneos, desde 1950 en adelante. Todos ellos pensadores que han reflexionado desde adentro, desde el continente acerca de la identidad cultural y social de América Latina: ¿qué es América, qué es ser americano, cuál es su historia, cuáles son sus contribuciones, qué problemas se derivan de sus relaciones con el Occidente, qué problemas del pasado inciden en su presente, de qué modo debe asumir ese pasado, qué conflictos se desprenden de su estructura de clases? Éstas son algunas de las preguntas que vertebran el nuevo movimiento, que se cuestiona fuertemente la identidad latinoamericana. La relevancia especial de "Semillas en el tiempo" reside en que los autores de los estudios son destacados especialistas en la materia, tanto por sus conocimientos acerca de la Filosofía, como por su dedicación al estudio de la problemática latinoamericana

Solidaridad y humanismo: principios constitucionales para el anclaje de la igualdad

La doctrina constitucional afirma la conveniencia de que los derechos fundamentales formen parte del texto de la ley suprema. De este modo, existe un catálogo mínimo de derechos que la Constitución recoge y aspira a garantizar. Sin embargo, cuando la Constitución carece de la directriz del humanismo y la solidaridad, es previsible su ineficacia en la protección y aseguramiento de los derechos humanos, concretamente de la igualdad y la libertad.Universidad Politécnica de Valenci