On the benefits of bringing cloud-awareness to network virtual functions

Proceeding of: 2018 European Conference on Networks and Communications (EuCNC), June 18-21, Ljubljana, SloveniaWe are currently observing the softwarization of communication networks, where network functions are translated from monolithic pieces of equipment to programs running over a shared pool of computational, storage, and communication resources. As the amount of this resources might vary over time, in this paper we discuss the potential benefits of introducing resource awareness to softwarized network functions. More specifically, we focus on the case of computational elasticity, namely, the ability to endure shortages of computational resources while providing an adequate (although non-ideal) service. We discuss how to enable this ability by re-designing network functions, and illustrate the potential benefits of this approach with a numerical evaluation

Radiation Testing of a Multiprocessor Macrosynchronized Lockstep Architecture With FreeRTOS

Nowadays, high-performance microprocessors are demanded in many fields, including those with high-reliability requirements. Commercial microprocessors present a good tradeoff between cost, size, and performance, albeit they must be adapted to satisfy the reliability requirements when they are used in harsh environments. This work presents a high-end multiprocessor hardened with macrosynchronized lockstep and additional protections. A commercial dual-core Advanced RISC Machine (ARM) cortex A9 has been used as a case study and a complete hardened system has been developed. Evaluation of the proposed hardened system has been accomplished with exhaustive fault injection campaigns and proton irradiation. The hardening approach has been accomplished for both baremetal applications and operating system (OS)-based. The hardened system has demonstrated high reliability in all performed experiments with error coverage up to 99.3% in the irradiation experiments. Experimental irradiation results demonstrate a cross-sectional reduction of two orders of magnitude.This work was supported in part by the Spanish Ministry of Science and Innovation under Project PID2019-106455GB-C21 and in part by the Community of Madrid under Project 49.520608.9.18Publicad

c-Jun N-terminal kinase phosphorylation is a biomarker of plitidepsin activity

Plitidepsin is an antitumor drug of marine origin currently in Phase III clinical trials in multiple myeloma. In cultured cells, plitidepsin induces cell cycle arrest or an acute apoptotic process in which sustained activation of c-Jun N-terminal kinase (JNK) plays a crucial role. With a view to optimizing clinical use of plitidepsin, we have therefore evaluated the possibility of using JNK activation as an in vivo biomarker of response. In this study, we show that administration of a single plitidepsin dose to mice xenografted with human cancer cells does indeed lead to increased phosphorylation of JNK in tumors at 4 to 12 h. By contrast, no changes were found in other in vitro plitidepsin targets such as the levels of phosphorylated-ERK, -p38MAPK or the protein p27KIP1. Interestingly, plitidepsin also increased JNK phosphorylation in spleens from xenografted mice showing similar kinetics to those seen in tumors, thereby suggesting that normal tissues might be useful for predicting drug activity. Furthermore, plitidepsin administration to rats at plasma concentrations comparable to those achievable in patients also increased JNK phosphorylation in peripheral mononuclear blood cells. These findings suggest that changes in JNK activity provide a reliable biomarker for plitidepsin activity and this could be useful for designing clinical trials and maximizing the efficacy of plitidepsin.This work has been partially supported by grants (Programa Cenit, CEN-20091016, SAF2010-18302 and Fondo Europeo de Desarrollo Regional-Instituto de Salud Carlos III, RD12/0036/0021) from Ministerio de Economíay Competitividad of Spain.S

PM060184, a new tubulin binding agent with potent antitumor activity including P-glycoprotein over-expressing tumors

PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides. This compound is currently produced by total synthesis and is under evaluation in clinical studies in patients with advanced cancer diseases. It was recently published that PM060184 presents the highest known affinities among tubulin-binding agents, and that it targets tubulin dimers at a new binding site. Here, we show that PM060184 has a potent antitumor activity in a panel of different tumor xenograft models. Moreover, PM060184 is able to overcome P-gp mediated resistance in vivo, an effect that could be related to its high binding affinity for tubulin. To gain insight into the mechanism responsible of the observed antitumor activity, we have characterized its molecular and cellular effects. We have observed that PM060184 is an inhibitor of tubulin polymerization that reduces microtubule dynamicity in cells by 59%. Interestingly, PM060184 suppresses microtubule shortening and growing at a similar extent. This action affects cells in interphase and mitosis. In the first case, the compound induces a disorganization and fragmentation of the microtubule network and the inhibition of cell migration. In the second case, it induces the appearance of multipolar mitosis and lagging chromosomes at the metaphase plate. These effects correlate with prometaphase arrest and induction of caspase-dependent apoptosis or appearance of cells in a multinucleated interphase-like state unrelated to classical apoptosis pathways. Taken together, these results indicate that PM060184 represents a new tubulin binding agent with promising potential as an anticancer agent.This work was supported by grants BIO2010-16351 (JFD), CAM S2010/BMD-2457 (JFD), CAM S2010/BMD-2353 (JMA), BFU2011-23416 (JMA) and PharmaMar-CSIC contracts. BP had a contract from Comunidad de Madrid

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

BACKGROUND: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. METHODS: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. RESULTS: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation. CONCLUSION: Our results show that MI130110 ADC combines the antitumor potential of the PM050489 payload with the selectivity of the TEA1/8 monoclonal anti-CD13 antibody and confirm the correct intracellular processing of the ADC. These results demonstrate the suitability of CD13 as a novel ADC target and the effectiveness of MI130110 as a promising antitumor therapeutic agent.This work was partially supported by grant IPT-2012-0198-090000 (“MARINMAB” project) from Ministerio de Economía y Competitividad (MINECO) and European Regional Development’s funds (ERDF) and by CSIC grant 2019AEP146.S

Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bor tezomib and dexamethasone

Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.This work was in part funded by the Spanish ISCIII-FIS (PI 15/0067 and PI15/02156) and FEDER, the Spanish RTICC (RD12/0036/0058), "Asociación Española Contra el Cancer" (AECC, GCB120981SAN), the regional Council from “Castilla y León” (GRS 1175/A/15 and FIC335U14) and a research grant from Pharmamar SAU. MMS were also supported by the Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León, Spain. A-A López-Iglesias was supported by a grant from the Spanish Society of Hematology and Hemotherapy.Peer Reviewe

Blood stasis imaging predicts cerebral microembolism during acute myocardial infarction

Background: Cardioembolic stroke is a major source of mortality and disability worldwide. The authors hypothesized that quantitative characterization of intracardiac blood stasis may be useful to determine cardioembolic risk in order to personalize anticoagulation therapy. The aim of this study was to assess the relationship between image-based metrics of blood stasis in the left ventricle and brain microembolism, a surrogate marker of cardiac embolism, in a controlled animal experimental model of acute myocardial infarction (AMI). -- Methods: Intraventricular blood stasis maps were derived from conventional color Doppler echocardiography in 10 pigs during anterior AMI induced by sequential ligation of the mid and proximal left anterior descending coronary artery (AMI-1 and AMI-2 phases). From these maps, indices of global and local blood stasis were calculated, such as the average residence time and the size and ratio of contact with the endocardium of blood regions with long residence times. The incidence of brain microemboli (high-intensity transient signals [HITS]) was monitored using carotid Doppler ultrasound. -- Results: HITS were detected in 0%, 50%, and 90% of the animals at baseline and during AMI-1 and AMI-2 phases, respectively. The average residence time of blood in the left ventricle increased in parallel. The residence time performed well to predict microemboli (C-index = 0.89, 95% CI, 0.75–1.00) and closely correlated with the number of HITS (R = 0.87, P < .001). Multivariate and mediation analyses demonstrated that the number of HITS during AMI phases was best explained by stasis. Among conventional echocardiographic variables, only apical wall motion score weakly correlated with the number of HITS (R = 0.3, P = .04). Mural thrombosis in the left ventricle was ruled out in all animals. -- Conclusions: The degree of stasis of blood in the left ventricle caused by AMI is closely related to the incidence of brain microembolism. Therefore, stasis imaging is a promising tool for a patient-specific assessment of cardioembolic risk.This study was supported by grant PI15/02211, Rio Hortega (CM17/00144), and Juan Rodés fellowships (JR15/00039) from Instituto de Salud Carlos III; grant DPI2016-75706-P and a Juan de la Cierva fellowship (IJCI-2014-19507) from Ministerio de Economía y Competitividad; synergy grant Y2018/BIO-4858-PREFI-CM from Comunidad Autónoma de Madrid; the European Union - European Regional Development Fund; by the Spanish Society of Cardiology (ISBI-DCM); by the University of California,San Diego, CTRI Galvanizing Engineering and Medicine Program; American Heart Association grant 16GRNT27250262; and National Institutes of Health UC CAI grant CII4560. P.M.-L. was also funded by CIBERCV. P.M.-L., L.R., J.C.A., and J.B. are inventors of a method for quantifying intracardiac stasis from imaging data under a Patent Cooperation Treaty patent application (WO2017091746A1)

Segundo Congreso Salesiano de Ciencia, Tecnología e Innovación para la Sociedad

La segunda edición del Congreso Salesiano de Ciencia, Tecnología e Innovación para la Sociedad, CITIS, realizado el 2 y 3 de diciembre de 2015 y organizado por la Universidad Politécnica Salesiana (sede Guayaquil), ofreció un espacio idóneo para la presentación, difusión e intercambio de importantes investigaciones (nacionales e internacionales) a los docentes investigadores y a la comunidad universitaria en general. Los trabajos recogidos en estas Memorias Académicas pertenecen a diferentes líneas de investigación del área de la Ingeniería: Telecomunicaciones, Automatización y Control, Procesos Industriales, Sistemas Eléctricos de Potencia, Telemática e Informática Aplicada, áreas de interés en esta segunda edición del CITIS. Cabe destacar que se evidencia la preocupación por la dimensión humana y social mediante el desarrollo responsable de la ciencia y la tecnología. La realización de este Congreso ha puesto en evidencia la importancia y pertinencia de la actividad investigativa que se genera en las universidades (en proyectos desarrollados por los docentes investigadores e, incluso, por los estudiantes de grado y posgrado), así como los altos niveles de compromiso académico y social

A clinical method for mapping and quantifying blood stasis in the left ventricle

In patients at risk of intraventrcular thrombosis, the benefits of chronic anticoagulation therapy need to be balanced with the pro-hemorrhagic effects of therapy. Blood stasis in the cardiac chambers is a recognized risk factor for intracardiac thrombosis and potential cardiogenic embolic events. In this work, we present a novel flow image-based method to assess the location and extent of intraventricular stasis regions inside the left ventricle (LV) by digital processing flow-velocity images obtained either by phase-contrast magnetic resonance (PCMR) or 2D color-Doppler velocimetry (echo-CDV). This approach is based on quantifying the distribution of the blood Residence Time (TR) from time-resolved blood velocity fields in the LV. We tested the new method in illustrative examples of normal hearts, patients with dilated cardiomyopathy and one patient before and after the implantation of a left ventricular assist device (LVAD). The method allowed us to assess in-vivo the location and extent of the stasis regions in the LV. Original metrics were developed to integrate flow properties into simple scalars suitable for a robust and personalized assessment of the risk of thrombosis. From a clinical perspective, this work introduces the new paradigm that quantitative flow dynamics can provide the basis to obtain subclinical markers of intraventricular thrombosis risk. The early prediction of LV blood stasis may result in decrease strokes by appropriate use of anticoagulant therapy for the purpose of primary and secondary prevention. It may also have a significant impact on LVAD device design and operation set-up

Present and future of parkinson’s disease in Spain: Parkinson-2030 delphi project

Parkinson’s disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000–150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients’ and caregivers’ lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.This project was funded by Zambon S.A.U