Allogeneic adipose tissue-derived mesenchymal stem cells in ischaemic stroke (AMASCIS-02): A phase IIb, multicentre, double-blind, placebo-controlled clinical trial protocol

Introduction Stroke is a serious public health problem, given it is a major cause of disability worldwide despite the spread of recanalisation therapies. Enhancement of brain plasticity with stem cell administration is a promising innovative therapy to reduce sequelae in these patients. Methods and analysis We have developed a phase IIb, multicentre, randomised, double-blind, placebo-controlled clinical trial protocol to evaluate the safety and efficacy of intravenous administration of allogeneic adipose tissue-derived mesenchymal stem cells (AD-MSCs) in patients with acute ischaemic stroke, concurrently with conventional stroke treatment. Thirty patients will be randomised on a 1:1 basis to receive either intravenous placebo or allogeneic AD-MSCs as soon as possible within the first 4 days from stroke symptom onset. Patients will be followed up to 24 months after randomisation. The primary objective is the safety assessment of early intravenous administration of allogeneic AD-MSCs by reporting all adverse events and neurological or systemic complications in both treatment groups. Secondary objectives assess efficacy of early intravenous AD-MSC treatment in acute ischaemic stroke by evaluating changes in the modified Rankin Scale and the National Institutes of Health Stroke Scale throughout the follow-up period. In addition, brain repair biomarkers will be measured at various visits. Ethics and dissemination This clinical trial has been approved by the Clinical Research Ethics Committee of La Paz University Hospital (Madrid, Spain) and by the Spanish Agency of Medication and Health Products and has been registered in Eudra CT (2019-001724-35) and ClinicalTrials.gov (NCT04280003). Study results will be disseminated through peer-reviewed publications in Open Access format and at conference presentationsThis clinical trial has been promoted by the La Paz University Hospital Institute for Health Research—IdiPAZ (La Paz University Hospital—Universidad Autónoma de Madrid) and sponsored from a competitive grant from the Carlos III Health Institute Healthcare Research Fund, and cofunded by the European Regional Development Fund (ERDF) 'A way to make Europe'/'Investing in your future' (PIC18/00016). This clinical trial has been supported by Plataforma Española de Investigación Clínica y Ensayos Clínicos, SCReN (Spanish Clinical Research Network), funded by Carlos III Health Institute-General Subdirection for Evaluation and Promotion of Research, research PT17/0017/0013; State Plan for Scientific Investigation, Technology and Innovation (2017–2020) and cofunded by European Regional Development Fund/European Social fund 'A way to make Europe'/'Investing in your future' (grant ID PT17/0017/0013

Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke

The electronic version of this article is the complete one and can be found online at: http://stemcellres.com/content/4/1/11Introduction: Stem cell therapy can promote good recovery from stroke. Several studies have demonstrated that mesenchymal stem cells (MSC) are safe and effective. However, more information regarding appropriate cell type is needed from animal model. This study was targeted at analyzing the effects in ischemic stroke of acute intravenous (i.v.) administration of allogenic bone marrow- (BM-MSC) and adipose-derived-stem cells (AD-MSC) on functional evaluation results and brain repair markers. Methods: Allogenic MSC (2 × 106 cells) were administered intravenously 30 minutes after permanent middle cerebral artery occlusion (pMCAO) to rats. Infarct volume and cell migration and implantation were analyzed by magnetic resonance imaging (MRI) and immunohistochemistry. Function was evaluated by the Rogers and rotarod tests, and cell proliferation and cell-death were also determined. Brain repair markers were analyzed by confocal microscopy and confirmed by western blot. Results: Compared to infarct group, function had significantly improved at 24 h and continued at 14 d after i.v. administration of either BM-MSC or AD-MSC. No reduction in infarct volume or any migration/implantation of cells into the damaged brain were observed. Nevertheless, cell death was reduced and cellular proliferation significantly increased in both treatment groups with respect to the infarct group. At 14 d after MSC administration vascular endothelial growth factor (VEGF), synaptophysin (SYP), oligodendrocyte (Olig-2) and neurofilament (NF) levels were significantly increased while those of glial fiibrillary acid protein (GFAP) were decreased. Conclusions: i.v. administration of allogenic MSC - whether BM-MSC or AD-MSC, in pMCAO infarct was associated with good functional recovery, and reductions in cell death as well as increases in cellular proliferation, neurogenesis, oligodendrogenesis, synaptogenesis and angiogenesis markers at 14 days post-infarctThis study was supported by grants from Cellerix, FIS 060575 and PS09/ 01606 (Spanish Ministry of Science), CIDEM (Center for Innovation and Business Development) and by RENEVAS (RD07/0026/2003) (Spanish Neurovascular Network), the Carlos III Research Institute and the Ministry of Science and Innovatio

Utilization of lactose and presence of the phospho-β-galactosidase (lacG) gene in Lactococcus garvieae isolates from different sources

This study evaluates the utilization of lactose (Lac) and the presence of the phospho-β-galactosidase (lacG) gene as markers for distinguishing between fish (Lac-/lacG-) and dairy isolates (Lac+/lacG+) of Lactococcus garvieae, using a panel of L. garvieae isolates from different sources. None of the fish isolates produced acid from lactose (Lac-), however Lac-/lacG- isolates were observed in pigs, cows, birds and humans. Most of the dairy isolates (77.8%) were Lac+/lacG+, but some dairy isolates did not produce acid from this sugar. Data in the present study show that the ability to metabolize lactose and the presence of the lacG gene are heterogeneously scattered among L. garvieae isolates of different sources. Therefore, the use of these criteria as markers to differentiate between L. garvieae isolates of dairy and fish origin should be considered with caution

Didactic strategies to promote competencies in sustainability

Higher education is a principal agent for addressing the sustainable development goals proposed by the 2030 Agenda, because of its key mission of knowledge generation, teaching and social innovation for sustainability. In order to achieve this, higher education needs to integrate transversally the values of sustainability in the way of developing the field of management, as well as research, university life and, of course, teaching. This paper focuses on teaching, and more specifically on the didactic strategies considered most relevant for training in sustainability competencies in college students, according to the guidelines commonly accepted by the international academic community. Through collaborative work among experts from six Spanish universities taking part in the EDINSOST project (education and social innovation for sustainability), funded by the Spanish R&D+i Program, in this paper the role of five active learning strategies (service learning, problem-based learning, project-oriented learning, simulation games and case studies) in education for sustainability are reviewed, and a systematic approach of their implementation in higher education settings is presented. The results provide a synthesis of their objectives, foundations, and stages of application (planning, implementation, and learning assessment), which can be used as valuable guidelines for teachersThe Spanish Ministry of Economy, Industry and Competitiveness has financed this work under contract EDU2015-65574-R

Protocolo de sedo-analgesia para prevención del espasmo radial en hemodinámica cardíaca

Introducción y objetivo: El espasmo es la complicación más habitual en los cateterismos por arteria radial. Su frecuencia oscila entre el 10-30% y puede ser un factor limitante que impida la realización del cateterismo por esa vía. El objetivo de este estudio es evaluar con un nuevo protocolo de sedo-analgesia la reducción de la frecuencia del espasmo radial y la disminución de la ansiedad del paciente. Material y método: Estudio aleatorizado y prospectivo de 300 pacientes sometidos a cateterismo radial. Se randomizaron dos grupos, el Grupo I (n=150) con la pauta de sedación habitual (10mg diazepam sl) y el Grupo II (n=150) con una pauta de sedación con 2 mg de Midazolam + 0,035 mg/kg de Cloruro Mórfico y en caso de procedimientos de más de 45 minutos se añadía Fentanilo a 1 mcgr/kg. Resultados y conclusión: No se observaron diferencias significativas entre los dos grupos estudiados en cuanto a las características basales. La edad media de la población fue de 65 ± 11 años; 223 pacientes (74%) fueron hombres y el índice de masa corporal (IMC) medio 27,7 ± 3,8. Los pacientes del Grupo II presentaron reducción significativa del espasmo respecto a los del Grupo I (9,3% frente a 22,6%; p=0,002). También se objetivó una reducción significativa del dolor (2,05 frente a 2,77; p=0,007). La pauta sedo-analgésica propuesta demostró ser eficaz en la reducción del espasmo radial y del dolor durante el cateterismo

The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma

[EN]Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunostaining, cell cycle and short interfering ribonucleic acid studies. Filanesib showed in vitro, ex vivo, and in vivo synergy with pomalidomide plus dexamethasone treatment. Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and was shown to be mediated by the impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, the triple combination increased the activation of the proapoptotic protein BAX, which has previously been associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone, and supported the initiation of a recently activated trial being conducted by the Spanish Myeloma group which is investigating this combination in relapsed myeloma patients.Array BioPharma, the Spanish ISCIII-FIS and FEDER, the Spanish RTICC, Spanish Association Against Cancer (AECC) and the Regional Council of Castilla y León (Consejería de Medicina y Educación)

Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.This work was supported by funding from Spanish FIS (PI15/00067, PI15/02156 and PI18/01600) and FEDER, AECC (GCB120981SAN), Junta de Castilla y León, Consejería de Sanidad (GRS 862/A/13 and BIO/SA05/14), Fundación Memoria de D. Samuel Solórzano Barruso of the University of Salamanca (FS/22-2015), Fundación Ramón Areces (FRA16/003), Sociedad Española de Hematología y Hemoterapia and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. E.M.O. was supported by an Inplant grant from IDIVAL. T.P. is supported by a grant from AECC (INVES18043PAÍN)

Stroma-Mediated Resistance to S63845 and Venetoclax through MCL-1 and BCL-2 Expression Changes Induced by miR-193b-3p and miR-21-5p Dysregulation in Multiple Myeloma.

BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pro-apoptotic BIM protein in MM cells. In this study, we assess the efficacy of S63845 and venetoclax in MM cells in direct co-culture with MSCs derived from MM patients (pMSCs) to identify additional mechanisms involved in the stroma-induced resistance to these agents. MicroRNAs miR-193b-3p and miR-21-5p emerged among the top deregulated miRNAs in myeloma cells when directly co-cultured with pMSCs, and we show their contribution to changes in MCL-1 and BCL-2 protein expression and in the activity of S63845 and venetoclax. Additionally, direct contact with pMSCs under S63845 and/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-XL. Finally, we show a potent effect of the combination of S63845 and venetoclax even in the presence of pMSCs, which supports this combinatorial approach for the treatment of MM

Tenemos cita con el arte: a pilot project of visits and workshops with people affected by Alzheimer's disease in the Prado Museum, the Centro de Arte Reina Sofía Museum and the Faculty of Fine Arts at the Complutense University of Madrid

GIMUPAI is a research group comprising teachers and researchers from the Faculty of Fine Arts (University Complutense of Madrid) and the Department of Social Psychology and Anthropology (Salamanca University) who have been working in art and health projects over the last thirteen years. Recently, we have carried out Tenemos cita con el arte, part of a national research project entitled "Art education in museums and other cultural institutions as a tool for increasing the wellbeing of people affected with Alzheimer" (Ministry of the Economy and Competitiveness-EDU2013-43253-R). The main objective of the program is to make the museum‘s artworks available to people with Alzheimer‘s and their caregivers, at the same time encouraging them to participate in artistic activities and artistic creation through art workshops. Tenemos cita con el arte has been designed as a program of visits of the Prado Museum and the Centro de Arte Reina Sofia Museum. The program also has included participation in workshops on visual arts and artistic creativity in the Faculty of Fine Arts. The program was undertaken between October and December 2015 with a group of 15 participants (Alzheimer‘s patients, caregivers, and other health and social workers)

Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma

This work was supported by the Spanish ISCIII-FIS and FEDER Funds (PI 15/00067 and PI 15/02156) and the Regional Health Council of Castilla y León (GRS 1604/A/17). EMA was supported by a grant from the Regional Education Council of Castilla y León co-financed by the European Social Fund